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Home » Entrectinib in patients with advanced or metastatic NTRK...
Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials
Robert C Doebele MD a†, Alexander Drilon MD bc†, Luis Paz-Ares MD d, Salvatore Siena Prof ef, Alice T Shaw Prof g, Anna F Farago MD g, Collin M Blakely MD h, Takashi Seto MD i, Byung Chul Cho Prof j, Diego Tosi MD k, Benjamin Besse MD l, Sant P Chawla MD m, Lyudmila Bazhenova Prof n, John C Krauss MD o, Young Kwang Chae MD p, Minal Barve MD q, Ignacio Garrido-Laguna MD r, Stephen V Liu MD s, Paul Conkling MD t, Thomas John MD u, Marwan Fakih Prof v, Darren Sigal MD w, Herbert H Loong MD x, Gary L Buchschacher MD y, Pilar Garrido MD zaaab, Jorge Nieva MD ac, Conor Steuer MD ad, Tobias R Overbeck MD ae, Daniel W Bowles MD af, Elizabeth Fox MD ag, Todd Riehl PharmD ah, Edna Chow-Maneval PhD ai, Brian Simmons PharmD ah, Na Cui PhD ah, Ann Johnson MS ai, Susan Eng PharmD ah, Timothy R Wilson PhD ah, George D Demetri Prof ajon behalf of the trial investigators
Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2 , and NTRK3 gene fusions treated in three ongoing, early-phase trials.
An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG ( NCT02650401 ; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov , NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001).
Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.
Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.
Fusions involving the NTRK gene family— NTRK1, NTRK2, and NTRK3 —lead to the expression of chimeric rearrangements in tropomyosin receptor kinases (TRKs) A, B, and C, respectively, with constitutively active kinase function. 1 NTRK fusions act as oncogenic drivers and are potential therapeutic targets across a broad range of tumour types, including sarcomas, non-small-cell lung cancer (NSCLC), and mammary analogue secretory carcinoma. 2 3 These gene fusions were originally identified in colorectal cancer 4 5 and occur in approximately 0·3% of all solid tumours, although frequency varies widely by cancer type, 1 6 7 8 as does that of corresponding aberrant expression of the TRK proteins. 9
We searched PubMed and major congress abstracts with the search terms "NTRK", "fusion", "cancer", and "inhibitor", with no publication date or language restrictions. Of the TRK inhibitors currently under development for the treatment of NTRK gene fusions, larotrectinib and entrectinib yielded the greatest number of search results. Larotrectinib has shown systemic efficacy in three phase 1–2 trials; based on these data, larotrectinib was granted US Food and Drug Administration approval in November, 2018, for the treatment of adults and children with solid tumours harbouring an NTRK gene fusion without a known acquired resistance mutation. However, there is insufficient evidence that this compound can penetrate the CNS and its intracranial efficacy has not been clearly shown. Entrectinib is a potent inhibitor of TRK A, B and C; ROS1; and ALK that was designed to penetrate and remain in the CNS, and which showed clinical activity in phase 1 studies of patients with NTRK fusion-positive tumours, including primary CNS cancers.
In this integrated analysis of three phase 1–2 clinical trials, we report the efficacy and safety of entrectinib in patients with a range of metastatic, locally advanced, or unresectable TRK inhibitor-naive, NTRK fusion-positive solid tumours. Overall, entrectinib treatment was associated with clinically meaningful and durable systemic and intracranial responses, irrespective of tumour type or the presence of baseline CNS lesions. Entrectinib was well tolerated with a manageable safety profile.
Entrectinib is a highly effective treatment for patients with NTRK fusion-positive solid tumours, with both systemic and CNS activity. On the basis of the results of this integrated analysis, entrectinib could become an effective first-line therapeutic option for patients with NTRK fusion-positive solid tumours, with or without CNS involvement.
Novel compounds under development for the treatment of cancers with NTRK gene fusions include selective inhibitors of the TRK family of kinases. In November, 2018, the US Food and Drug Administration (FDA) granted accelerated approval of larotrectinib use in adults and children with solid tumours harbouring an NTRK gene fusion without a known acquired resistance mutation. 10 11 However, only a few patients with CNS involvement have been reported to respond to larotrectinib, and its efficacy in such settings has not been well delineated. 12 13 Additionally, intracranial objective response and duration of response have not been reported for larotrectinib. Thus, an unmet medical need exists for effective treatments with CNS activity for patients with NTRK fusion-positive tumours.
Entrectinib is a potent inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK that is specifically designed to have systemic activity and cross the blood–brain barrier. 14 15 In vitro, entrectinib potently inhibits TRKA, TRKB, and TRKC at low nanomolar concentrations, with an average median inhibitory concentration of 0·002 μM. 15 Animal studies have reported substantial concentrations of entrectinib in the CNS, with blood-to-brain concentration ratios in dogs, rats, and mice ranging from 0·43 to 1·90. 14
Three clinical trials have been done to assess the safety and activity of entrectinib in adult patients with advanced or metastatic cancer. Two phase 1 trials (ALKA-372–001 and STARTRK-1) showed that entrectinib was well tolerated with clinical activity in patients with NTRK, ROS1, or ALK fusion-positive tumours, including those with CNS involvement. 16 Among those patients treated in the ALKA-372–001 and STARTRK-1 studies, four patients had NTRK fusion-positive tumours that responded to entrectinib, with dramatic intracranial activity observed in one patient with metastatic NTRK fusion-positive NSCLC. 16 17 A phase 2 trial (STARTRK-2) subsequently focused on a cohort of patients with cancers harbouring fusions involving the NTRK1, NTRK2, and NTRK3 genes (the other cohorts focused on ROS1 fusion-positive cancers).
In this pooled analysis, we aimed to evaluate the activity of entrectinib in patients across these three phase 1–2 trials, representing a range of metastatic or locally advanced or unresectable NTRK fusion-positive solid tumours, including those with CNS disease, and to characterise its safety in the context of all available data in adult and paediatric populations.
Patients (aged ≥18 years) with metastatic or locally advanced NTRK fusion-positive solid tumours were enrolled in one of two phase 1 studies (ALKA-372–001 or STARTRK-1) or a phase 2 global basket study (STARTRK-2). ALKA-372–001 was done at two cancer centres in Italy. STARTRK-1 was done at ten sites (one medical centre in Korea, one hospital in Spain, and one hospital and seven cancer centres in the USA). STARTRK-2 is ongoing at more than 150 sites (cancer and medical centres, research institutes, hospitals, and universities) in 15 countries ( appendix pp 2–10 ) Patients with ROS1 or ALK gene rearrangements were also enrolled in the three clinical trials, but were not included in this NTRK fusion-positive focused integrated analysis.
Patients were included in this prespecified integrated analysis if they had a solid tumour that harboured a fusion in any NTRK gene ( NTRK1, NTRK2 , or NTRK3 ), had measurable disease assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (regardless of line of therapy), had received no previous therapy with TRK-targeted treatments (although previous treatment with other cancer therapies was allowed), and had received at least one dose of entrectinib at or above the recommended phase 2 dose established as 600 mg once daily.
Patients were assessed for eligibility for the three trials using either local molecular profiling or central RNA-based next-generation sequencing (Trailblaze Pharos, Ignyta, San Diego, CA, USA) to test for the presence of NTRK fusions. Local testing could include fluorescence in-situ hybridisation tests, quantitative PCR, or DNA-based or RNA-based next-generation sequencing. In ALKA-372–001 and STARTRK-1, patients were enrolled based on local testing only. In STARTRK-2, patients enrolled by local testing were required to provide tumour tissue (unless a biopsy was medically contraindicated) for independent central next-generation sequencing testing after enrolment. Patients enrolled in the trials were TRK inhibitor naive, had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, a life expectancy of at least 3 months (ALKA-372–001 and STARTRK-1) or at least 4 weeks (STARTRK-2), and adequate organ function. Patients with brain metastases could be enrolled if they had previous treatment resulting in control of symptoms or were asymptomatic. Patients requiring steroids for their brain metastases were allowed to continue their steroids, but must have received stable or decreasing doses for at least 2 weeks before the start of entrectinib treatment.
Patients were excluded if they had any of the following comorbidities: history of other previous cancer or currently active second malignancy; prolonged QTc interval; active infections; gastrointestinal disease; interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis; or peripheral neuropathy grade 2 or worse ( appendix pp 14–18 ).
All studies were done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. Written, informed consent was obtained from all patients. The protocols for all studies were approved by relevant institutional review boards or ethics committees (the protocol is available in the appendix ).
Initial doses of entrectinib in capsule form were 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1600 mg in ALKA-372–001; 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg in STARTRK-1; and 600 mg in STARTRK-2, and were administered as intermittent (ALKA-372–001) or continuous once daily dosing (ALKA-372–001, STARTRK-1, and STARTRK-2) schedules (depending on what schedule patients in ALKA-372-001 were on, they could receive intermittent or continuous dosing). Patients continued treatment until documented radiographic progression, unacceptable toxicity, or withdrawal of consent). 15 16
Tumour response was assessed using CT or MRI scans. Screening tumour assessments (including brain scans) were done within 30 days of first administration of entrectinib. On-treatment tumour assessments were scheduled at the end of cycle 1 (4 weeks) and at the end of alternate cycles thereafter (ie, every 8 weeks), or whenever a clinical deterioration was observed, and at end of treatment if not done in the previous 4 weeks. Brain scans were done at the same frequency as on-treatment tumour assessments in patients with CNS disease at baseline per RECIST (version 1.1), according to investigator assessment. For patients without baseline CNS lesions, brain scans were done as clinically indicated, in accordance with standard clinical practice. For patients with a complete response or partial response, radiographic confirmation of objective tumour response or disease progression was based on RECIST (version 1.1) and assessed both locally (investigator assessment) and by blinded independent central review no later than 4 weeks from when response criteria were first met. Tumour response was re-assessed at time of study drug discontinuation, unless an assessment had been done within the previous 4 weeks. All imaging scans were submitted for blinded independent central review. Patients were followed up until radiographic progression was documented by blinded independent central review, unacceptable toxicity, or withdrawal of consent. A patient could discontinue from study treatment at any time if the patient, the investigator, or the sponsor felt that it was not in the patient's best interest to continue. The following are possible reasons for early discontinuation of study treatment: disease progression, an adverse event that could not be adequately managed with dose modifications or interruption (if needed, dose reductions due to toxicity or treatment-related adverse events could occur for a maximum of 28 days and no more than two dose reductions were allowed), protocol violation, non-compliance with study procedures, loss to follow-up, or withdrawal of consent.
Safety was assessed by physical examination, clinical laboratory tests, and monitoring of adverse events, which were coded using the Medical Dictionary for Regulatory Activities (version 21.0 or higher) and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Information on adverse events and laboratory samples were collected at each patient contact (days 1 and 15 of cycles 1–3, and day 1 of cycle 4 and of every subsequent cycle thereafter).
Molecular characterisation and fusion detection in tumour tissue were done by local or central assay methods that varied between studies ( appendix p 19 ).
The co-primary endpoints of this integrated analysis were objective response (defined as the proportion of patients with a complete response or partial response as assessed by RECIST version 1.1 and Response Assessment in Neuro-Oncology Brain Metastases) and duration of response (measured from the date of first objective response [either complete or partial response] to first documentation of radiographic disease progression or the date of death due to any cause, whichever occurred first) by blinded independent central review.
Key secondary endpoints included progression-free survival (defined as time from first dose of entrectinib to first documentation of radiographic disease progression or death due to any cause at the time of data cutoff) according to blinded independent central review, overall survival (defined as the time from the first dose of entrectinib to the date of death due to any cause), clinical benefit rate (defined as confirmed complete response or partial response, or stable disease for ≥6 months from the first dose of entrectinib), time to CNS progression (defined as months from first dose of entrectinib to first documentation of radiographic CNS disease progression or death due to any cause), and safety (safety monitoring consisted of collection of adverse events, serious adverse events, laboratory tests, and physical observations and measurements, including vital signs, electrocardiograms, ECOG performance status, eye exams, chest x-rays, and neurological functions). Additional prespecified secondary endpoints, assessed in patients with CNS disease at baseline, were intracranial response, intracranial duration of response, and intracranial progression-free survival by blinded independent central review according to RECIST 1.1.
The hypothesis of this integrated analysis was to show the activity of entrectinib in patients with any solid tumour that harbours an NTRK1, NTRK2 , or NTRK3 gene fusion. For the primary and secondary outcomes, the integrated efficacy-evaluable population included patients with NTRK fusion-positive solid tumours who were TRK-inhibitor naive and had received at least one dose of entrectinib, had measurable disease at baseline, and at least 6 months' follow-up from the onset of treatment; patients were not assessable if they did not have measurable disease at baseline. The NTRK fusion-positive safety-evaluable population included all patients with NTRK fusion-positive solid tumours from all three studies who had received at least one dose of entrectinib at a dose of at least 600 mg. The overall safety-evaluable population also included safety data from the paediatric phase 1 study STARTRK-NG 18 in patients aged 4·9–20 years. STARTRK-NG enrolled patients with NTRK1, NTRK2, NTRK3, ROS1 , or ALK gene fusions, with non-neuroblastoma extracranial solid tumours, neuroblastoma, or primary CNS tumours. Entrectinib dosing in STARTRK-NG was dependent on drug formulation (up to 600 mg once daily in patients aged <18 years, as 300 mg/m 2 capsules or sprinkled on food for patients unable to swallow capsules for the recommended phase 2 dose for children of 550 mg/m 2 ). 19
For the integrated analysis, with the assumption that the true proportion of patients achieving an objective response was 60%, a sample size of 56 patients would yield a two-sided 95% CI with precision of at least 14%, with the lower confidence bound exceeding 30%. A proportion of responding patients greater than 30% was considered clinically meaningful.
Demographics, baseline characteristics, and safety data were summarised with descriptive statistics. The Kaplan–Meier method was used to estimate the median for time-to-event endpoints (duration of response, progression-free survival, and overall survival), with corresponding 95% CIs calculated. For objective responses according to blinded independent central review, the number, proportion, and corresponding two-sided Clopper–Pearson exact 95% CIs were summarised. SAS (version 9.3 or higher) was used for all statistical analyses. No interim analyses were planned. Investigator assessments of the primary efficacy endpoints were used for sensitivity analyses, which are not reported here.
These studies are registered as follows: ALKA-372–001, with the European clinical trials database, EudraCT 2012–000148–88; STARTRK-1, with Clinicaltrials.gov , NCT02097810 ; and STARTRK-2, with Clinicaltrials.gov , NCT02568267 .
The studies were funded by Ignyta and F Hoffmann-La Roche, and designed by the funders and study investigators. Data were collected, analysed, and interpreted by the funders, with the authors and investigators. All authors contributed to the writing and approval of this report. Professional medical writing assistance was funded by Ignyta/F Hoffmann-La Roche. TR, EC-M, BS, NC, AJ, SE, and TRW had access to the raw data. The lead (RCD and AD) and corresponding (GDD) authors had full access to all the data in the studies and the final responsibility for the decision to submit for publication.
Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018 (both studies were closed on May 17, 2018); and in STARTRK-2 on Nov 19, 2015 (enrolment is ongoing). All studies were ongoing on May 31, 2018, which was the data cutoff date for this integrated analysis. The median duration of follow-up was 12·9 months (IQR 8·77–18·76).
54 adult patients with advanced or metastatic NTRK fusion-positive solid tumours from STARTRK-2 (51 [94%] patients), STARTRK-1 (two [4%]), and ALKA-372–001 (one [2%]) were included in the integrated efficacy-evaluable population ( table 1 ). Three patients in the two phase 1 studies received more than 600 mg entrectinib.
All patients in NTRK gene fusion-positive efficacy-evaluable population (n=54)
Asian 7 (13%)
Other 4 (7%)
Previous lines of systemic therapy
3 4 (7%)
≥4 5 (9%)
Previous treatment *
Chemotherapy 46 (85%)
Targeted therapy 13 (24%)
Hormonal therapy 9 (17%)
Immunotherapy 7 (13%)
CNS metastases at baseline
Yes 12 (22%)
No 42 (78%)
Previous radiotherapy to the brain
Yes 7 (13%)
Time from end of previous radiotherapy of the brain to first dose of entrectinib †
<2 months 2 (29%)
2 to <6 months 4 (57%)
≥6 months 1 (14%)
Tumour type
Sarcoma ‡ 13 (24%)
NSCLC 10 (19%)
Mammary analogue secretory carcinoma (salivary) 7 (13%)
Breast 6 (11%)
Thyroid 5 (9%)
Colorectal 4 (7%)
Neuroendocrine 3 (6%)
Pancreatic 3 (6%)
Gynaecological 2 (4%)
Ovarian 1 (2%)
Endometrial 1 (2%)
Cholangiocarcinoma 1 (2%)
* Patient might have received multiple or combination therapies, resulting in the sum of previous treatments being >100%.
† Patients with baseline CNS metastases.
‡ Subtypes of soft tissue sarcoma included cervical adenosarcoma (n=1), dedifferentiated chondrosarcoma (n=1), endometrial stromal sarcoma (n=1), follicular dendritic cell sarcoma (n=1), gastrointestinal stromal tumour (n=1; wild-type gastrointestinal stromal tumour, succinate dehydrogenase complex subunit B immunohistochemistry—tumour cells retain normal expression), malignant peripheral nerve sheath tumour (n=1), and sarcoma not otherwise specified (n=7).
Data are median (IQR) and n (%). NSCLC=non-small-cell lung cancer.
Table 1Baseline characteristics
Most patients had a NTRK1 or NTRK3 fusion; the most frequently represented gene fusion was ETV6–NTRK3 , which was identified in 25 (46%) patients ( appendix pp 20–21 ). Two other frequent gene fusions, TPM3–NTRK1 (in four [7%] patients) and TPR–NTRK1 (four [7%]), were reported. Ten tumour types were treated, with at least 19 distinct histologies represented; the predominant tumour types were sarcoma (in 13 [24%] patients), NSCLC (ten [19%]), and mammary analogue secretory carcinoma of the salivary gland (seven [13%]; table 1 ).
Among the 54 patients who comprised the efficacy-evaluable population, 31 (57%; 95% CI 43·2–70·8]) had an objective response: four (7%) had a complete response and 27 (50%) had a partial response. Nine patients (17%) had stable disease as their best overall response to entrectinib ( table 2 ).
Efficacy-evaluable population * (n=54)
Patients with baseline CNS disease † (n=12)
Patients with no baseline CNS disease * † (n=42)
Proportion of patients achieving a response 31 (57%) 6 (50%) 25 (60%)
Complete response 4 (7%) 0 4 (10%)
Partial response 27 (50%) 6 (50%) 21 (50%)
Stable disease 9 (17%) 4 (33%) 5 (12%)
Progressive disease 4 (7%) 0 4 (10%)
Non-complete response or progressive disease 3 (6%) 0 3 (7%)
Missing or unevaluable ‡ 7 (13%) 2 (17%) 5 (12%)
Median duration of response, months 10·4 (7·1–NE) NE 12·9 (7·1–NE)
Median progression-free survival, months 11·2 (8·0–14·9) 7·7 (4·7–NE) 12·0 (8·7–15·7)
* Systemic response.
† CNS disease status determined by the investigator.
‡ Missing or unevaluable included patients with no post-baseline scans available, missing subsets of scans at all time points, or patients who discontinued before obtaining adequate scans to evaluate or confirm response.
Data are n (%) or median (95% CI). NE=not estimable.
Table 2Activity outcomes
54 patients had a best overall response recorded at any single time point from the start of treatment until disease progression, which was also based on RECIST (version 1.1) of which 48 patients are included in the waterfall plot (excludes six patients without matched pre-therapy or post-therapy scans; figure 1A ).
Individual responses by tumour type
(A) Responses in 48 patients with NTRK fusion-positive solid tumours (six patients without matched pre-therapy or post-therapy scans were excluded). (B) Duration of response in in 54 patients with NTRK fusion-positive solid tumours. (C) Kaplan–Meier curve of median duration of response. All assessments shown are based on blinded independent central review. Waterfall plot represents the greatest change at any single timepoint. The dashed horizontal line on figure 1A represents the minimum 30% shrinkage in target lesions that defines an objective response. NSCLC=non-small-cell lung cancer. MASC=mammary analogue secretory carcinoma
The proportion of patients achieving a response were similar in patients with NTRK1 fusions (13 [59%; 95% CI 36·4–79·3] of 22) and NTRK3 fusions (18 [58%; 39·1–75·5] of 31; appendix p 12 ). Only one (2%) patient had an NTRK2 fusion; this patient did not have a response to entrectinib, with a change from baseline in the sum of the longest diameter of target lesions of −2% ( appendix p 12 ).
Responses were recorded in all tumour types included in the analysis: six (86%; 95% CI 42–100) of seven patients in mammary analogue secretory carcinoma, five (83%; 36–100) of six patients with breast cancer, seven (70%; 35–93) of ten with NSCLC, two (67%; 9–99) three with pancreatic cancer, six (46%; 19–75) of 13 with sarcoma, one (25%; 1–81) of four with colorectal cancer, and one (20%; 1–72) of five with thyroid cancer ( figure 1A ). Response to entrectinib did not seem to be related to the fusion partner ( appendix p 13 ).
Median duration of response by blinded independent central review was 10 months (95% CI 7·1 to not estimable; figure 1B, 1C ). At data cutoff, 29 patients had disease progression or had died, and median progression-free survival was 11 months (95% CI 8·0–14·9; figure 2A ). At data cutoff, 16 (30%) of 54 patients had died, and the estimated median overall survival was 21 months (95% CI 14·9 to not estimable; figure 2B ).
Time to event analyses
(A) Progression-free survival and (B) overall survival in patients with NTRK fusion-positive solid tumours in the efficacy-evaluable population (n=54). All assessments shown are based on blinded independent central review.
In the 12 (22%) of 54 patients with baseline CNS disease, as assessed by investigator, six (50%) had a partial response per blinded independent central review and four (33%) had stable disease ( figure 3A , table 2 ). These results, which represent both intracranial and extracranial lesions, are similar to the responses recorded in the 42 (78%) patients without CNS metastatic disease at baseline (of whom 25 [60%; 95% CI 43.28–74.37)]patients had an objective response per blinded independent central review, with 4 [10%] complete responses, and 21 [50%] partial responses). 17 patients in the whole efficacy-evaluable population of 54 patients had a CNS progression event. Median time to CNS progression was 17 months (95% CI 14·3 to not estimable).
Individual responses by presence or absence of CNS metastases
(A) Response by CNS tumour involvement at baseline (six patients without matched pre-therapy or post-therapy scans were excluded) and (B) Intracranial responses in six patients with measurable CNS metastases at baseline by blinded independent central review (12 patients had CNS metastases at baseline according to investigator assessment, 11 confirmed by blinded independent central review. Of these 11 patients with CNS metastases, seven had measurable disease, of whom one had missing/unevaluable data). All assessments shown are based on blinded independent central review. Waterfall plot represents the best change at any single timepoint.
According to blinded independent central review assessment, 11 (20%) of 54 patients had brain metastases at baseline and, in this population, six patients (55%; 95% CI 23·4–83·3) had an intracranial response according to blinded independent review ( figure 3B ). Seven (64%) of these 11 patients had previously received radiotherapy to the brain.
Median intracranial duration of response according to blinded independent central review was not estimable (95% CI 5·0 to not estimable). At data cutoff, five patients with intracranial disease at baseline had an intracranial progression-free survival event, and median intracranial progression-free survival according to blinded independent central review assessment was 14 months (95% CI 5·1 to not estimable).
The safety analysis included two safety populations: the NTRK fusion-positive safety-evaluable population (68 patients from STARTRK-1, STARTRK-2, and ALKA-372-001 who received at least one dose of entrectinib) and the overall safety-evaluable population (355 patients), which included patients from the phase 1 STARTRK-NG study with any tumour type and gene rearrangement who received at least one dose of entrectinib, and was divided into four groups: patients with NTRK fusion-positive tumours (68 [19%]), those with ROS1 fusion-positive NSCLC (134 [38%]), paediatric patients (16 [6%]), and other ( ROS1 fusion-positive non-NSCLC, ALK fusion-positive, or patients with no gene fusion; 137 [39%]; appendix p 11 ). Safety data from both populations are presented to provide a broad safety summary gained from the 355 patients who have received entrectinib across four clinical trials, as well as providing the specific safety information for those patients with NTRK fusion-positive solid tumours. At data cutoff, the median treatment duration in the NTRK fusion-positive safety-evaluable population was 7·85 months (IQR 3·68–12·71) and in the overall safety populations was 5·8 months (1·50–11·60). The median number of entrectinib cycles received was 9·5 (IQR 5–16) for the NTRK fusion-positive safety-evaluable population and 8 (2–15) for the overall safety population. The number of reported safety events in the NTRK fusion-positive population treated with 600 mg entrectinib was consistent with the overall safety-evaluable population (data not shown).
In the NTRK fusion-positive safety-evaluable population (n=68), most adverse events regardless of causality were grade 1−2 and non-serious ( appendix pp 22–25 ). In the overall safety population (n=355), the most frequently reported all-causality grade 3–4 adverse events (in ≥2% of patients) were anaemia (in 38 [11%] patients), increased weight (23 [7%]), dyspnoea (22 [6%]), and fatigue (15 [4%]; data not shown).
In both safety populations, most treatment-related adverse events were grade 1−2 and reversible ( table 3 ). The most commonly reported serious treatment-related event was cognitive disorder in the overall safety population. In the NTRK fusion-positive population, there were three serious treatment-related events reported (one cognitive disorder, one cerebellar ataxia, and one dizziness). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). Serious treatment-related adverse events were reported in seven (10%) patients in the NTRK fusion-positive and in 30 patients (9%) in the overall safety population. The most frequent in both populations were nervous system disorders (three [4%] vs ten [3%]). Three (4%) of 68 patients in the NTRK fusion-positive population and 14 (4%) of 355 patients in the overall safety population discontinued entrectinib due to treatment-related adverse events; 21 (31%) and 90 (25%) had dose interruption due to a treatment-related adverse event; and 27 (40%) versus 97 (27%) had a dose reduction due to a treatment-related adverse event. The most common adverse events leading to dose reductions were anaemia (5 [7%] patients), increased blood creatinine levels (4 [6%]), and fatigue (4 [6%]). At data cutoff, six (9%) deaths had occurred in the NTRK fusion-positive safety population (two acute respiratory failure, two cardio-respiratory arrest, one pneumonia, and one sepsis), and 20 (6%) deaths had occurred in the overall safety population (two acute respiratory failure, two cardio-respiratory arrest, two dyspnoea, two metastases to meninges, two pneumonia, two sepsis, one cardiogenic shock, one cerebral infarction, one suicide, one large intestine perforation, one pulmonary embolism, one respiratory failure, one septic shock, and one tumour lysis syndrome). All of these deaths were deemed unrelated to treatment.
NTRK fusion-positive safety-evaluable population * (n=68)
Overall safety-evaluable population † (n=355)
Dysgeusia 32 (47%) 0 0 146 (41%) 1 (<1%) 0
Constipation 19 (28%) 0 0 83 (23%) 1 (<1%) 0
Fatigue 19 (28%) 5 (7%) 0 89 (25%) 10 (3%) 0
Diarrhoea 18 (27%) 1 (2%) 0 76 (21%) 5 (1%) 0
Oedema peripheral 16 (24%) 1 (2%) 0 49 (14%) 1 (<1%) 0
Dizziness 16 (24%) 1 (2%) 0 88 (25%) 2 (1%) 0
Blood creatinine increased 12 (18%) 1 (2%) 0 52 (15%) 2 (1%) 0
Paraesthesia 11 (16%) 0 0 67 (19%) 0 0
Nausea 10 (15%) 0 0 74 (21%) 0 0
Vomiting 9 (13%) 0 0 48 (14%) 0 0
Arthralgia 8 (12%) 0 0 42 (12%) 2 (1%) 0
Myalgia 8 (12%) 0 0 52 (15%) 2 (1%) 0
Weight increased 8 (12%) 7 (10%) 0 51 (14%) 18 (5%) 0
AST increased 7 (10%) 0 1 (2%) 35 (10%) 3 (1%) 1 (<1%)
ALT increased 6 (9%) 0 1 (2%) 30 (9%) 3 (1%) 1 (<1%)
Muscular weakness 6 (9%) 1 (2%) 0 22 (6%) 3 (1%) 0
Anaemia 5 (7%) 8 (12%) 0 27 (10%) 16 (5%) 0
Asthenia 5 (7%) 0 0 28 (8%) 2 (1%) 0
Peripheral sensory neuropathy 4 (6%) 1 (2%) 0 20 (6%) 4 (1%) 0
Neutrophil count decreased 4 (6%) 0 0 13 (4%) 8 (2%) 0
Rash 4 (6%) 0 0 18 (5%) 2 (1%) 0
Disturbance in attention 3 (4%) 0 0 13 (4%) 1 (<1%) 0
Pain of skin 3 (4%) 0 0 9 (3%) 1 (<1%) 0
Neutropenia 3 (4%) 2 (3%) 0 9 (3%) 9 (3%) 0
Localised oedema 2 (3%) 1 (2%) 0 3 (1%) 1 (<1%) 0
Hyperaesthesia 2 (3%) 0 0 22 (6%) 1 (<1%) 0
Ataxia 2 (3%) 0 0 9 (3%) 3 (1%) 0
Platelet count decreased 2 (3%) 0 0 4 (1%) 0 1 (<1%)
Hyperuricaemia 2 (3%) 0 2 (3%) 13 (4%) 0 5 (1%)
Hypophosphataemia 2 (3%) 2 (3%) 0 6 (2%) 4 (1%) 0
Dehydration 2 (3%) 0 0 5 (1%) 2 (1%) 0
Diplopia 1 (2%) 1 (2%) 0 4 (1%) 1 (<1%) 0
Hypotension 1 (2%) 1 (2%) 0 14 (4%) 2 (1%) 0
Pyrexia 1 (2%) 0 0 7 (2%) 1 (<1%) 0
Lymphocyte count decreased 1 (2%) 0 0 4 (1%) 1 (<1%) 0
Pruritus 1 (2%) 0 0 15 (4%) 1 (<1%) 0
Hypoxia 1 (2%) 0 0 1 (<1%) 1 (<1%) 0
Fall 1 (2%) 0 0 6 (2%) 1 (<1%) 0
Osteoarthritis 0 1 (2%) 0 2 (1%) 1 (<1%) 0
Blood uric acid increased 0 0 1 (2%) 3 (<1%) 0 1 (<1%)
Dysarthria 0 0 0 5 (1%) 2 (1%) 0
Anorectal disorder 0 0 0 0 0 1 (<1%)
Generalised oedema 0 0 0 5 (1%) 2 (1%) 0
Electrocardiogram QT prolonged 0 0 0 5 (1%) 1 (<1%) 0
Lipase increased 0 0 0 2 (1%) 2 (<1%) 1 (1%)
Amylase increased 0 0 0 1 (<1%) 3 (1%) 0
Blood creatine phosphokinase increased 0 0 0 2 (<1%) 1 (<1%) 1 (<1%)
Hyponatraemia 0 0 0 3 (1%) 2 (1%) 0
Hypermagnesaemia 0 1 (2%) 0 0 1 (<1%) 0
Hypoalbunimaemia 0 0 0 0 1 (<1%) 0
Pulmonary oedema 0 0 0 0 2 (1%) 0
Mental status changes 0 0 0 0 2 (1%) 0
Agitation 0 0 0 0 1 (<1%) 0
Mood altered 0 0 0 0 1 (<1%) 0
Orthostatic hypotension 0 0 0 2 (1%) 1 (<1%) 0
Hypertension 0 0 0 0 1 (<1%) 0
Cardiac failure 0 1 (2%) 0 0 2 (1%) 0
Cardiac failure congestive 0 1 (2%) 0 0 1 (1%) 0
Myocarditis 0 0 0 0 0 1 (<1%)
* All patients with NTRK gene fusions who received ≥1 dose of entrectinib, regardless of dose or duration of follow-up.
† All patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (regardless of tumour type or gene rearrangement) who received ≥1 dose of entrectinib. No deaths due to adverse events were reported.
Data are n (%). Adverse events were encoded using MedDRA (version 21.0). ALT=alanine aminotransferase. AST=aspartate aminotransferase.
Table 3Treatment-related adverse events
In this integrated analysis of patients with a wide variety of advanced cancers harbouring NTRK1, NTRK2, or NTRK3 fusions, we show that entrectinib is active in multiple tumour types, showing both systemic antitumour activity and activity in CNS metastases. The proportion of patients achieving an objective response was 57%, with a similar proportion (55%) achieving an intracranial response. Anti-tumour activity was similar in both NTRK1 and NTRK3 gene fusion-positive cancers. Disease control was durable, with a median progression-free survival of 11 months and a median duration of response of 10 months. These results are especially encouraging for patients with tumour types with few treatment options, such as sarcomas. 20 On the basis of these and other data, entrectinib was granted accelerated approval by the US FDA in August, 2019 for the treatment of adults and children with solid tumours that have a NTRK gene fusion.
Previous reports initially documented case studies with substantial antitumour activity of entrectinib in patients with NTRK fusions. 17 21 Importantly, other than a small number of patients with neuroblastoma harbouring ALK point mutations, there is no evidence of activity of entrectinib in tumours with any genomic aberrancies other than gene fusions, such as single nucleotide variants or copy number gain. 16 22 Entrectinib administration induced a response and durable antitumour activity against intracranial metastases in a high proportion of patients with CNS involvement in this study. The inclusion of patients with ROS1 -positive NSCLC and CNS disease in this integrated analysis has provided important CNS data that support the ability of entrectinib to cross the blood–brain barrier and to maintain intracranial therapeutic levels, highlighting its value as a CNS-active therapy in patients with existing brain metastases or in those who are at risk of developing brain metastases.
Several other TRK inhibitors are under investigation. 11 23 24 25 Of these agents, larotrectinib has received accelerated approval by the US FDA for the treatment of adult and paediatric patients with NTRK fusion-positive solid tumours. 11 26 In the pivotal integrated analysis of larotrectinib that comprised three trials (phase 1 adult, phase 2 adult and adolescent, and phase 1–2 paediatric) the proportion of patients achieving an objective response was higher than the response from this integrated analysis of entrectinib (75% vs 57%). However, direct comparisons between these separate trials of entrectinib and larotrectinib are challenging because of potentially confounding factors, including the fact that the differences in responses reported might be explained by the substantial differences in patient populations enrolled and study design. Additionally, potentially less responsive cancers such as colorectal ad thyroid cancer were much less represented in the integrated analysis of larotrectinib than that of entrectinib 11 and the generally more responsive subtype of infantile fibrosarcoma was not represented in the entrectinib analysis. Moreover, patients in the entrectinib integrated analysis were older (adults only for the entrectinib analysis vs adults, children, and adolescents [22% of patients were aged ≤14 years] for larotrectinib) and 22% of enrolled patients in the entrectinib analysis had CNS metastases at baseline compared with only 2% in the larotrectinib analysis. 11 19 Several patients in the larotrectinib study underwent tumour resection on study, which suggests that these patients had non-advanced disease and thus a better prognosis. These factors might affect the overall results because paediatric patients with cancer have the potential for better outcomes than adults 27 and patients with CNS involvement are a poor-prognosis population with worse outcomes than those without CNS disease. Additionally, in the adult population, each trial included a wide variety of different tumour histologies, accounting for differing percentages of the overall patient population, further limiting study-to-study comparisons. Efficacy and safety testing of entrectinib in children with cancer is currently in progress (STARTRK-NG, NCT02650401 ).
NTRK1, NTRK2 , and NTRK3 gene fusions can be regarded as an oncogenic family because of their high homology in the kinase domain and ATP binding pocket. 28 These structural similarities might account for the almost identical responses seen in the entrectinib analysis in patients with NTRK1 fusions and NTRK3 fusions. The presence of large introns that are typically inadequately sequenced and difficult to analyse can make detection of NTRK2 and NTRK3 fusions more difficult, and only one patient with an NTRK 2 fusion was included in this dataset.
In cancers harbouring NTRK fusions, resistance to treatment can occur and cases of resistance to entrectinib and larotrectinib have been observed. 29 In one patient with entrectinib-resistant colorectal cancer, two resistance mutations (Gly595Arg and Gly667Cys) in the NTRK1 kinase domain were found in the patient's circulating tumour DNA collected longitudinally during treatment. 28 Both mutations were detected in patient plasma obtained at progression, suggesting that both could be associated with acquired resistance to entrectinib in the clinical setting. Therefore, next-generation TRK inhibitors are now being tested in the clinic. Repotrectinib has shown preclinical evidence to overcome resistance due to acquired solvent-front mutations involving ROS1 and NTRK1, NTRK2 , and NTRK3 . 30 BAY 2731954 (LOXO-195) has also shown the ability to overcome recurrent resistance mutations. 15 30 31
In this integrated analysis, entrectinib was well tolerated with a manageable safety profile. Most adverse events were transient and managed successfully with dose interruption or reduction and the number of discontinuations due to treatment-related adverse events was low. Overall, the safety profile of entrectinib in patients with NTRK fusion-positive cancer was consistent with that of the overall safety population and with that previously reported with other drugs of the same class such as larotrectinib and repotrectinib. 11 15 16 32
The limitations of this integrated analysis of entrectinib are based around the relatively small numbers of patients enrolled and the single-arm nature of these studies. The number of patients included in the analysis was slightly below the sample size requirement that was calculated a priori, although the lower bound of the 95% CI for response (43%) was sufficiently above the threshold of 30% that a high degree of confidence can be attached to the finding that entrectinib produces clinically meaningful responses in this patient population. Because of the rarity and variety of these tumour types, to do phase 3 studies or enrol large numbers of patients is difficult. Basket trials such as STARTRK-2 are designed to enable recruitment of such rare disease populations.
The results from this integrated analysis of entrectinib clinical trials indicate that entrectinib is an active treatment for patients with NTRK fusion-positive solid tumours either with or without malignant lesions in the CNS. The ongoing STARTRK-2 and STARTRK-NG trials will hopefully provide additional data to support the use of entrectinib as a targeted treatment for patients with NTRK fusion-positive tumours who have, or are at risk of developing, CNS metastases.
RCD, AD, TS, SPC, SS, JCK, E-CM, and GDD were involved in the study conception and design. RCD, AD, LP-A, SS, ATS, AFF, CMB, BCC, DT, BB, LB, YKC, MB, IG-L, SVL, PC, TJ, MF, DS, HHL, GLB, PG, CS, TRO, DWB, EF, and GDD recruited patients. RCD, AD, LP-A, SS, ATS, AFF, CMB, TS, BCC, DT, BB, SPC, LB, JCK, YKC, MB, IG-L, SVL, PC, TJ, MF, DS, HHL, GLB, PG, JN, CS, TRO, and EF were principal investigators at contributing sites. RCD, CMB, TS, DT, SPC, JCK, IG-L, PC, JN, DWB, EC-M, NC, and TRW collected the data. RCD, AD, SPC, IG-L, SVL, HHL, TRO, DWB, TR, EC-M, BS, NC, AJ, SE, TRW, and GDD were involved in data analysis. NC oversaw data and statistical analysis. All authors were involved in data interpretation, writing of the report and approval of the report.
RCD has received consulting fees from Ignyta, Genentech/Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, and Rain Therapeutics; sponsored research agreements from Ignyta, Loxo, Mirati, Pfizer, Eli Lilly, and Strategia; royalties or licensing fees for intellectual property from Ignyta, Loxo, Abbott Molecular, Genentech/Roche, Chugai, Foundation Medicine, Black Diamond, and Rain Therapeutics; and has stock ownership in Rain Therapeutics. GDD has received grants from Novartis, Bayer, Ignyta, Roche, Epizyme, Pfizer, Loxo Oncology, AbbVie, Adaptimmune, GlaxoSmithKline, Janssen, PharmaMar, and Daiichi-Sankyo; personal fees from Novartis, Bayer, Polaris Pharmaceuticals, Ignyta, Roche, Epizyme, Mirati Therapeutics, Pfizer, Sanofi, EMD-Serono, Loxo Oncology, AbbVie, ZioPharm, WIRB Copernicus Group, MJ Hennessey/OncLive, Adaptimmune, Blueprint Medicines, G1 Therapeutics, CARIS Life Sciences, Janssen, CHAMPIONS Oncology, PharmaMar, and Daiichi-Sankyo; non-financial support from Novartis, Bayer, AbbVie, Roche, Epizyme, PharmaMar, and Daiichi-Sankyo; travel support to consulting meetings from Novartis, Bayer, Mirati Therapeutics, Roche, Loxo Oncology, Epizyme, Pfizer, EMD-Serono, WIRB Copernicus Group, MJ Hennessey/OncLive, Adaptimmune, Blueprint Medicines, CARIS Life Sciences, CHAMPIONS Oncology, PharmaMar, and Daiichi-Sankyo; minor equity from Blueprint Medicines, CARIS Life Sciences, Bessor Pharmaceuticals, ERASCA Pharmaceuticals, G1 Therapeutics, and Merrimack Pharmaceuticals; is a member of the Board of Directors for Blueprint Medicines and Merrimack Pharmaceuticals; and has a use patent on imatinib for GIST, licensed to Novartis with royalties paid to the Dana-Farber Cancer Institute. LB has received advisory board fees from Takeda, AstraZeneca, LOXO oncology, Abbvie, Bayer, and G1 therapeutics; received travel support from Mirati to travel to a scientific meeting; has research funding to the institution from Beyondspring pharma; and has stock in Epic sciences. BB reports sponsored research at Gustave Roussy Cancer Center from AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Ignyta, Ipsen, Merck KGaA, Merck Sharp & Dohme, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma. CMB reports grants and non-financial support from Ignyta/Roche, Novartis, AstraZeneca, Mirati, Spectrum, and MedImmune; and has received personal fees from Revolution Medicines. DWB is on a data safety monitor board for BioMimetrix Pharmaceuticals. YKC has received research grants from Abbvie, Bristol-Myers Squibb, Biodesix, Lexent Bio, and Freenome; honoraria for his participation as an advisory board member from Roche/Genentech, AstraZeneca, Foundation Medicine, Counsyl, Neogenomics, Guardant Health, Boehringer Ingelheim, Biodesix, Immuneoncia, Lilly Oncology, Merck, and Takeda. SPC has received grants from Amgen, Roche, Threshold Pharmaceuticals, GlaxoSmithKline, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, SARC, Karyopharm Therapeutics, and Janssen. BCC has received research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, and Merck Sharp & Dohme; has had consulting roles for Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme; owns stocks from TheraCan Vac; and has received royalties from Champions Oncology. PC has received grants from Roche and US Oncology Research. AD has received honoraria and consulting fees for advisory boards for Ignyta/Roche/Genentech, Loxo/Bayer/Lily, TP Therapeutics, AstraZeneca, Pfizer, Blueprint, Takeda/Ariad/Millennium, Helsinn, Beigene, BergenBio, Hengrui, Exelixis, Tyra, Verastem, and MORE Health; and received associated research funds from Pfizer and Exelixis. MF has received compensation for consulting and advisory board activity by Array, Amgen, Seattle Genetics, and Bayer Pharmaceuticals; and has received honoraria from Amgen for education activities. AFF has received consulting fees from Millennium Pharmaceuticals, AbbVie, Stemcentrx, PharmaMar, Loxo, Bayer, Genentech, AstraZeneca, Boehringer Ingelheim; and research funding from AbbVie, Stemcentrx, PharmaMar, Loxo, Bayer, Genentech, AstraZeneca, Ignyta, Bristol-Myers Squibb, Merck, and Amgen. EF reports membership on data safety monitoring committee for Helsinn Pharmaceuticals and support to Children's Hospital of Philadelphia for clinical trials from Ignyta, Merck, and Novartis. IG-L reports ad-hoc scientific advisory boards for Array, Ignyta, Glycyx. He has received financial support to the Huntsman Cancer Institute from Agios, Bayer, Bristol-Myers Squibb, Lilly, Halozyme, Incyte, Medimmune, Novartis, Oncomed, Pfizer, Taiho, Redhill, Glenmark, GSK, Newlink Genetics, Armo, Amgen, and Rafael. PG reports consulting fees and advisory service fees from Roche, MSD, BMS, Boehringer Ingelheim, Pfizer, AbbVie, Guardant Health, Novartis, Lilly, AstraZeneca, Janssen, Sysmex, Blueprint Medicines, and Takeda; fees for speaking and public presentations from Roche, MSD, Bristol-Myers Squibb, Pfizer, Novartis, Boehringer Ingelheim; and travel support to consulting meetings from Bristol-Myers Squibb, Takeda, and Janssen. TJ has received advisory or consulting fees for advisory boards for Roche, Ignyta, Pfizer, AstraZeneca, Boehringer-Ingelheim, Merck, Takeda, Novartis, and Bristol-Myers Squibb. JCK reports grants from AbbVie, Amgen, Boston Biomedical, Isofol, and Oncomed. SVL has received consulting fees from Apollomics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, G1 Therapeutics, Genentech/Roche, Heron, Ignyta, Janssen, Lilly, Merck, Pfizer, Regeneron, Taiho, and Takeda; sponsored research agreements from AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Clovis, Corvus, Esanex, Genentech/Roche, Ignyta, Lilly, Lycera, Merck, Molecular Partners, OncoMed, Pfizer, Rain Therapeutics, and Threshold. HHL reports being on advisory boards for Boehringer-Ingelheim, Celgene, Eli Lilly, Novartis, Merck Serono, Roche, and Takeda; being part of speakers' bureaus for AbbVie, Bayer, Eisai, Eli Lilly, Guardant Health, and Novartis; has received travel support from Bayer, Merck Sharp & Dohme, Novartis, and Pfizer; and has received research funding from Merck Sharp & Dohme, Mundipharma, and Novartis. JN has received consulting fees from AstraZeneca, Bayer, Roche/Genentech, Takeda, Turnstone, and Western Oncolytics; sponsored research agreements from Merck; travel support from Caris; and has equity interest in Epic Sciences. TRO has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Medac, Merck Sharp & Dohme, Novartis, and Roche/Genentech; sponsored research agreements from AstraZeneca, Eli Lilly, Roche/Genentech, and Sanofi-Aventis; and travel support from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, and Roche/Genentech. LP-A or his relative has received consulting fees from Genentech/Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, Bayer, Merck Sharp & Dohme, Novartis, Amgen, Pharmamar, Boehringer Ingelheim, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Sanofi, and Blueprint Medicines; sponsored research agreements from BMS, AstraZeneca, and Merck Sharp & Dohme; and serves on the board of Genómica. TS has received research grants from Chugai Pharmaceuticals; grants and honoraria from Astellas Pharma, AstraZeneca, Chugai Pharmaceuticals, Eli Lilly Japan, Kissei Pharmaceutical, Merck Sharp & Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; honoraria from Bristol-Myers Squibb, Kyowa Hakko Kirin, Nippon Kayaku, Ono, Roche Singapore, Taiho Pharmaceutical, Thermo Fisher Scientific, and YakultHonsha; and research grants from Bayer Yakuhin, Daiichi Sankyo, Eisai, LOXO Oncology, and Merck Serono. ATS has served as a compensated consultant or received honoraria from ARIAD, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, LOXO, Natera, Novartis, Pfizer, Servier, Taiho Pharmaceutical, Takeda, and TP Therapeutics; has received research (institutional) funding from Daiichi Sankyo, Ignyta, Novartis, Pfizer, Roche/Genentech, and Turning Point Therapeutics; and has received travel support from Pfizer and Roche/Genentech. SS is an advisory board member for Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Celgene, Daiichi Sankyo, Incyte, Merck, Novartis, Roche, and Seattle Genetics. DS is an advisory board member for Celularity, Molecular Stethoscope, and Curematch; is on the speaker bureau for Celgene and Bayer; and has a patent on 'methods of treating a neuroendocrine tumour'. CS has received consulting fees from AbbVie, Merck, EMD Serono, Armo, Bergen Bio and Eli Lilly; and research funds from Vaccinex. DT has received grants from Janssen and Astellas; and support for meeting travel from Sanofi, Pfizer, Janssen, and Astellas. TR, BS, and SE are employees of Genentech. NC was an employee of Genentech. EC-M and AJ were employees of Ignyta. TRW is employed by Genentech and has equity in Roche. MB and GLB report no competing interests.
Qualified researchers can request access to individual patient-level data through the clinical study data request platform . Further details on Roche's criteria for eligible studies are available online. Those interested in accessing study data should view Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents can also be found online.
The studies were funded by Ignyta and Hoffmann-La Roche. Third-party medical writing assistance, under the direction of the authors, was provided by Charlotte Kennerley and Caroline Loder of Gardiner-Caldwell Communications, Macclesfield, UK, and was funded by F Hoffmann-La Roche. We thank the patients, their families, and the participating study centres. We would also like to acknowledge the investigators of the STARTRK-NG study for the collation of safety data for use in the overall analysis of safety in patients given entrectinib across the three four clinical trials. GD acknowledges the support of the Ludwig Cancer Research, the Adelson Medical Research Foundation, Team Russo, the Rotenberg and Mandelbaum Families, and the Pan Mass Challenge cancer charities (Paul's Posse, Leslie's Links, and Erica's Entourage). EF acknowledges the support of the Alex's Lemonade Stand Foundation.
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Tour the Secrets of Coney Island: Past, Present, Future, & Unknown
Michelle Young 04/05/2016 Tour
Titled America's first playground, Coney Island was a small strip of sand on Brooklyn's south coast that became synonymous with the burlesque, the bizarre, the outlandish and the corrupt. Join, author, playwright and Untapped Cities tour guide, Justin Rivers, in a new Untapped Cities tour, The Secrets of Coney Island: Past, Present, Future, & Unknown, as you trace the steps of the two main characters from his graphic novel, The Wonder City: The Great Whale of Coney Island on their visit one hot summer in 1942. Through their eyes you'll see what Coney Island was like at the height of its mid-century popularity.
Unearth old secrets of the many long-gone amusement parks
Learn about what's in store for the hotly contested future development of the island
What to bring: Comfortable walking shoes
What to know: The tour is approximately 2 hours long; please note that the MTA is unpredictable and detours due to construction could arise.
See all upcoming Untapped Cities Behind the Scenes Tours.
coney island, Featured Tour, history, manhattan, NYC
Tour the Secrets of Coney Island: Past, Present, Future, & Unknown Purchase Gift Card

redpajama_set_name: RedPajamaCommonCrawl


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These harsh situations undoubtedly put limits on the production assortment, but at the same time they pressured the artists to experiment with glass. These extraordinary glassworks started in 1940 with Emanuel Beranek who made his authentic glass in essentially the most primitive conditions. Because the very starting, Beranek glassworks stood apart from the commonplace glass production. At the time when many of the hand-made glass producers used generator fuel heated furnaces, minecraft villa schematic Beranek and his three brothers used peat for heating. The mixture of raw supplies is loaded into the pots two or three times on any given day. Glass products have been minimize on a crank-brace and bits of bottle glass mixed with charcoal were used as uncooked materials. The finished products are carried into electrical cooling furnaces that are pre-set to comply with a 48-hour cooling curve to insure an ideal resistance of product in opposition to cracking. Most items are blown utilizing the flying-hand technique on the working temperature of about 1250 °C. The first load goes in at about 3 pm, at the temperature of 1350 °C to 1400°C. The final normally goes in at 10 pm.
Your complete course of is accomplished at about 2 am and the temperature is lowered to 1350 - 1280 °C. The temperature is raised to 1450 °C to drive any air bubbles out of the liquid and to let the glass grow to be pure and homogeneous. This temperature is well reached via fuelling by natural gasoline, which additionally permits a working cycle of 24 hours. The work on the following day's melt begins within the afternoon, towards the tip of the working day. It now has the viscosity vital for working. It's now that the unshapely chemical compound will develop into a marvelous piece that can travel many miles, beautify houses all through the world, maybe even make somebody's day better, and on a grand scale, turn into a part of the human history. Once the plans have been revised and completed they'll then be given to the developer or the proprietor of the build to look over.
All of this is by the hands of a talented glassmaker whose private contact and part of his being will dwell with every piece for years to come back. Each piece reflects the successful synergy of the old style glass making strategies and essentially the most distinctive ideas of fashionable glass design, which bring to its proprietor nice beauty and delight. The air bubbles of probably the most vivid shapes and sizes are intentionally compelled into the glass only where they belong in response to the unique design of each piece. Most items are made from the standard soda-potash glass - it's shaped into its closing kind and decorated whereas it remains to be in its molten state right by the furnace. It's believed to be unintentionally found by humans around 5000BC when Phoenician merchants, while feasting on a seashore, could find no stones on which to put their cooking pots. The homogeneity and transparency of the wonderful blown glass are dependent upon the purity of raw inputs and glass-melting methods, that is the flexibility to reach furnace temperatures over 1450 °C.
All items are hand made, most of them are scorching-formed with out using moulds. Among them are glass vases, glass spheres, and decorative glass platters. One example is the bubble glass. The sunshine reflects in every bubble and bounces back leading to a comfortable surrounding glow including an ultra futuristic tone to any setting. Since its creation, the bubble glass has discovered admirers all through the world. Emanuel Beranek discovered the way in which to turn the original glass flaw into a magnificent inventive intricacy. Some actually distinctive glass items are created by an meeting of Czech glass artists on the Beranek manufacturing unit situated in the heart of the Highlands, on the border between Bohemia and Moravia. Building plans are the one most vital element in construction constructing. Both forms of building require properly prepared building plans if they're to be constructed efficiently. All of the aspects of the development business might be divided into two categories: residential work (constructing properties) and commercial work which includes constructing faculties, shops, places of work and other industrial buildings. The furnace is the guts of the glasswork.
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text:
El Empire Back Story
As any fan of Science Fiction books and movies knows, almost every story assumes Evolution to be true whether they specifically state it or not. [Even the famous "logical" Spock of Star Trek fame would spout Evolution as an established fact.] The "life on other planets," with all its variety, must have evolved over millions or billions of years differently on those other planets. Many alien races are assumed to be much older than humans and, therefore, more technologically advanced.
So how does a "young earth creationist" Christian author develop a back story for Science Fiction stories while remaining true to the young universe idea clearly taught in Scripture? One wants to have alien races, spaceships and all the fun stuff without adopting a destructive Evolutionary point-of-view. One also has to consider how Adam's rebellion, which introduced sin and death into the universe, could justly be applied to the imaginary races in the far-flung reaches of the universe who have never even heard of earth.
A challenge to be sure. The simplest way to solve the problem is to ignore it. The problem with that solution is the story would then tend to fall back on Evolutionary assumptions. Below is my solution as the back story for my growing collection of Sci-Fi adventure stories set in the fictional [of course!] El Empire. I hope it helps you to "suspend disbelief" long enough to enjoy them. If you want to know what I believe about aliens and UFO's you can read the article What Does The Bible Teach About UFOs And Aliens?
About 6,000 years ago, El created the universe and all that is in it in 6 days. Although He created many planets spread throughout the universe that could support life - and did support an endless variety of plant and animal life - He only created one man and one woman [Adam and Eve] with spirits and in His likeness. These two people were created on the planet Earth. On the seventh day of creation, they rebelled and introduced sin into the universe.
These humans made children rapidly and lived long lives, up to 900 years. Because of this, the human population quickly spread over the earth. These human beings had incredible intelligence as they were able to use their brains to nearly total capacity.
About 500 years after its creation, humanity developed the technology for space travel and was able to build spaceships. As they began traveling in space, they discovered Time Tunnels. Time Tunnels were tunnels where time appeared to stand still. A person/ship entering a Time Tunnel could reappear on the other side of the galaxy or even the universe, and it only seemed to have taken minutes or hours in travel time. People used Time Tunnels to explore and settle the furthest reaches of the universe. So not only was earth being populated but also habitable planets around the universe were being populated.
After another 500 years, the evil descendants of Cain began to experiment with genetics. They would take human DNA and cross it with animal DNA to develop intelligent beings with a soul and spirit whose body was part human and part animal. The Centaurs, werewolves, fauns, and much more came from these cruel experiments. These actions sparked the Genetic War as the people who followed El objected to this unnatural mutation. This war raged over the planet Earth for 300 years. During that time, many people and mutants left in spaceships to settle in other parts of the universe. The end of this war resulted in the near destruction of the followers of El; however, they, on their part, managed to destroy the labs, research and technology that had been developed, including the capability of space travel. A few scattered spaceships remained hidden in remote parts of the earth.
Because the wicked now reigned over the planet, except for one man, El decided to destroy all life on Earth except for that man and his family by sending a global flood. As the flood began, one man, Dale Waig, escaped in the last surviving spaceship through a time tunnel as it collapsed. He spread the rumour that Earth had been destroyed. Earth became shrouded in mystery and is now called the Lost Planet. Some believe Dale's story and feel the Lost Planet no longer exists. Followers of El hold that the planet was judged by the predicted global flood but was then restarted by a new family. Great Prophets throughout the millennia have confirmed this, but no one has ever been able to find the Lost Planet to verify its existence.
Since the universe was created to be ever-expanding, as space was stretched, Time Tunnels began collapsing. Until now, there are no known Time Tunnels in the universe. Scientists have attempted to manufacture Time Tunnels but so far have been unsuccessful.
And so humanity became the seed to populate the universe. As a side note, all of this happens before what is known as the Tower of Babel on Earth, where God divided the languages. This means all languages that developed through the rest of the universe came from one original language.
The El Empire dates are counting up from the year of Creation. For example, The Gallant Mystery takes place in the year 6081, which would be 6,081 years after Creation [or AD 2018 Earth time].
Four thousand five hundred twenty-six years after Creation, the El Empire was formed, beginning with three planets and developing over time to thousands of member worlds.


text:
using Abp.MultiTenancy;
using Abp.Zero.SampleApp.Users;

namespace Abp.Zero.SampleApp.MultiTenancy
{
    public class Tenant : AbpTenant<User>
    {
        protected Tenant()
        {

        }

        public Tenant(string tenancyName, string name)
            : base(tenancyName, name)
        {
        }
    }
}

redpajama_set_name: RedPajamaGithub


Pre-Construction. To be built. Pre-Construction. Completion 1 Quarter of 2021. Majestic Sand Condos is an exclusive 14 unit residences on tranquil northern end of Clearwater beach with 60 ft frontage on white sandy beach of Gulf of Mexico. Extraordinary expanse of the gulf with unobstructed views. Relax by the oversized pool and spa or spend time in the fitness center. The unit construction will encompass 9 '-4" ceiling heights with tray ceilings, floor coverings with wood, carpet or stoneware, European custom made kitchen cabinets with granite or onyx, smart system through-out, bathrooms with frameless glass showers, tubs, designer fixtures. Each residence comes with 2 parking spaces and access for electric car charging.
Waterfront Paradise Found! The best boating water on the beach, with a wide open channel directly across from the Yacht club. Here is your chance to own a piece of paradise on world renowned Clearwater Beach. One of the widest lots on the street with 86 feet of waterfront! Direct Gulf access. From the moment you walk in the front door, this home is welcoming and inviting. BIG, beautiful picture windows throughout the home offer gorgeous panoramic water views. With 5 large bedrooms, this home has room for everyone. The very spacious master bedroom has a tiled fireplace and French doors which lead to the brick pavered patio and large pool. Expansive dock with electric boat lift and fixed, hard roof will keep your boat out of the sun. Gas appliances in the kitchen for the chef. From enjoying your morning coffee overlooking the water, to an afternoon boating, and finally a beautiful sunset. This is how it feels to truly enjoy the best in waterfront living. First time offered since 1999. Make this magnificent waterfront home yours.
Stunning 2002-built home in the historic Harbor Oaks neighborhood of downtown Clearwater was designed by its current owner-architect to exemplify the charm and uniqueness of the area, without sacrificing modern amenities. Begin with the fact that this property includes two structures, a two-story main house, 6,115 square feet with five bedrooms, four full baths and two half baths and an 812-square-foot guest cottage which sits above the detached two-car garage. These structures hug a pool and garden area. Reminiscent of old Palm Beach splendor, this home's main floor is open and inviting, with its separate formal living and dining rooms and two guest bedrooms with access to one-and-a-half baths. Its bright chef's kitchen complete with concrete countertops, a gas stove and large island opens onto a large family room with fireplace and bar. The expansive staircase reveals three additional bedrooms and the laundry room. Here you find the oversized master suite with high ceilings, fireplace, secluded office, balcony overlooking the pool and walk-in closet with custom built-ins. The master bath features dual sinks, hydro massage tub and separate shower. The mature, landscaped backyard retreat with huge saltwater pool and outdoor space which includes a fireplace leads guests to their fully equipped guest house. In case you are wondering, this home can be outfitted with an elevator and the attic can be made into a third floor. These gems rarely come on the market. Don't miss your private showing of this one!
Views of the turquoise waters of the Gulf await from the expansive west side of this custom designed 6/5 family home with an open living plan located in Carlouel. A spectacular great room offers a panoramic wall of windows and sliding doors, a wet bar with wine cooler and media cabinets for the television shelf flanked by decorative columns. An open dining area adjoins the island kitchen featuring light oak look cabinets, solid surface counters and a built-in desk. There are three bedrooms, two baths and a laundry room on this level. The upper level master bedroom suite provides another window wall with Gulf views and a luxury bath with dual sink vanity, whirlpool tub, glass front shower and walk-in custom closet. On this level there is a large second bedroom suite with private bath and walk-in closet, sixth bedroom used as an office and loft area. Other features include a ground level entertainment space with a bar and sliding doors opening to a screened backyard lanai, neutral ceramic tile floors, elevator and three car garage. Walk to the deeded beach access to wade in the Gulf or watch the sunset. Private Carlouel Yacht Club is located nearby, and it is only minutes to Clearwater Beach restaurants and attractions.
A stunning reflection of waterfront living, this beautifully remodeled masterpiece rests on a protected deep water lot in the exclusive community of Island Estates. Double entry doors reveal a spacious and open floor plan. Meticulously renovated and updated, this sensational home includes 3 Bedrooms and 3 full Bathrooms with luxurious finishes throughout the interior. An inviting Great Room includes a substantial seating area and features a delightful fireplace. The epicenter of every great home is its kitchen and with rich quartz counters and sleek stainless steel appliances you are prepared to delight family and friends in this artfully designed space. A split bedroom floor plan affords privacy to the Master bedroom. The master suite includes a spa like bathroom complete with soaking tub. Additional interior amenities include an executive home office and home theater with state-of-the-art components. Transition to the backyard through one of the many sets of sliding glass doors and out to the spacious lanai, enjoy a sparkling pebbletec pool that is heated, tropical landscaping and a large dock. Designed for both comfortable living and entertaining, this exceptionally generous home is ready for your arrival.
Private and secure condo Band new construction! - LARGE 2 bedroom 2 1/2 bath with direct Gulf views from every room. Access to all of the hotel amenities at no charge. 24 hour security, private and secure parking, personal and secure elevator opens into unit. Absolutely beautiful!
Rare opportunity in the area of Belcher and Harn roads in Clearwater. This large home with a above garage efficiency sits on 4.75 acres with a 3/4 acre pond at the rear. Pond is believed to be spring fed and leads to Allen's Creek. Home is in good condition. Large kitchen, beautiful wood floors in most living areas. All bedrooms are very large. Split floor plan. Spacious indoor laundry room. Light and bright sunroom/bonus room at back of house great for home office. Separate dining room, and lots of eat in space at the kitchen island. Walking distance to Oak Grove Middle. Currently zoned R3, but possible to explore other options with the county. Move right in, redevelop, or a combination thereof.


text:
Мошовце () е село в Словакия.

История
Запазени са много исторически сгради като доказателство за 770-годишното съществуване. За първи път селището е споменато в документите за дарения на крал Андраш II.

Първоначално на мястото на Мошовце има две селища. Първото, Махиух е било разположено в района на днешни Стари Рад, а второто Тера Моус, което дава настоящето име на селото, е заемало мястото на запазения и до днес Видърмох. Името на второто селище означава Земята на Мойш и ни дава основание да вярваме, че цялото селище преди е принадлежало на господин Мойш, което име е може било абревиатура от сложното славянско име Мойтех, подобно на имената Войтех или Моймир. Във всяко отношение името на селището е претърпяло много промени – от Мошовых, Мошоц, Мошовец, Вила региа Майос алио номине Мошових, опидиум Маыус сие Мошоц, Мошоц олим Маыус и до наши дни Мошовце. Името на обособената стара част от Мошовце Хорнуков е запазено в модерната форма Черньаков.

Мошовце отначало се е развило като кралско селище със свободна адвокатура и от средата на 14 век е привилегирован град, присъединен към кралската крепост на Блатница. През 1527 попада в ръцете на фамилията Ревай, което отнема градските привилегии на Мошовце за повече от 400 години.

В миналото, Мошовце е важен занаятчийски център на Туриецкия
регион. В града има около 15 активни гилдии - обущарската и най-известната кожухарска гилдия са оцелелите най-дълго време. В наши дни Мошовце е важен туристически район с много забележителности.

Забележителности
Един от най-забележителните паметници в Мошовце е феодалното имение, построено в стил рококо-класицизъм от втората половина на 18 век с просторен английски двор. Други забележителни места в града са родното място на Ян Колар, неоготическа католическа църква със скъпоценен олтар, построена на мястото на предишна древна църква, лутеранска църква построена през 1784 година, Арт нуво зелена къща и павилион от 1800 г., а в мавзолея сега се помещава Музеят на занаятите.

Природа
Околната среда на Мошовце е наистина уникална. Комплекс от исторически булеварди с дървета и гори създаващи естетичен и внушителен пейзаж, който е като продължение на гористата местност от планината Голяма Фатра. Тази планина е сред най-атрактивните в Словакия. Фантастични форми от варовик и доломит, както и прекраснатата природа близо до Блатнишката и Гадерската долина привличат посетители от целия свят.

Култура и Традиции
В Мошовце са израснали много важни личности. Най-великите са Фрицо Кафенда (1883-1963), композитор; Анна Лацкова – Зора (1899-1988), писателка; Щефан Кърчмери (1892-1955), литературен критик, историк и поет; Юр Тесак Мошовски, бароков драматург; и Милослав Шмид, основателят на аматьорската противопожарна служба в Словакия.

Все пак, вероятно най-важната личност родена в Мошовце е великият
славянски поет, философ, и лутерански проповедник, Ян Колар (1793-1852), който е повлиял до голяма степен литературата през последните две поколения с неговата поетична композиция Дъщерята на Славянина. Неговата творба е смятана за основа или мотив за съвременните словашки патриоти и националисти. Преведена е на различни славянски, както и на много неславянски езици.

Външни препратки

 Официални сайт
 Брожура
 Инфо
 Дриенок

Изгледи

Села в Словакия
Жилински край

redpajama_set_name: RedPajamaWikipedia


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text:
Apoorva Mehta had 20 failed start-ups before Instacart
In four years, Apoorva Mehta has grown Instacart to more than 300 full-time employees and tens of thousands of part-time grocery shoppers.
(Instacart)
By Tracey Lien
Reporting from San Francisco —
The gig: Apoorva Mehta, 30, is the founder and chief executive of San Francisco grocery delivery start-up Instacart. Over the last four years, he has grown the company to more than 300 full-time employees and tens of thousands of part-time grocery shoppers. The start-up offers on-demand and same-day grocery delivery in hundreds of cities in 20 states.
Electrical engineering: Growing up in Canada, Mehta had an avid curiosity in how technology worked. "Everything from atoms, all the way to what you see on a computer when you go to Google.com," Mehta said. "I wanted to learn everything in between." Not knowing what he wanted to do after college, he enrolled in an electrical engineering course at the University of Waterloo.
Bored at Amazon: Mehta spent his post-college years working for technology companies such as Qualcomm and BlackBerry, and even did a stint at a steel factory. His goal was to try a bit of everything to help figure out what he really wanted to do. He eventually moved to Seattle to be a supply chain engineer at Amazon.com, where he developed fulfillment systems to get packages from Amazon's warehouses to customers' doors.
During those years, he learned two things: He liked to build software, and he wanted to be challenged. After two years at Amazon, he felt that he was no longer being challenged. With no other role lined up, he quit his job.
Twenty companies: He spent the next two years putting his learnings into practice. Between leaving Amazon and founding Instacart, Mehta estimates he started 20 companies. He tried building an ad network for social gaming companies. He spent a whole year developing a social network specifically for lawyers. "I knew nothing about these topics, but I liked putting myself in a position where I had to learn about an industry and try to solve problems they may or may not have had," he said. None of the companies worked out.
"After going through all these failures, releasing feature after feature, I realized it wasn't that I couldn't find a product that worked, I just didn't care about the product," Mehta said of the social network for lawyers. "When I went home, I wouldn't think about it because I didn't care about lawyers. I didn't think of what lawyers did day to day."
Which led him to lesson No. 3: solve a real problem you actually care about.
Groceries: With 20 failed start-up ideas under this belt, Mehta put some thought into the problems he experienced day to day. He lived in San Francisco. He didn't own a car. He loved to cook, but he couldn't get the groceries he wanted in his neighborhood.
"It was 2012, people were ordering everything online, meeting people online, watching movies online, yet the one thing everyone has to do every single week — buying groceries — we still do in an archaic way," he said. As soon as he came up with the idea for an on-demand grocery delivery platform, he couldn't stop thinking about it. In less than a month, he'd coded himself a crude version of an app that could be used by people who needed groceries, and a version for those who were shopping in-store for customers. On its first test-run, because Mehta hadn't hired any shoppers yet, he ordered through the app, went to the store and delivered the groceries to himself.
Webvan: The idea of ordering groceries online and having them delivered to your home wasn't new. Webvan, a company founded on that very premise, famously went under during the dotcom bust. But this didn't faze Mehta, who believed that the success of a company rests not only on the quality of the idea but also on timing. "It was very clear to me that the idea was a good one and the time was now for the same reason why Uber and Lyft were finding success," he said.
Smartphones had become ubiquitous, people were comfortable performing transactions over their phones, and the idea of using an app to hire someone to perform a task was fast becoming the norm. "As a result of smartphones, the equation had changed," he said.
Teething troubles: Although Mehta landed on a hot idea and was able to partner with stores such as Whole Foods, Target and Safeway, the expansion of Instacart wasn't without problems. The company was slapped with a class-action lawsuit in 2015, alleging that the workers who shopped for and delivered groceries were misclassified as independent contractors. Instacart eventually made its shoppers part-time employees, with some qualifying for benefits such as health insurance. "We went from having zero part-time employees to having people at thousands of individual store locations," he said, "We had to figure out scheduling and what kinds of training had to be provided. We needed to figure out a lot of things."
Advice: Most start-ups fail, and those who start a company for the sake of starting a company are even more likely to fail, Mehta said. "The reason to start a company is to bring a change that you strongly believe in to this world," he said. "You really have to want to do this."
Personal: Mehta lives in San Francisco. He's an avid reader and enjoys biking in the city.
tracey.lien@latimes.com
Twitter: @traceylien
Directors Guild of America ratifies new contract boosting streaming residuals
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Former DreamWorks Chief Jeffrey Katzenberg raises nearly $600 million for his next act
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Tracey Lien
Tracey Lien covered Silicon Valley and the technology industry for The Times' business section before leaving in 2018 to pursue her MFA at the University of Kansas. A Sydney native, she came to the U.S. because the servings are bigger. She enjoys perpetuating lies about Australian animals, specifically drop bears and boxing kangaroos.
Google abuses its power over start-ups, Sonos CEO tells Congress
At a House of Representatives antitrust hearing, Sonos CEO Patrick Spence said Google and Amazon are "using their gatekeeper power in abusive and coercive ways"
Microsoft to invest $1 billion in carbon capture with pledge to go carbon-negative by 2030
Microsoft says reducing emissions won't be enough to stop catastrophic climate change. It's investing in efforts to pull carbon out of the atmosphere.
Microsoft pledges $250 million more for Seattle-area affordable housing
The region's affordable-housing gap is growing, not shrinking, Microsoft noted, although last year it grew more slowly than before.
Commentary: Google is enhancing privacy and maybe its own power at the same time
Google's decision on cookies in its Chrome browser will better protect user data but also gives Google a chance to extend its online advertising dominance.
Your $14 salad's not as eco-friendly as advertised — but Sweetgreen's trying
Sweetgreen has long said nothing from its stores goes to landfill. On closer inspection, that's more aspiration than guarantee.
Facebook is piling up patents for its augmented reality push
Facebook has been racking up patents at an accelerating rate, with a large number that highlight the company's big ambitions around augmented reality.
Grindr, Tinder and OkCupid apps share personal data, group finds
Popular dating apps share users' information — including sexual orientation — with ad-tech firms, a report says. That raises questions about how they're tackling California's new privacy law.
Google to end third-party ad-targeting cookies in Chrome browser
Google says it plans to "render obsolete" a key tool advertisers use to track people around the web, following Apple and Mozilla's similar moves.
NSA discovers security flaw in Microsoft Windows
The National Security Agency alerted Microsoft about a Windows vulnerability — an unusual step for the agency, which said it wants to build trust.


This past Monday I got those first hints of a cold coming on. I hate the whole "treat the symptoms" thing, so I immediately went on the offensive to strengthen my immune system and flush out an invaders. It was a three pronged attack: echinacea and peppermint teas, Neti pot, and a couple days of (marginal) rest. I say marginal because while I didn't go running, I did dig two 4-foot diameter holes for our new trees, and I may have gotten an extra hour of sleep in the three days.
One thing that cannot be reiterated enough regarding echinacea tea: IT IS NOT A TONIC HERB. I hear about people who take echinacea every day for the entire flu season and then wonder why they get sick. If you take echinacea as a tonic you are actually hurting your immune system in the long run. Echinacea essentially revs up the immune system, so it is effective when taken at the first hint of illness, but taken over a long period of time it will eventually "wear out" the immune system and lead to a crash in your body's ability to protect itself. So never take echinacea as a preventive measure, that's what vitamin packed foods and moderate exercise are for.
Previously, I didn't bother with the Neti pot until the end of a cold in an attempt to help it go away faster. Only recently did I come to understand the preventive nature of the Neti pot in helping to rinse away any viruses in the sinuses to sort of reduce the load on the immune system. Apparently some people do that every day. That seems a little excessive to me, and maybe unhealthy actually. If a healthy immune system is partially developed from successfully fighting off the multitude of invaders that we are exposed to on a daily basis, than wouldn't using a Neti pot every single day be a crutch? Akin to my father's admonition not to wear an ankle brace on an uninjured ankle because then the muscle gets weak and is more prone to injury. Using it as a preventive measure at the first sign of a cold does make sense to me, though, and at least in this case it worked. In one day I went from congested to clear, and now I actually feel better than I had in about a week.


Men's Blue Diamond Band in Stainless Steel, 6MM. . From gold, silver, and black wedding rings for that special day, or fashionable rings for every other day, .
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You searched for: mens blue diamond wedding band!. Black Tungsten Ring Step Edge Brushed Comfort Fit Classic Wedding Band Anniversary band Ring Art .
Reminiscent of the sun reflecting off of the ocean, our blue diamonds glitter like no other. They have been hand set into the finest gold and diamond settings to .
On your wedding day, express your love for him with this elegant band. Created in bold black ion-plated stainless steel, this 8.0mm-wide band features a long .
Honor your non-traditional husband with a non-traditional wedding band. Created in bold black ion-plated stainless steel, this 6.0mm side band shimmers with a .
Your Men will say "I DO" to this Black Gold Blue Diamonds Mens Wedding Band, The blue diamonds are setting on both sides.


This Abu Dhabi and Sri Lanka twin centre really captures the essence of two contrasting, yet equally fascinating cultures. Experience the buzz of Abu Dhabi, the capital of the United Arab Emirates, and explore its futuristic architecture, huge shopping malls and famous Sheikh Zayed Mosque.
Once in Sri Lanka, let the natural beauty take hold of you. This large and diverse island is a haven for wildlife enthusiasts, culture vultures and those simply wanting to laze around the pool or on one of its spectacular golden beaches.
Abu Dhabi, the capital of the UAE is the largest of the seven emirates. This beautiful, modern city features spectacular skyscrapers interspersed with vibrant parks and gardens. The sublime climate of Abu Dhabi is perfect for visitors wanting to explore its stunning array of attractions, with the cultural zone of Saadiyat Island a particular highlight.
Set on the breathtaking Yas Island between Dubai and the coast of Abu Dhabi, the luxurious Yas Hotel Abu Dhabi five star resort offers a total of 499 suites and rooms packed with modern conveniences.
Sri Lanka is a destination of immense scenic beauty with evergreen rainforests, ancient Buddhist ruins, iconic palaces, impressive architecture and beautiful sandy beaches. Experience the abundance of wildlife available within this unusual island country.