Background

In the Phase III MONALEESA-7 trial (NCT02278120), RIB + NSAI/tamoxifen (TAM) + goserelin (GOS) prolonged progression-free survival (PFS) vs placebo (PBO) + NSAI/TAM + GOS in premenopausal patients (pts) with HR+, HER2– ABC. RIB benefit was observed irrespective of endocrine therapy (ET) partner (NSAI or TAM). Here we report a preplanned analysis from a subset of Asian pts, with a focus on pts who received RIB + NSAI + GOS.

Methods

Premenopausal pts (≤1 line of prior chemotherapy; no prior ET for ABC) received RIB or PBO + NSAI (letrozole or anastrozole)/TAM + GOS. Primary endpoint: PFS, with a prespecified subset analysis in pts of Asian race. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), and safety.

Results

198 pts were of Asian race (RIB 99 vs PBO 99); of which, 166 received NSAI (82 vs 84). 474 pts were of non-Asian race; of which, 329 pts received NSAI (166 vs 163). As of Aug 20, 2017, among pts of Asian race, 48 pts in the RIB + NSAI arm vs 26 pts in the PBO + NSAI arm and 83 vs 67 pts of non-Asian race were still receiving treatment; the most common reason for discontinuation was disease progression (Asian: 27 vs 49; non-Asian 61 vs 76). Consistent PFS benefit for RIB + NSAI vs PBO + NSAI was observed in Asian and non-Asian pts (Table). ORR and CBR were higher for RIB + NSAI vs PBO + NSAI in Asian and non-Asian pts with measurable disease. The most common (≥5% in either arm) Grade 3 and 4 adverse events are shown in the table. New Fridericia’s corrected QT interval >500 ms occurred in (RIB + NSAI vs PBO + NSAI) 3.8% vs 0% of Asian pts and 0.6% vs 0% of non-Asian pts.Table: 39O

Conclusions

Consistent treatment benefit with RIB + NSAI + GOS was observed in pts of Asian and non-Asian race. The safety profile was manageable, irrespective of race, and was consistent with that observed in the full population.

Editorial acknowledgement

Editorial assistance was provided by Kate Gaffey, PhD of ArticulateScience Ltd.

Clinical trial identification

NCT02278120.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

S-A. Im: Advisory role: Novartis; Grants: AstraZeneca; Advisory role: Hanmi, Roche, Pfizer. D. Tripathy: Grants, personal fees: Novartis; Personal fees: Pfizer. L. Chow: Travel expenses: Novartis, Roche, Pfizer. N. El Saghir: Honorarium for lectures and advisory boards: Novartis, Pfizer, Lilly. M-C. Liu: Advisory board: Pfizer, Roche, Novartis; Travel fee: International Congress on Clinical Trials in Hemto-Oncology. I. Diaz-Padilla, O. Kong, M. Miller: Employee, stock holder: Novartis. J. Alam: Employee: Novartis. All other authors have declared no conflicts of interest.

Background

TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al., NEJM 2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19^th Feb 2018.

Methods

Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1.

Results

As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median DoR and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients.

Conclusions

TRK fusion cancer is detected in a broad range of tumor types. Larotrectinib is an effective tumor-agnostic treatment for TRK fusion cancer with a favorable safety profile. Screening patients for NTRK gene fusions in solid tumors should be actively considered.

Clinical trial identification

NCT02122913; NCT02637687; NCT02576431.

Legal entity responsible for the study

Loxo Oncology Inc and Bayer AG.

Funding

Loxo Oncology Inc; Bayer AG.

Disclosure

S. Cruickshank, N.C. Ku, M.C. Cox: Employment: Loxo Oncology Inc. All other authors have declared no conflicts of interest.

Background

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions lead to the transcription of chimeric TRK proteins with overexpressed kinase function; this confers oncogenic potential across several tumor types. Entrectinib is a central nervous system (CNS)-active, potent inhibitor of TRKA/B/C and ROS1. We show integrated efficacy and safety analyses from entrectinib clinical trials.

Methods

Patients (pts) with locally advanced/metastatic NTRK-fusion positive (fp) tumors confirmed by nucleic acid-based methods and enrolled in global (>150 sites, 15 countries) phase 1/2 entrectinib trials (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) were included. Tumors were assessed after cycle 1 (4 wk) then every 8 wk. Scans underwent blinded independent central review (BICR) using RECISTv1.1. Primary endpoints: overall response rate (ORR); duration of response (DOR) by BICR. Secondary endpoints: progression-free survival (PFS), overall survival (OS) in pts with and without baseline CNS disease; safety.

Results

The efficacy-evaluable population comprises 54 adult pts with advanced/metastatic NTRK-fp solid tumors (10 tumor types, >19 histopathologies), including pts with baseline CNS metastases. After 15.5 mo follow-up, BICR ORR was 57.4% (95% CI 43.2–70.8), complete responses n = 4 (7.4%); responses seen in all tumor types. Median BICR DOR: 10.4 mo (95% CI 7.1–NR); median BICR PFS: 11.2 mo (95% CI 8.0–14.9); median OS: 20.9 mo (95% CI 14.9–NR). Per baseline CNS status (investigator assessed), median BICR PFS was 12.0 mo (95% CI 8.7–15.7) and 7.7 mo (95% CI 4.7–NR) for patients without (n = 42) and with CNS disease (n = 12), respectively. In the safety population (355 pts who received entrectinib across clinical trials), most treatment-related AEs were grade 1–2 and managed with dose reduction (27.3%); few pts discontinued (3.9%) due to treatment-related AEs.

Conclusions

In this multicenter, pooled analysis of global clinical trials, entrectinib was well tolerated overall and induced clinically meaningful, durable systemic responses in pts with NTRK-fp solid tumors, type agnostic, with and without CNS disease.

Editorial acknowledgement

Charlotte Kennerley at Gardiner Caldwell Communications.

Clinical trial identification

EudraCT 2012-000148-88; NCT02097810; NCT02568267.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.

Disclosure

G.D. Demetri: Advisory board or board of directors: Blueprint Medicines, Merrimack Pharmaceuticals, G1 Therapeutics, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals. A.F. Farago: Corporate sponsored research: Research funding (to institution): Ignyta, Loxo Oncology, AbbVie, AbbVie/Stemcentrx, Pharmamar, AstraZeneca, Novartis, Merck, BMS. S.V. Liu: Advisory board or board of directors: Ignyta, Genentech, Pfizer, Takeda, Celgene, Lilly, Taiho, Bristol-Myers Squibb, AstraZeneca. C.M. Blakely: Corporate sponsored research: Ignyta, Mirati, Novartis, Medimmune, Clovis. B. Besse: Corporate sponsored research: AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, Onxeo, OncoMed, Inivata, OSE Pharma, Loxo. J. Wolf: Corporate sponsored research: BMS, MSD, Novartis, Pfizer. T. Seto: Corporate sponsored research: Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd, Chugai Pharmaceutical Co., Ltd. Daiichi Sankyo Co. Ltd., Eisai Co., Ltd. E. Chow-Maneval, P.S. Multani: Employment at Ignyta A. Johnson: Corporate sponsored research: Ignyta. R.C. Doebele: Corporate sponsored research: Ignyta; Patent or Biological material licensing fees: Ignyta, Abbott Molecular, Rain Therapeutics. All other authors have declared no conflicts of interest.

Background

Despite the known association between MMR loss and Lynch syndrome (LS), data on EC is sparse; the degree of association is unknown as are the implications in term of prognosis and survival.

Methods

Descriptive analysis of 396 tumour samples of patients (pts), treated between Jan 2012 to Jan 2018, MMR proteins were tested by immunohistochemistry. Median follow up time was 23.2 months. Tumours with loss of at least one protein were considered MMR(d). Patient characteristics were recorded from our electronic records. Survival was assessed by Kaplan Mayer and log-rank test.

Results

29% (114) tumours were deemed MMRd. Predominant histological subtype was endometrioid, high grade serous (HGS) including carcinosarcoma and clear cell. The most common somatic loss was MLH1-PMS2 (69%). 41% (47 pts) underwent germline testing for LS, 13pts (27.6%) were diagnosed with LS, association rate was PMS2 (100%), MSH6 (87.5%) and MSH2 MHS6 (40%). Our data suggest a non-significant differential survival between MMR proficient (p) and MMRd tumours (OS 116 months vs 82.9 months p0.756).

Conclusions

Almost 30% of unselected EC pts have somatic loss MMR proteins; 27% of patients have a germline mutation that is more commonly associated with loss of PMS2, MSH6 and MSH2 MSH6, and endometrioid histology. Differences in survival between MMRp and MMRd tumours need to be further investigated.Table: 252O

Patient characteristics

Legal entity responsible for the study

Royal Marsden NHS Foundation Trust.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.