Background

As treatment outcomes for mTNBC are poor, new treatment options are needed. We present a subgroup analysis for the safety and antitumor activity of pembrolizumab (PEM) as a therapy for Japanese patients (pts) with mTNBC in Cohorts A and B of KEYNOTE 086.

Methods

Pts with centrally confirmed mTNBC, at least one systemic treatment (Cohort A) or no prior systemic therapy (Cohort B) for metastatic disease, ECOG PS 0-1, and regardless of tumor PD-L1 expression (Cohort A) or with a tumor PD-L1 combined positive score (CPS) ≥1% (Cohort B), received PEM 200 mg IV every 3 weeks (wk) for 24 months (m) or until disease progression, intolerable toxicity, or investigator or patient (pt) decision. Tumor imaging was performed Q9W for 12 m and Q12W thereafter. Clinically stable pts with PD could remain on PEM until PD was confirmed on subsequent assessment. Primary endpoints were ORR (RECIST, central review) in Cohort A and safety in Cohorts A and B. Secondary were ORR in Cohort B, disease control rate (CR + PR + SD ≥ 24 wk), PFS and OS in Cohorts A and B.

Results

Of 20 pts in Cohort A, 12 had PD-L1 (+) tumors and 8 had PD-L1 (-) tumors. The median age was 53.5 y, 11 pts had elevated LDH and 13 pts had visceral metastases. Of 9 pts in Cohort B, median age was 38.0 y, 1 pt had elevated LDH, 5 pts had visceral metastases. As of Nov 10, 2016, the best overall response was PR in 1 pt and SD in 2 pts in Cohort A, and CR in 1 pt and SD in 2 pts in Cohort B. Median PFS was 2.0 m (95% CI, 1.7 – 2.1) in Cohort A, and 2.1 m (95% CI, 1.6 – 4.2) in Cohort B. Median OS was 8.3 m (95% CI, 4.6 – 10.3) in Cohort A, and was not reached in Cohort B. Drug-related AEs (DRAEs) occurred in 20 pts (67.0%) in Cohorts A and B; the most common DRAEs were pruritus (4 pts), fatigue, pyrexia, anemia, rash, and diarrhea (3 pts each). Grade (Gr) 3-4 DRAEs were diarrhea, nausea, and bacteraemia (1 pt each), all in Cohort A. Infusion reaction (1 pt, Gr 2), interstitial lung disease (1 pt, Gr 1), hypersensitivity (1 pt, Gr 2) and hyperthyroidism (1 pt, Gr 1) were seen as irAE. No pts died or discontinued PEM due to AEs.

Conclusions

Data from 29 Japanese pts in Cohorts A and B suggest that PEM monotherapy has a well tolerated safety profile and anti-tumor activity which are similar to those reported in the overall populations.

Clinical trial identification

NCT02447003.

Legal entity responsible for the study

Merck & Co., Inc., Kenilworth, NJ, USA

Funding

Merck & Co., Inc., Kenilworth, NJ, USA

Disclosure

H. Mukai: Received personal fees as honoraria from AstraZeneca, Novartis Pharma, Daiichi Sankyo, and Taiho Pharmaceutical, and received research funds from Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Nippon Kayaku, Novartis Pharma, Pfizer Japan, and MSD.K.K. N. Masuda: Honoraria: Chugai, Astrazeneca. H. Ishiguro: Advisory board: MSD.K.K. T. Shimamoto, K. Yamamoto: Employees of MSD.K.K. Y. Ding, G. Aktan, V. Karantza: Employees of Merck

All other authors have declared no conflicts of interest.

Background

MONALEESASIA is an ongoing Phase Ib dose-escalation/-expansion study evaluating RIB + LET in a subset of Asian pts from Hong Kong and Singapore with HR+, HER2–ABC.

Methods

Postmenopausal pts from Hong Kong and Singapore with HR+, HER2– ABC and no prior systemic therapy for ABC received RIB (400 or 600 mg/day; 3-weeks-on/1-week-off) + LET (2.5 mg/day; continuous). Dose escalation used a Bayesian Logistic Regression Model with overdose control. The primary endpoint was to determine the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D); secondary endpoints included safety and pharmacokinetic (PK) profile. Blood samples for PK non-compartmental analysis were collected on Days 1 and 21 of Cycle 1 from pre-dose to 24 h post-dose.

Results

At data cut-off (Jan 16, 2017), 26 pts were enrolled (RIB 400 mg: n = 6; 600 mg: n = 20). One dose-limiting toxicity was observed at 600 mg (Grade 3 increased alanine transaminase [ALT]); the MTD/RP2D was RIB 600 mg/day (3-weeks-on/1-week-off) + LET 2.5 mg/day (continuous). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 4/6 pts at 400 mg and 17/20 pts at 600 mg during the dose-escalation and -expansion parts. The most common Grade 3/4 TRAEs (≥20% in either cohort; 400 mg vs 600 mg) were decreased neutrophil count (n = 3 vs n = 7), neutropenia (n = 1 vs n = 6), increased ALT (n = 1 vs n = 4), and increased aspartate transaminase (n = 0 vs n = 4). After a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21), absorption of both RIB and LET was rapid (Table); increases in RIB exposure were dose dependent.

Conclusions

The MTD/RP2D was declared as RIB 600 mg/day (3-weeks-on/1-week-off) + LET 2.5 mg/day (continuous) in Asian pts from Hong Kong and Singapore with HR+, HER2– ABC. Preliminary safety and PK data are consistent with prior observations in non-Asian pts.

Clinical trial identification

CLEE011A2115C/NCT02333370.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation

Funding

Novartis Pharmaceuticals Corporation

Disclosure

Y-S. Yap: Received honoraria and provided consultancy for Novartis. Y. Ito: Yoshinori Ito reports grants from MSD, AstraZeneca, Novartis, Parexel, Chugai, and Lilly. O. Bornstein: Orna Bornstein is an employee of Novartis Pharmaceuticals Corporation. Y. Han: Yu Han is an employee at Novartis Pharmaceuticals Corporation. T. Samant: Tanay Samant is an employee of Novartis Pharmaceuticals Corporation and owns stocks/shares in Novartis Pharmaceuticals Corporation. X. Liu: Xiaochun Liu is an employee of Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharmaceuticals Corporation. J. Chiu: Dr. Chiu served on advisory boards for Novartis and Pfizer.Table: 94O

Summary of RIB and LET PK profiles

Background

The efficacy and tolerability of palbociclib (P) + endocrine therapy (ET) in ABC patients (pts) was previously established; here, we report results in the Asia-Pacific (AP) region (Australia, Japan, Korea, Taiwan).

Methods

In PALOMA-2, postmenopausal women untreated for their HR+/HER2- ABC were randomized 2:1 to P (125 mg/d [3/1 schedule]) + letrozole (L; 2.5 mg/d) or placebo (PB)+L. In PALOMA-3, women of any menopausal status with HR+/HER2- ABC, whose disease had progressed after previous ET, were randomized 2:1 to P + fulvestrant (F; 500 mg) or PB+F.

Results

Of 666 PALOMA-2 pts, 92 (14%) were from the AP region (P+L, 64; PB+L, 28). Baseline characteristics: median age (61 y) younger than overall population; white (20%), Asian (79%); ≥2 disease sites (70%); visceral disease (59%); prior (neo)adjuvant ET (64%); disease-free interval >12 months since prior (neo)adjuvant therapy (58%). Median PFS (mPFS): 22 mo (95% CI, 19-26) for P+L vs 14 mo (7-22) for PB+L (HR, 0.49; 1-sided P=0.007). All-grade treatment-emergent adverse events (TEAEs) (P+L/PB+L) occurred in 100%/96% of pts; the most common AE in the P+L arm was neutropenia (91%). 55% of P+L pts required a dose reduction due to AEs. Of 521 PALOMA-3 pts, 114 (22%) were from the AP region (P+F, 78; PB+F, 36). Baseline characteristics: younger (median age 53 y) and more premenopausal pts (38%) vs overall population; white (23%), Asian (75%); ≥2 disease sites (66%); visceral disease (57%); prior ET (100%); prior chemotherapy for ABC (70%). mPFS: 13 mo (95% CI, 9-16) for P+F vs 6 (4-9) for PB+F (HR, 0.51; 1-sided P=0.002). All-grade TEAEs (P+F/PB+F) occurred in 100%/92% of pts; the most common AE in the P+F arm was neutropenia (95%). 51% of P+F pts required a dose reduction due to AEs.

Conclusions

Because PALOMA-2 only enrolled postmenopausal pts and percentages of premenopausal pts in AP vs other regions was higher, the proportion of AP pts was higher in PALOMA-3 vs -2. P+ET showed clinically meaningful improvement in mPFS vs PB+ET and a tolerable safety profile in AP pts with HR+/HER2- ABC in the 1^st-line and later-lines of therapy, regardless of menopausal status.

Clinical trial identification

Pfizer (NCT01740427; NCT01942135).

Legal entity responsible for the study

Pfizer Inc

Funding

Pfizer Inc.

Disclosure

S-A. Im: Consulting or advisory role for AstraZeneca, Novartis, Hanmi Corp, and Spectrum, N. Masuda: Honoraria from Chugai and AstraZeneca, K. Inoue: Research funding from Pfizer, Lilly, Chugai, Daiichi-Sankyo, Taiho, MSD, Parexel (Puma), S-B. Kim: Research funding from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, and Dongkook Pharma Co., Ltd. A. Redfern: Advisory board for Pfizer Australia, J. Lombard: Honoraria from Roche and AstraZeneca, D. Lu, K. Puyana Theall, E.G. Gauthier: Employee and owns stock in Pfizer, H. Mukai: Honoraria from AstraZeneca, Eisai, Novartis Pharma and Taiho Pharmaceutical, and received research funds from Chugai Pharmaceutical, Nippon Kayaku, Novartis Pharma, Pfizer Japan, and Sanofi

All other authors have declared no conflicts of interest.

Background

MONARCH 2 demonstrated that the addition of abemaciclib, a CDK4 & 6 inhibitor dosed on a continuous schedule, to fulvestrant (F) significantly improved progression-free survival (PFS) and objective response rate (ORR) compared to placebo (P) plus F (PFS hazard ratio [HR], 0.553, P<.0000001; ORR in measurable disease 48.1% vs 21.3%, P<.001) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who had progressed on endocrine therapy (ET).

Methods

MONARCH 2 is a Phase 3 double-blind trial of abemaciclib + F vs P + F in women with HR+, HER2- advanced breast cancer. Women who progressed on (neo)adjuvant endocrine therapy (ET), ≤12 m from end of adjuvant ET, or on first line ET for MBC and who had not received chemotherapy for metastatic disease were eligible; pre/perimenopausal pts received a gonadotropin-releasing hormone agonist. Pts were randomized 2:1 to receive abemaciclib at 150 mg Q12H (or 200 mg prior to amendment) or P plus F (500 mg, per label) and stratified by metastatic site (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). We present the primary objective of investigator-assessed progression-free survival (PFS), and secondary efficacy and safety endpoints in Asian pts.

Results

214 Asian pts were randomized to abemaciclib plus F (N = 149) and to P plus F (N = 65). In the ITT population, 122 PFS events were observed with a median PFS of 22.8 m for abemaciclib plus F and 11.6 m for P + F (HR: 0.515; 95% CI: 0.359, 0.740, P<.001 by log-rank test). In pts with measurable disease (n = 170, 79.4%), the ORR was significantly higher in abemaciclib plus F 48% (2.4% complete response [CR]) vs 23.4% (0% CR) for P plus F, P=.004. The most frequent adverse events for abemaciclib plus F vs P plus F were diarrhea (90.5% vs 20.0%), neutropenia (68.2% vs 4.6%), nausea (37.8% vs 16.9%), and fatigue (53.8% vs 30.9%).

Conclusions

Abemaciclib + F was an effective treatment in Asian pts with HR+, HER2- advanced breast cancer who progressed on endocrine therapy with significantly improved PFS and ORR. These findings were consistent with the intent-to-treat population in MONARCH 2.

Clinical trial identification

NCT02107703.

Legal entity responsible for the study

Eli Lilly and Company

Funding

Eli Lilly and Company

Disclosure

H. Iwata: Honoraria: Chugai Pharmaceutical, Eisai, AstraZeneca, Novartis, Daiichi Sankyo, Taiho Pharmaceutical. Research funding: GSK, Daiichi Sankyo, Chugai Pharmaceutical, Nippon Kayaku, Novartis, Pfizer, AstraZeneca, Eisai, Eli Lilly, and MSD. J.H. Sohn: Research Funding: AstraZeneca, Eli Lilly, Novartis, Genentech, Pfizer, MSD Oncology, N. Masuda: Honoraria: Chugai Pharma, AstraZeneca Research Funding: Chugai Pharma (Inst), AstraZeneca (Inst), Kyowa-Kirin (Inst), MSD Oncology (Inst), Novartis (Inst), Pfizer (Inst), Eli Lilly (Inst), Y. Lin, S. Sakaguchi, N. Bourayou: Employee of Eli Lilly and Company, A. Llombart: Honoraria: Roche, Novartis, Pfizer Consulting or Advisory Role: Roche, AstraZeneca, Eli Lilly Research Funding: Pfizer, Roche, G. Sledge: Leadership: Syndax Stock or Other Ownership: Syndax Honoraria: Symphogen Consulting or Advisory Role: Symphogen, Coherus Biosciences, Radius Health, Peregrine Pharmaceuticals, Taiho Pharmaceutical Research Funding: Roche (Inst)

All other authors have declared no conflicts of interest.