Background

ABACUS is a phase II single-arm study that evaluated the safety and efficacy of neoadjuvant atezolizumab in patients with muscle-invasive bladder cancer (MIBC) awaiting radical cystectomy (RC).

Methods

This single arm, phase II study investigated two cycles of atezolizumab (1200mg given every 3 weeks) prior to RC in MIBC(T2-4aN0M0) (NCT02662309). The study included patients who were ineligible or refused neoadjuvant cisplatin-based chemotherapy and had transitional cell histology. Pathological complete response (pCR) was the primary endpoint. Adverse events (AEs) and surgical complications were assessed using CTCAE v4.03 and the Clavien-Dindo classification.

Results

At data cut off (July 10, 2020), the minimum follow-up was 2 years since the last patient underwent surgery. Ninety-five patients received at least one cycle of therapy. Eight patients did not have cystectomy (only one due to disease progression). The pCR rate was 31% (27/88) [95%CI:21%-41%] in the treated population, meeting the primary endpoint of the study, and was 37% (13/35) [95%CI: 21-55%] in the PD-L1 positive population. 23% (20/88) patients had disease recurrence or died due to cancer-related causes. One patient with pCR presented recurrent disease. 24-month relapse-free (RFS) and overall survival rates for the 88 patients who underwent radical cystectomy were 77% (95%CI, 67-85%) and 82% (95%CI, 72-88%), respectively. Median relapse-free and overall survival were both not reached. There were no new safety signals or significant surgical complications. Survival was associated with high CD39/CD8, T effector signature PD-L1 and low fibroblast activation protein (FAP).

Conclusions

Neoadjuvant atezolizumab in patient with MIBC who were ineligible or refused neoadjuvant cisplatin-based chemotherapy confers meaningful clinical responses and is associated with high rates of relapse-free and overall survival. Baseline CD8+ T cells, CD39 expression on tumor infiltrating CD8+ T cells and post-treatment FAP correlated with RFS.

Clinical trial identification

NCT02662309.

Legal entity responsible for the study

Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London.

Funding

Roche.

Disclosure

All authors have declared no conflicts of interest.

Background

At the first preplanned interim analysis (median follow-up [defined as time from randomization to data cutoff], 14.2 mo) of the randomized phase III KEYNOTE-426 trial (NCT02853331), first-line pembro + axi vs sunitinib significantly prolonged OS, PFS, and ORR in patients (pts) with mRCC, resulting in pembro + axi becoming a standard of care. After a median 30.6 mo of follow-up, pembro + axi showed continued superior efficacy to sunitinib. Outcomes are presented in pts from KEYNOTE-426 who were enrolled from Eastern Asia.

Methods

Pts with clear cell mRCC and Karnofsky Performance Status score ≥70% were randomly assigned 1:1 to receive pembro 200 mg IV Q3W (maximum 35 cycles) + axi 5 mg PO BID or sunitinib 50 mg PO QD (4 wk on/2 wk off) until disease progression, unacceptable toxicity, death, or study withdrawal. Primary end points were OS and PFS (RECIST v1.1). Secondary end points were ORR and safety.

Results

Of 130 pts enrolled in Eastern Asia (pembro + axi: 62, sunitinib: 68), 44 (71.0%) and 58 (86.6%) treated with pembro + axi and sunitinib, respectively, discontinued. Median follow-up was 29.8 mo (range, 24.6-37.7) for pembro + axi and 29.9 mo (24.6-37.9) for sunitinib. Median OS (95% CI) was not reached in the pembro + axi and sunitinib groups (HR, 0.71; 95% CI, 0.38-1.31; 24-mo rate, 77.4% and 67.6%, respectively). Median PFS (95%CI) was 18.0 mo (12.5-23.5) with pembro + axi and 10.0 mo (7.1-15.0) with sunitinib (HR, 0.59; 95% CI, 0.37-0.93; 24-mo rate, 33.7% and 18.7%, respectively). ORR was 64.5% with pembro + axi and 44.1% with sunitinib; 14.5% and 5.9% of patients in the respective groups exhibited CR. Five (8.1%) and 33 (48.5%) pts in the pembro + axi and sunitinib groups, respectively, received a PD-1/PD-L1 inhibitor as subsequent therapy; 28 (45.2%) and 36 (52.9%), respectively, received a subsequent VEGF/VEGFR inhibitor. Grade 3-5 treatment-related adverse events occurred in 43 (69.4%) and 50 (74.6%) pts in the pembro + axi and sunitinib groups, respectively.

Conclusions

In KEYNOTE-426, in pts who enrolled in East Asia, treatment benefit and tolerability profile of pembro + axi compared to sunitinib were similar to what was observed in the global study population.

Clinical trial identification

NCT02853331; August 2, 2016.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

S. Tamada: Speaker Bureau/Expert testimony: MSD. G. Kimura: Honoraria (self): Ono, BMS, Novartis, Pfizer, Bayer, Chugai, MSD; Research grant/Funding (institution): Ono/BMS, Bayer, Chugai, MSD, Astellas, AstraZeneca, Taiho. J. Lin, R. Perini: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc. L.R. Molife: Shareholder/Stockholder/Stock options, Full/Part-time employment: MSD. T.B. Powles: Honoraria (self): BMS, Seattle Genetics, Ipsen, Merck, MSD, Novartis, Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca, Roche; Advisory/Consultancy: AstraZeneca, BMS, Exelexis, Incyte, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics. B. Rini: Advisory/Consultancy: Merck, Roche, Pfizer, AVEO, BMS, Arravive, 3D Medicines, Synthorx, Surface Oncology, Alkermes; Shareholder/Stockholder/Stock options: PTC Therapeutics; Travel/Accommodation/Expenses: Merck, BMS, Pfizer; Research grant/Funding (institution): Merck, Roche, Pfizer, AVEO, BMS, AstraZeneca. All other authors have declared no conflicts of interest.

Background

Pembro had antitumor activity as monotherapy in patients (pts) with mCRPC. KEYNOTE-365 (NCT02861573) evaluated safety and efficacy of pembro as combination therapy in pts with mCRPC. Findings for cohorts A, B, and C are reported with extended follow-up.

Methods

In this nonrandomized, multicohort, open-label phase Ib/II trial, pts with mCRPC were administered pembro (200 mg IV Q3W) in combination with olaparib (400-mg capsule or 300-mg tablet BID) if pretreated with docetaxel (cohort A); docetaxel (75 mg/m² IV Q3W) + prednisone (5 mg orally BID) if pretreated with abiraterone acetate or enzalutamide (enza; cohort B); or enza (160 mg/day orally) if pretreated with abiraterone acetate (cohort C). Primary end points: PSA response rate (confirmed PSA decrease ≥50%), ORR by blinded independent central review and safety.

Results

With a database cutoff of June 24, 2019, 84 (cohort A), 104 (cohort B), and 102 (cohort C) pts began treatment; median time from enrollment to data cutoff was 3.6, 19.9, and 19.1 mo, respectively; for pts with ≥27 wk of follow-up, it was 26.7, 21.8, and 21.4 mo. PSA response occurred in 9%, 28%, and 22% of pts in cohorts A, B, and C, respectively. ORR per RECIST v1.1 in pts with measurable disease and ≥27 wk of follow-up was 8% (2 PR), 18% (7 PR), and 12% (2 CR, 1 PR) for cohorts A, B, and C, respectively. Median rPFS was 4.3, 8.3, and 6.1 mo and median OS was 14.4, 20.4, and 20.4 mo in cohorts A, B, and C, respectively. Additional analyses are displayed in the table. In cohorts A, B, and C, grade ≥3 treatment-related adverse events (TRAEs) occurred in 35%, 40%, and 39% of pts, respectively. Two pts in cohort A (1 myocardial infarction, 1 cause unknown), 2 in cohort B (pneumonitis), and 1 in cohort C (cause unknown) died of TRAEs.

Conclusions

All 3 pembro combinations had antitumor activity against mCRPC, with a tolerability profile consistent with individual profiles of each agent. Phase III studies of these combinations is ongoing. Table: 217O

Efficacy outcomes

Clinical trial identification

NCT02861573, August 10, 2016.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

A.M. Joshua: Research grant/Funding (self): Bristol-Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Aptevo Therapeutics, Mayne Pharma, Roche/Genentech, Bayer, Macrogenics, Lilly. H. Gurney: Advisory/Consultancy: BMS, MSD, Pfizer, AstraZeneca, Ipsen, Roche. P.C.C. Fong: Advisory/Consultancy: MSD, Pfizer; Travel/Accommodation/Expenses: Pfizer. N.D. Shore: Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen, Astellas, AstraZeneca, Bayer, BMS, Dendreon, Ferring, Fergene, Janssen, Merck, MDxHealth, Myovant, Nymox, Pfizer, Sanofi-Genzyme, Tolmar; Speaker Bureau/Expert testimony: Bayer, Janssen, Pfizer, Astellas. E. Romano: Research grant/Funding (self): BMS, AZ; Travel/Accommodation/Expenses: AZ, Merck/MSD, Roche. M. Augustin: Advisory/Consultancy: Bristol-Myers Squibb, MSD, Pfizer, PharmaMar, Ipsen, AstraZeneca; Travel/Accommodation/Expenses: Lilly, Novartis, Bristol-Myers Squibb, PharmaMar, Ipsen; Research grant/Funding (institution): Bristol-Myers Squibb, MSD, Morphosys, AstraZeneca, Pfizer, PharmaMar. J.M. Piulats: Advisory/Consultancy: Roche, Novartis, Jansen, Astellas, Bayer, Sanofy-Genzyme, MSD, BMS, Merk-Serono, Clovis, AstraZeneca, Beigene, VCN Biotech; Research grant/Funding (self): Roche, Jansen, Astellas, MSD, BMS, Merk Serono, AstraZeneca, Beigene, VCN Biotech; Travel/Accommodation/Expenses: Roche, Astellas, Jansen. W.R. Berry: Research grant/Funding (self): Merck, Pfizer; Advisory/Consultancy: Pfizer, Genomic Health. M.P. Kolinsky: Honoraria (self): Janssen, Astellas, Bayer; Advisory/Consultancy: Janssen, Ipsen, BMS, AZ, Merck; Travel/Accommodation/Expenses: Novartis. S.S. Sridhar: Advisory/Consultancy: Merck, Pfizer, Roche, BMS, Janssen, Astellas, AstraZeneca, Bayer. H.J. Conter: Full/Part-time employment: Hoffman-La Roche Canada; Advisory/Consultancy: Janssen, Roche; Travel/Accommodation/Expenses: Bayer. T. Todenhöfer: Advisory/Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Roche, Sanofi. L.J. Appleman: Research grant/Funding (institution): Acerta, Agensys, Astellas, Aveo, Bayer, Bristol-Myers Squibb, Calithera, Esai, Exelixis, Genentech, Inovio, Novartis, Eli Lilly, Merck, Peloton, Tokai. H. Wu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. C. Schloss: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc. C.H. Poehlein: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc. J.S. de Bono: Advisory/Consultancy: AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystem, Daiichi Sankyo, Sierra Oncology, Bayer, Merck Sharp & Dohme, Merck Serono, Boehringer Ingelheim, Celgene, Taiho Pharmaceuticals, Genmab, GlaxoSmit; Research grant/Funding (self): AstraZeneca, Genentech, Sanofi, Taiho Pharmaceuticals, Daiichi Sankyo, Merck Serono, Astex Pharmaceuticals, Merck Sharp & Dohme, Orion Pharma, GlaxoSmithKline, Cellcentric, Celgene, Sierra Oncology, Bayer, MedImmune, Medivation, Terumo, Astellas Pharma, G. E.Y. Yu: Honoraria (institution): AbbVie, Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Clovis, Dendreon, EMD Serono, Incyte, Janssen, Merck, Pharmacyclics, QED, Sanofi Genzyme, Seattle Genetics, Tolmar; Advisory/Consultancy: AbbVie, Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Clovis, Dendreon, EMD Serono, Incyte, Janssen, Merck, Pharmacyclics, QED, Sanofi Genzyme, Seattle Genetics, Tolmar; Research grant/Funding (institution): Daiichi-Sankyo, Dendreon, Merck, Pharmacyclics, Seattle Genetics, Taiho. All other authors have declared no conflicts of interest.