Background

KEYNOTE-181 (NCT02564263) was an open-label, randomized, phase 3 trial of pembrolizumab (pembro) vs investigator choice of single-agent paclitaxel/docetaxel/irinotecan (chemo) in advanced/metastatic esophageal AC or SCC. Pts were enrolled in partially overlapping periods, initially globally and then in China with an extension period. We present results from the global and China cohorts.

Methods

Pts were randomized 1:1 to receive pembro or chemo. Randomization was stratified by histology (SCC vs AC) and region (Asia vs rest of world). Primary end points were OS in the ITT, SCC, and PD-L1 CPS ≥10 populations.

Results

There were 628 and 123 pts in the global and China cohorts, respectively. In the global cohort, 314 pts were randomized to receive pembro (199 [63%] had SCC; 107 [34%] had CPS ≥10 tumors); 314 pts to chemo (204 [65%] had SCC; 115 [37%] had CPS ≥10 tumors). Median follow-up was 7.1 mo (pembro) vs 6.9 mo (chemo). Median OS with pembro vs chemo was similar in the ITT group (7.1 vs 7.1 mo) and longer in the SCC (8.2 vs 7.1 mo) and CPS ≥10 groups (9.3 vs 6.7 mo). 12-month OS rates were higher with pembro in all groups (ITT 32% vs 24%; SCC 39% vs 25%; CPS ≥10 42% vs 20%). In the China cohort, 62 pts were randomized to pembro (60 had SCC; 25 had CPS ≥10 tumors); and 61 pts to chemo (59 had SCC; 29 had CPS ≥10 tumors). Median follow-up was 8.3 mo (pembro) vs 5.6 mo (chemo). Median OS was higher with pembro in the ITT (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.36-0.82), SCC (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.37-0.83), and CPS ≥10 groups (12.0 vs 5.3 mo; HR 0.34; 95% CI 0.17-0.69). 12-month OS rates were higher with pembro in all groups (ITT 36% vs 17%; SCC 36% vs 16%; CPS ≥10 53% vs 16%). Fewer pts had TRAEs with pembro than chemo (global 64% vs 86%; China 76% vs 83%). TRAE rates resulting in discontinuation with pembro vs chemo were comparable in the global cohort (6% each) and lower with pembro in the China cohort (6% vs 12%).

Conclusions

Pembro and chemo showed comparable OS as 2L therapy for esophageal AC/SCC in the global ITT cohort. Pembro showed favorable OS in SCC and CPS ≥10 groups in the global cohort and in all groups in the China cohort, in which most patients had SCC. Pembro showed favorable safety in both cohorts.

Clinical trial identification

NCT02564263.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Traci Stuve, MA, 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-B. Kim: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi-Aventis; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): DongKook Pharmaceutical. T. Doi: Advisory / Consultancy: Kyowa Hakko Kirin, MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer; Research grant / Funding (institution): Taiho Pharmaceutical, Novartis, Merck Serono, MSD, Boehringer Ingelheim, Pfizer, Lilly Japan, Sumitomo Group, Kyowa Hakko Kirin, Daiichi Sankyo, Bristol-Myers Squibb, AbbVie, Quintiles, Eisai. K. Kato: Research grant / Funding (institution): MSD, ONO Pharmaceutical, Shionogi, Merck Serono. M. Shah: Research grant / Funding (institution): Merck, Roche, Boston Biomedical. A. Adenis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier. T. Kojima: Non-remunerated activity/ies, Other- Patents, Royalties, other Intellectual Property: Ono Pharmaceutical, MSD, Shionogi Pharma, Oncolys BioPharma, Astellas Amgen BioPharama; Honoraria (self): Oncolys BioPharma. J-P. Metges: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Honoraria (self): Bayer-Health; Honoraria (self): Lilly; Advisory / Consultancy: ERYTECH Pharma; Advisory / Consultancy: Sanofi. E. Francois: Research grant / Funding (institution): MSD; Non-remunerated activity/ies, +Personal Fees: Roche; Non-remunerated activity/ies, +Personal Fees: Servier; Non-remunerated activity/ies, +Personal Fees: Merck; Non-remunerated activity/ies, +Personal Fees: Amgen; Non-remunerated activity/ies, +Personal Fees: Sanofi; Non-remunerated activity/ies, +Personal Fees: Novartis; Non-remunerated activity/ies, +Personal Fees: Bayer. K. Muro: Honoraria (self): Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, Taiho Pharmaceutical, Lilly, Ono Pharmaceutical, Bayer; Research grant / Funding (institution): Ono Pharmaceutical, MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Merck Serono, Pfizer, Sanofi. R. Wang: Full / Part-time employment: Merck & Co., Inc. Y. Cui: Full / Part-time employment: MSD China. P. Bhagia: Full / Part-time employment: Merck & Co., Inc. All other authors have declared no conflicts of interest.

Background

KEYNOTE-062 (NCT02494583) was a randomized, active-controlled study of first-line (1L) pembrolizumab (pembro) or pembro+chemotherapy vs chemotherapy (chemo) in patients (pts) with PD-L1 combined positive score ≥1 (CPS ≥1), HER2^–, advanced GC.

Methods

Eligible pts were randomly assigned 1:1:1 to pembro 200 mg Q3W, pembro+chemo (cisplatin 80 mg/m² + 5-FU 800 mg/m²/d on d1-5 Q3W [or capecitabine 1000 mg/m² BID on d1-14 Q3W per local guidelines]) or placebo+chemo Q3W for up to 2 y. Randomization was stratified by region, disease status, and fluoropyrimidine treatment. Primary end points were OS in CPS ≥1 and CPS ≥10 for pembro+chemo vs chemo and pembro vs chemo, and PFS (RECIST v1.1; central review) in CPS ≥1 for pembro+chemo vs chemo. Secondary end point was ORR (RECIST v1.1; central review) in CPS ≥1 for pembro+chemo vs chemo. Final analysis cutoff date was March 26, 2019.

Results

763 pts (281 with CPS ≥10 tumors) were randomly assigned to pembro+chemo (n = 257), pembro (n = 256), or chemo (n = 250). Median follow-up was 11.3 mo. Pembro was noninferior to chemo for OS in CPS ≥1 per prespecified margins. Pembro prolonged OS vs chemo in CPS ≥10 (median 17.4 vs 10.8 mo; HR 0.69; 95% CI 0.49-0.97) but was not tested per analysis plan. Pembro+chemo was not superior to chemo for OS in CPS ≥1 or CPS ≥10; the trend for pembro+chemo was favorable. Pembro+chemo did not significantly prolong PFS in CPS ≥1. ORR was higher with pembro+chemo than with chemo. In pts with microsatellite instability–high tumors, median OS was not reached (pembro) vs 8.5 mo (chemo) (HR 0.29; 95% CI 0.11-0.81) and not reached (pembro+chemo) vs 8.5 mo (chemo) (HR 0.37; 95% CI 0.14-0.97). Grade 3-5 drug-related AE rates were 17% (pembro), 73% (pembro+chemo), and 69% (chemo).

Conclusions

As 1L therapy for advanced GC, pembro was noninferior to chemo for OS in CPS ≥1; improvement in OS was clinically meaningful in CPS ≥10. Pembro+chemo was not superior for OS and PFS in CPS ≥1 or OS in CPS ≥10. The safety profile was more favorable for pembro than for chemo.Table:

125O

Clinical trial identification

NCT02494583.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Traci Stuve, MA, 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

H.C. Chung: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck-Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self): Foundation Medicine; Advisory / Consultancy, Research grant / Funding (institution): Taiho; Advisory / Consultancy: Celltrion; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Research grant / Funding (institution): GSK; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS-ONO. Y-J. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Taiho; Advisory / Consultancy, Research grant / Funding (institution): Daiichi-Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy, Research grant / Funding (institution): GreenCross; Advisory / Consultancy: Samyang Biopharm; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Genexine; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): MacroGenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Ono, CKD Pharma. J. Tabernero: Advisory / Consultancy, Scientific consultancy role: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partn. E. Van Cutsem: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Incyte; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim. C.S. Fuchs: Advisory / Consultancy: Agios; Advisory / Consultancy: Bain Capital; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors, unexercised stock options: CytomX; Advisory / Consultancy: Dicerna; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy, Shareholder / Stockholder / Stock options, unexercised stock options: Entrinsic Health; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Genentech; Advisory / Consultancy: Gilead Sciences; Advisory / Consultancy: KEW; Advisory / Consultancy: Merck; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Taiho; Advisory / Consultancy: Unum. L. Wyrwicz: Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): BMS; Non-remunerated activity/ies, Patent, royalties, other intellectual property: Cervico; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Halozyme; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Servier. K-W. Lee: Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Green Cross Corp.; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Pfizer. M. Garrido: Research grant / Funding (institution): Novartis. W. Mansoor: Honoraria (self), Speaker Bureau / Expert testimony, Speaker\'s Bureau - ESMO 2018: Lilly. M.I. Braghiroli: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Merck. E. Goekkurt: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Servier. J. Chao: Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novonco Therapeutics; Advisory / Consultancy: Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: FivePrime Therapeutics. Z.A. Wainberg: Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Research grant / Funding (institution): Five Prime Therapeutics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Pfizer. U. Kher: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. . S. Shah: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. K. Shitara: Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy: MSD; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): MediScience. All other authors have declared no conflicts of interest.

Background

The unmet need for effective and tolerable mPC treatments is high. PC pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) have shown response to the PARP inhibitor olaparib (O; Kaufman 2015). POLO (NCT02184195), the first Phase III trial to evaluate the efficacy of maintenance PARP inhibitor treatment in PC, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) from maintenance O vs placebo (P) for pts with a gBRCAm and mPC whose disease had not progressed during PBC (median 7.4 vs 3.8 months; hazard ratio [HR] 0.53; 95% CI 0.35–0.82; P = 0.004). At 2 years, 22.1% of pts on O vs 9.6% of pts on P were progression free. At an interim overall survival analysis (46% maturity), the HR was 0.91 (95% CI 0.56–1.46; P = 0.68). Safety was consistent with the known profile for O (Golan 2019).

Methods

POLO is a randomized, double-blind, placebo-controlled trial of pts with a gBRCAm and pancreatic adenocarcinoma who had received ≥16 weeks of first-line PBC for mPC without progression. There was no limit to duration of chemotherapy. Pts were randomized 3:2 to maintenance O tablets (300 mg bid) or P. Treatment began 4–8 weeks after the last PBC dose, continuing until investigator-assessed progression or unacceptable toxicity. The primary endpoint, PFS, and objective response were assessed by blinded independent central review (modified RECIST 1.1).

Results

Objective response rate among pts with measurable disease at baseline was 23.1% (18/78) in the O and 11.5% (6/52) in the P arm (odds ratio 2.30; 95% CI 0.89–6.76; P = 0.103).Table:

126O Best objective response in the full study population

Conclusions

Pts with a gBRCAm and mPC whose disease had not progressed on PBC derived a statistically significant and clinically meaningful PFS benefit from maintenance O. O-arm pts were more likely to maintain disease control or achieve a response than P-arm pts, and responses were durable, lasting a median of more than 2 years.

Clinical trial identification

NCT02184195.

Editorial acknowledgement

Medical writing assistance was provided by Elin Pyke, MChem, from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Legal entity responsible for the study

AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Funding

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

Disclosure

D-Y. Oh: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme. T. Golan: Honoraria (self), Research grant / Funding (self), International coordinating investigator service fee: AstraZeneca; Research grant / Funding (self): MSD Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie. P. Hammel: Research grant / Funding (self): Celgene; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self), Non-remunerated activity/ies: Erythec; Research grant / Funding (self): Halozyme. M. Reni: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Non-remunerated activity/ies, Steering committee member: Celgene; Advisory / Consultancy: Baxalta; Advisory / Consultancy: Shire; Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novocure; Advisory / Consultancy: Novartis; Advisory / Consultancy, Steering Committee member: AstraZeneca; Advisory / Consultancy, Steering Committee member: Boston Pharma. E. Van Cutsem: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Celgene; Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (self): Merck KGaA; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy, Research grant / Funding (self): Servier; Research grant / Funding (self): Amgen; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Ipsen. T. Macarulla: Honoraria (self): Genzyme; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi/Aventis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Shire; Honoraria (self): Tesaro; Advisory / Consultancy: Baxalta; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: H3B; Advisory / Consultancy: QED; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Aslan; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Bayer, Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Hallozyme; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merimarack; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis, Novocure, Pfizer, Pharmaclynics. M.J. Hall: Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (institution): Merck; Travel / Accommodation / Expenses: Caris Lifesciences; Non-remunerated activity/ies: Myriad; Non-remunerated activity/ies: Ambry; Non-remunerated activity/ies: Invitae; Non-remunerated activity/ies: Foundation Medicine; Non-remunerated activity/ies: Caris; Non-remunerated activity/ies: Merck. J. Oh Park: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Celgene; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Shire; Advisory / Consultancy: Merck; Advisory / Consultancy: Sereno. D. Arnold: Honoraria (self): AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self): Biocompatibles; Honoraria (self): Eli Lilly; Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (self), Non-remunerated activity/ies: Servier; Honoraria (self), Non-remunerated activity/ies: Sanofi; Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): Terumo; Honoraria (self), Non-remunerated activity/ies: Sirtex. A. Reinacher-Schick: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Baxalta; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Honoraria (self): Shire; Research grant / Funding (institution): Astra. G. Tortora: Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis. H. Algül: Honoraria (self): Celgene; Honoraria (self), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Chugai. E.M. O\'Reilly: Advisory / Consultancy: 3DMedcare, Agios, Alignmed, Amgen, Antengene, Aptus, Aslan, Astellas, AstraZeneca; Advisory / Consultancy: Bayer, Beigene, Bioline, BMS, Boston Scientific, Bridgebio, ; Advisory / Consultancy: Carsgen, Celgene, Casi, Cipla, CytomX; Advisory / Consultancy: Daiichi, Debio, Delcath; Advisory / Consultancy: Eisai, Exelixis, Genoscience; Advisory / Consultancy: Halozyme, Hengrui; Advisory / Consultancy: Incyte, Inovio, Ipsen; Advisory / Consultancy: Jazz, Janssen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM, Lilly, Loxo; Advisory / Consultancy: Merck, Mina; Advisory / Consultancy: Novella; Advisory / Consultancy: Onxeo; Advisory / Consultancy: PCI Biotech, Pfizer, Pieris; Advisory / Consultancy: QED, Redhill; Advisory / Consultancy: Sanofi, Servier, Silenseed, Sillajen, Sobi; Advisory / Consultancy: Targovax, Tekmira, Twoxar; Advisory / Consultancy: Vicus, Yakult, Yiviva; Research grant / Funding (institution): ActaBiologica, Agios, Array, AstraZeneca, Bayer, Beigene, BMS, Casai, Celgene, Exelisis, Genentech, Halozyme, Incyte, Lilly, Mabvax, Novartis, OncoQuest, Polaris Puma, QED, Roche. D. McGuinness: Full / Part-time employment: AstraZeneca. K.Y. Cui: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Research grant / Funding (institution): Merck and Co. Inc. K. Schlienger: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. G.Y. Locker: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H.L. Kindler: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Aldeyra Therapeutics; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Erytech; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Ipsen Pharmaceuticals; Advisory / Consultancy: Kyowa; Advisory / Consultancy, Travel / Accommodation / Expenses: Paredox Therapeutics; Research grant / Funding (institution): Aduro; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Glaxo Smith Kline; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Polaris; Research grant / Funding (institution): Verastem. All other authors have declared no conflicts of interest.

Background

Immunoscore® is an in vitro diagnostic test that predicts the risk of relapse in patients with Colon Cancer (CC) by measuring the host immune response at the tumor site. It is an immune risk-assessment tool providing independent and superior prognostic value than traditional histopathological risk parameters, and is intended to be used as an adjunct to the TNM classification. Currently, Immunoscore plays a critical role to guide post-surgery decisions in stage II & III CC patients. In stage I, survival rates are high and adjuvant chemotherapy is not typically recommended. However, approximately 10% of stage I CC tumors will recur even after surgical resection.

Methods

A subgroup analysis was performed on the stage I patients (n = 451) from the Immunoscore international validation study (Pagès et al. The Lancet 2018). Patients were classified by Immunoscore based on pre-defined cutoffs, either in 5 (IS 0-4) or in 3 categories: IS Low (IS0-1), Intermediate (IS 2), High (IS 3-4). Time to recurrence (TTR) was compared between Immunoscore categories.

Results

Immunoscore Low, Intermediate and High were observed in 14%, 47% and 39% of the cohort, respectively. Immunoscore was positively and significantly correlated with TTR. When adjusting the model with Immunoscore, age, gender, T-stage sidedness and MSI, Immunoscore remained the sole significant parameter (stratified by participating center HR_{low vs high}=7.82; 95% CI 1.49 − 41.01; p = 0.015). In multivariate analysis, the variable with the most important relative contribution to the risk (Chi2) was Immunoscore. The robust correlation between Immunoscore classification and TTR was further corroborated by a separate analysis of the same cohort distributed into five IS categories. In MSS stage I patients, TTR rates at 5 years were 100%, 98.1%, 93.5%, 85.4%, 87.5% for IS4, IS3, IS2, IS1, IS0, respectively.

Conclusions

Immunoscore® is a robust prognostic indicator of the risk of recurrence in stage I CC. This risk assessment tool reliably identifies a sub-group of patients with an increased risk of relapse for whom a more intensive surveillance program after curative resection may be recommended.

Legal entity responsible for the study

SITC (Society for ImmunoTherapy of Cancer) / INSERM.

Funding

Grants from National Institute of Health and Medical Research (INSERM), the LabEx Immuno-oncology, the Transcan ERAnet European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, INCA translationnel, Japan-AMED (P-DIRECT) and MEXT (Grants-in-aid for Scientific Research-S), and Ministry of Health of the Czech Republic (AZV CR 15-28188A) Progres Q25-LF1.

Disclosure

J. Galon: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Co-founder : HalioDx; Research grant / Funding (institution): Perkin-Elmer; Advisory / Consultancy, Research grant / Funding (institution): IObiotech; Advisory / Consultancy, Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Imcheck Therapeutics; Advisory / Consultancy: BMS; Advisory / Consultancy: Northwest Biotherapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy: Gilead; Advisory / Consultancy: CatalYm GmbH; Advisory / Consultancy: Sanofi; Licensing / Royalties, Patent holder: INSERM. F. Hermitte: Shareholder / Stockholder / Stock options, Full / Part-time employment, Co-founder : HalioDx. B. Mlecnik: Licensing / Royalties, Patent holder: INSERM. F. Pagès: Licensing / Royalties, Patent holder: INSERM. All other authors have declared no conflicts of interest.

Background

We investigated the feasibility of adding FOLFOXIRI to neoadjuvant chemoradiotherapy for patients (pts) with high risk rectal adenocarcinoma (T3-4 +/- node positivity, threatened margin and/or sphincter involvement).

Methods

Eligible patients were treated with 4 cycles of modified FOLFOXIRI (D1: CPT-11 165mg/m2, D1: oxaliplatin 85mg/m2, D1-2 200mg/m2 leucovorin, D1-2 5FU 400mg/m2 30min, then D1-2 5FU 600mg/m2 over 22hrs, with GCSF support), followed by capecitabine (825mg/m2 b.d) given concurrently during pre-operative radiotherapy (CRT, 50.4 Gy, 28 fr, 5 wks). Pts underwent surgery at planned 8-10 weeks after CRT, followed by adjuvant chemo. The primary endpoints were pathologic complete response rate (pCR) and objective response rate (ORR, RECIST ver 1.1).

Results

40 eligible pts were enrolled (median age 60 yrs; male:female=82%:18%), 1 pt was excluded before starting treatment. Baseline stage distribution was stage II (10.2%), IIIB (64.1%) and IIIC (25.7%). Of the 39 pts evaluated for response (ITT), ORR to FOLFOXIRI was 38.5% (15 PRs, 24 SDs); ORR to CRT was 64.1% (25 PRs, 9 SDs, 1 PD, 4NA). Total of 28 pt (out of 38 evaluated, 73.7%) had a reduced overall TNM stage. Of the 27 pts who underwent surgery (18.5% had permanent stoma), pCR rate was 25.9%, 26 pts had negative and 1 pt had close margin, respectively. At median follow-up of 30.2 months, the 2-yr overall survival and relapse-free rates were 79.3% and 82.8%, respectively. The top three most common grade 3-4 toxicities: (1) To FOLFOXIRI were diarrhea (12%), neutropenia (7.7%) and hyponatremia (5.1%); (2) To CRT – diarrhea (2.5%), RT-dermatitis (2.5%) and rectal hemorrhage (2.5%). No treatment-related deaths or perioperative mortality were encountered.

Conclusions

In summary, neoadjuvant FOLFOXIRI followed by Cape-RT for high risk rectal cancer is feasible and the pCR rate compares favorably with the historic rate of 13.8% with CRT alone (Yeung et al. Hong Kong Med J 2016;22) This strategy is being evaluated in a randomized study.

Clinical trial identification

NCT01941641.

Legal entity responsible for the study

The Chinese University of Hong Kong.

Funding

Hong Kong Research Grant Council General Research Fund 471613.

Disclosure

All authors have declared no conflicts of interest.

Background

Reverse-phase protein array (RPPA) allows us to simultaneously measure multiple protein features, such as expression, modification of proteins, and interaction with ligands from the samples. To overcome current limitation of genomic studies, we generated genomic and proteomic data together from HCC tumors and performed integrated analysis of both data sets.

Methods

We generated gene expression profile data and proteomic data from 300 HCC tumors by using expression microarrays and RPPA platform. Supervised and unsupervised approaches were applied to analyze proteomic data and multiple genomic data such as somatic mutations, mRNA expression, miRNA expression, and copy number alterations were integrated with proteomic data to uncover most correlated genomic alterations with functional products.

Results

Integrative analysis of genomic and proteomic data uncovered three subtypes of HCC with substantial difference in clinical outcomes. Interestingly, one of HCC subtype has strong mesenchymal characteristics as reflected in low expression of epithelial marker like CDH1 and CTNNB1. When assessed clinical relevance, the overall survival rate of patients in mesenchymal subtype was significantly worse than those in other two subtypes (P = 0.001). For validation of clinical association, we collected additional genomic and proteomic data from independent cohort of patient. Poor clinical outcomes of mesenchymal subtype is validated in multiple independent cohorts (in total of > 500 patients). Gene network analysis with integrated genomic and proteomic data further revealed association of subtypes with currently available treatments of HCC such as sorafenib and immunotherapy. In addition, multiple in-depth analysis of integrated data identified potential therapeutic target candidates for each subtype. Functional validation with cell lines demonstrated that some of candidates are essential for growth and survival of HCC cells.

Conclusions

HCC can be classified into distinct subtypes by analyzing integrated genomic and proteomic data. These analyses have identified potential therapeutic targets as well as biomarkers associated with therapeutic targets. Our study demonstrated merit of integrated analysis of proteomic data with genomic data to uncover potential driver genes of HCC development.

Legal entity responsible for the study

The authors.

Funding

MD Anderson Cancer Center.

Disclosure

All authors have declared no conflicts of interest.