KEYNOTE-059 cohort 3: safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients (pts) with PD-L1-positive advanced gastric/gastroesophageal (G/GEJ) cancer

Abstract

Background: In contrast to the TRIBE trial, which investigates FOLFIRI/Bevacizumab (bev)+/>=Oxaliplatin, CHARTA was designed to investigate FOLFOX/bev +/>= Irinotecan. For comparison with TRIBE the same treatment protocol and doses as TRIBE have been applied in CHARTA. Methods: The study was powered for an increase of PFS rate @ 9 months from 56% to 68%, with p=/= 1 measurable lesion >1cm; stratification was done by ESMO-Group 1,2,3. Treatment: Induction for 6 months, followed by maintenance with Capecitabine+ bev. until progression or max.12 months, at progression followed by reinduction (by investigators decision). 25% dose reduction was allowed in cycle 1+ 2 at the investigator's discretion, with escalation in the following cycles. Randomization from 07/2011 - 12/2014, with 250 pts randomised and 241 pts evaluable (1 not elig., 8 prot. violation) after a follow up of 31.4 (0.1-51) months. Pts. characteristics: m/f: 65%/35%, age 61y (21-82), ECOG 0-1/2: 96%/4%. Results: The Primary Endpoint was met: PFS @9months 56% vs. 68%, p=0.086; PFS 9.8 vs. 12.0 months (HR 0.7, ns.), identical to TRIBE (9.7 vs. 12.1 months). Response rate (A/B): CR+PR 60%/69% (ns), PFS 10.3/12 months (ns), OS 24/28 months (ns). PFS was significantly improved (p=0.027) in the subgroup of pts. with synchronous metastases (91% of pts); The strongest improvement by the 4 drug combination was shown in those pts. with synchronous mets., who never had resection of the primary (52% of the pts.): 17 vs. 26.5 mos. (p= 1 measurable lesion >1cm; stratification was done by ESMO-Group 1,2,3. Treatment: Induction for 6 months, followed by maintenance with Capecitabine+ bev. until progression or max.12 months, at progression followed by reinduction (by investigators decision). 25% dose reduction was allowed in cycle 1+ 2 at the investigator's discretion, with escalation in the following cycles. Randomization from 07/2011 - 12/2014, with 250 pts randomised and 241 pts evaluable (1 not elig., 8 prot. violation) after a follow up of 31.4 (0.1-51) months. Pts. characteristics: m/f: 65%/35%, age 61y (21-82), ECOG 0-1/2: 96%/4%. Results: The Primary Endpoint was met: PFS @9months 56% vs. 68%, p=0.086; PFS 9.8 vs. 12.0 months (HR 0.7, ns.), identical to TRIBE (9.7 vs. 12.1 months). Response rate (A/B): CR+PR 60%/69% (ns), PFS 10.3/12 months (ns), OS 24/28 months (ns). PFS was significantly improved (p=0.027) in the subgroup of pts. with synchronous metastases (91% of pts); The strongest improvement by the 4 drug combination was shown in those pts. with synchronous mets., who never had resection of the primary (52% of the pts.): 17 vs. 26.5 mos. (p= 1 measurable lesion >1cm; stratification was done by ESMO-Group 1,2,3. Treatment: Induction for 6 months, followed by maintenance with Capecitabine+ bev. until progression or max.12 months, at progression followed by reinduction (by investigators decision). 25% dose reduction was allowed in cycle 1+ 2 at the investigator's discretion, with escalation in the following cycles. Randomization from 07/2011 - 12/2014, with 250 pts randomised and 241 pts evaluable (1 not elig., 8 prot. violation) after a follow up of 31.4 (0.1-51) months. Pts. characteristics: m/f: 65%/35%, age 61y (21-82), ECOG 0-1/2: 96%/4%. Results: The Primary Endpoint was met: PFS @9months 56% vs. 68%, p=0.086; PFS 9.8 vs. 12.0 months (HR 0.7, ns.), identical to TRIBE (9.7 vs. 12.1 months). Response rate (A/B): CR+PR 60%/69% (ns), PFS 10.3/12 months (ns), OS 24/28 months (ns). PFS was significantly improved (p=0.027) in the subgroup of pts. with synchronous metastases (91% of pts); The strongest improvement by the 4 drug combination was shown in those pts. with synchronous mets., who never had resection of the primary (52% of the pts.): 17 vs. 26.5 mos. (p 300U/l, CEA 20ng/ml and synchronous/ metachronous metastases. However, in the multivariate model only CEA and syn-/metachr. mets. remained significant; treatment arm was not significant. The CMS-classification analysis is ongoing. Toxicity was low to moderate without major differences except 90%of the pts., PFS is significantly improved, mainly driven by the worst subgroup of those pts., who never achieved primary tumor resection. The strongest single prognostic and predictive factor is synchronous vs.metachronousmets. and CEA <20ng/ml.However, a combination of clinical factors (ESMOgroups), lab scores (Risk Score), andCMS classificationmight be optimal for a combined prognostic and predictive model for better prediction of pts. who have better benefit fromthe combination.