Pembrolizumab Improves OS in Patients With High PD-L1 Gastric Cancers

Zev A. Wainberg, MD

Overall survival (OS) was meaningfully improved with treatment of pembrolizumab (Keytruda) in first and later lines for patients with advanced gastric/gastroesophageal junction (G/GEJ0) cancer with a high number of PD-L1—expressing cells in the tumor, lymphocytes, and macrophages compared with chemotherapy.¹

A collective analysis of the use of pembrolizumab as first, second, or third or greater line of therapy in patients with advanced G/GEJ cancers across three clinical trials revealed enhanced OS compared with chemotherapy in patients with a combined positive score (CPS) ≥10, said Zev A. Wainberg, MD, at the 2020 GI Cancers Symposium.

“CPS ≥10 is a recognized cutoff, at least for gastric cancer. A CPS ≥10 cutoff represents approximately 30% of patients with gastric cancer,” said Wainberg, co-director of the GI Oncology Program, University of California, Los Angeles. “I think the benefit of pembrolizumab is pretty much in the MSI (microsatellite instability)-high and in the CPS ≥10 populations. I think the best bang for your buck is in the CPS ≥10 patients.”

When used as initial therapy in patients with CPS ≥10 who were enrolled in the KEYNOTE-062 study (n = 182), pembrolizumab monotherapy was associated with a median OS of 17.4 months compared with 10.8 months in the chemotherapy arm (cisplatin plus 5-fluorouracil [5-FU] or capecitabine).

“There’s a higher response rate with chemotherapy in the frontline, but in survival analyses, which is the most important endpoint, there is a much better median OS in the patients with CPS ≥10 with pembrolizumab,” he said.

The objective response rate (ORR) in KEYNOTE-062 in the CPS ≥10 subcohort was 25.0% in the pembrolizumab arm (complete response [CR], 7.6%; partial response [PR], 17.4%) compared with 37.8% in the chemotherapy arm (CR, 4.4%; PR, 33.3%), but the duration of response was longer in the pembrolizumab arm at 19.3 months versus 6.8 months in the chemotherapy arm. The ORR in the overall study population was 14.8% in the pembrolizumab group versus 37.2% in the chemotherapy group, but the duration of response was longer with pembrolizumab (13.7 vs. 6.8 months, respectively).²

When used as second line in patients with CPS ≥10 who were enrolled in KEYNOTE-061 (n = 108), the median OS was 10.4 months in the pembrolizumab arm compared with 8.0 months in the chemotherapy arm (paclitaxel).

When used as third line or later in the KEYNOTE-059 study, pembrolizumab was associated with a median OS of 7.9 months in the subset with CPS ≥10 (n = 46). Because KEYNOTE-059 was a single-arm study,³there was no comparator; however, in KEYNOTE-061 and KEYNOTE-062, pembrolizumab prolonged OS in the CPS ≥10 subset compared with chemotherapy.

The median OS in the pembrolizumab arms in the entire study cohorts was 5.8 months in KEYNOTE-059, 9.1 months in KEYNOTE-061 (vs 8.3 months in paclitaxel arm), and 10.6 months in KEYNOTE-062 (vs 11.1 months with chemotherapy).

In the chemotherapy arm in KEYNOTE-061, patients received paclitaxel at 80 mg/m²on days 1, 8, and 15 of 4-week cycles. In KEYNOTE-062 the chemotherapy regimen comprised at cisplatin, 80 mg/m²every 3 weeks, plus 5-FU at 800 mg/m²/day for 5 days every 3 weeks, or capecitabine at 1000 mg/m²twice daily on days 1 to 14 every 3 weeks (with cisplatin capped at 6 cycles in accordance with guidelines in the country in which patients were enrolled). Pembrolizumab was administered at 200 mg every 3 weeks for up to 35 weeks in all 3 trials.

The 12-month OS rate was 32.6% and the 24-month OS rate was 15.2% with pembrolizumab in patients with CPS ≥10 in KEYNOTE-059.

In KEYNOTE-061, in patients with CPS ≥10, the 12-month OS rates were 45.3% in the pembrolizumab arm and 23.6% in the paclitaxel arm, and the 18-month OS rates were 35.7% and 18.8%, respectively. In KEYNOTE-062, in the subpopulation with CPS ≥10, 12-month OS rates were 56.5% and 46.7% in the pembrolizumab and paclitaxel arms, respectively, and 24-month OS rates were 39.0% and 22.2%, respectively.

The median progression-free survival (PFS) was 2.1 months with pembrolizumab in the CPS ≥10 subset in KEYNOTE-059, with 12- and 24-month PFS rates of 8.7% each. Data from the other 2 studies showed that the median PFS was not longer with pembrolizumab compared with chemotherapy in the first- and second-line settings in the CPS ≥10 subset. In the second-line setting in KEYNOTE-061, the median PFS was 2.7 months and 3.4 months in the pembrolizumab and chemotherapy, arms, respectively, and in the first-line setting in KEYNOTE-062, the median PFS was 2.9 months in the pembrolizumab arm versus 6.1 months in the chemotherapy arm.

The ORR in KEYNOTE-059 with pembrolizumab in the CPS ≥10 subset was 17.4%, with a CR rate of 2.2% and a PR rate of 15.2%. The duration of response in this trial with pembrolizumab was 20.9 months. In patients with PD-L1—positive tumors who were enrolled in KEYNOTE-059, the ORR was 15.5% and the duration of response was 16.3 months.³

The ORR in KEYNOTE-061 in the CPS ≥10 subcohort was 24.5% in the pembrolizumab arm (CR, 9.4%; PR, 15.1%) compared with 9.1% in the chemotherapy arm (CR, 1.8%; PR, 7.3%), with a duration of response that was not reached in the pembrolizumab group versus 6.9 months in the chemotherapy group. In the overall KEYNOTE-061 population, the ORR was 16.6% with pembrolizumab and 14% with chemotherapy, with a longer duration of response with pembrolizumab (18.0 vs 5.2 months).⁴

“Keep in mind that this is a retrospective posthoc analysis of CPS ≥10, but it is, at least so far, the most comprehensive efficacy analysis of CPS ≥10 in the gastric cancer population out there,” said Wainberg.

References:

1. Wainburg ZA, Fuchs CS, Taberno J, et al. Efficacy of pembrolizumab (pembro) monotherapy versus chemotherapy for PD-L1—positive (CPS ≥10) advanced G/GEJ cancer in the phase II KEYNOTE-059 (cohort 1) and phase III KEYNOTE-061 and KEYNOTE-062 studies. Presented at GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 427.    
2. Taberno J, Van Cutsem EV, Bang Y-J, et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study.J Clin Oncol.2017; 35 (suppl; abstr LBA4007).
3. Fuchs CS, Doi T, Jang RW-J, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer.J Clin Oncol.2017;35 (suppl; abstr 4003).
4. Shitara K, Özgüroglu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.Lancet. 2018;392:123-133.

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