Pembrolizumab remains effective in PD-L1-positive advanced gastric, gastroesophageal cancer
First-line pembrolizumab remained effective, safe and noninferior to chemotherapy among certain patients with PD-L1-positive advanced gastric, gastroesophageal junction cancer, according to follow-up results of the KEYNOTE-062 study.
The findings, presented at ASCO Gastrointestinal Cancers Symposium, additionally confirmed that the combination of pembrolizumab (Keytruda, Merck) and chemotherapy did not demonstrate superiority to chemotherapy alone with regard to OS among those with a PD-L1 combined positive score (CPS) of 1 or higher.
“The additional 25 months of follow-up on efficacy and safety outcomes with first-line pembrolizumab or pembrolizumab plus chemotherapy compared with chemotherapy alone were consistent with previous data from the final analysis of KEYNOTE-062,” Zev A. Wainberg, MD, professor of medicine at University of California, Los Angeles, co-director of the UCLA GI oncology program, and oncologist at UCLA Health’s Santa Monica Cancer Care, said during his presentation.
Rationale
An unmet need remains for safe and effective treatments for patients with untreated, advanced gastric or gastroesophageal junction cancer. Previous data showed an association of pembrolizumab with antitumor activity with a manageable safety profile in this population of patients.
Methods
As Healio previously reported, the multicenter KEYNOTE-062 study included 763 patients (median age, 62 years; range, 20-87; 72.6% men) with untreated, locally advanced unresectable or metastatic gastric or gastroesophageal cancer and a PD-L1 CPS of 1 or higher.
Investigators randomly assigned patients 1:1:1 to pembrolizumab dosed at 200 mg every 3 weeks for up to 2 years (n = 256), pembrolizumab plus chemotherapy (n = 257) or placebo plus chemotherapy (n = 250).
Primary endpoints included OS among those with a PD-L1 CPS of 1 or greater and PFS among those with a PD-L1 CPS of 10 or greater.
Wainberg presented final analysis results after an additional 25 months of follow-up. Median follow-up was 54.3 months (range, 46.8-66.1).
Key findings
At the time of data cutoff on April 19, 2021, 90.3% of patients died.
Results showed 2-year OS rates of 26.6% with pembrolizumab and 24.5% with pembrolizumab plus chemotherapy vs. 18.8% with chemotherapy among patients with a CPS of 1 or higher, and 39.1% and 28.3% vs. 21.1% among those with a CPS of 10 or higher.
Pembrolizumab demonstrated noninferiority to chemotherapy with regard to OS among patients with a CPS of 1 or greater (median, 10.6 months vs. 11 months; HR = 0.9; 95% CI, 0.75-1.08) but conferred a clinical meaningful OS benefit among those with a CPS of 10 or greater (median, 17.4 months vs. 10.8 months; HR = 0.62; 95% CI, 0.45-0.86).
Pembrolizumab plus chemotherapy did not appear superior to chemotherapy for OS, nor for PFS among patients with a CPS of 1 or higher (median, 6.9 months vs. 6.5 months; HR = 0.84; 95% CI, 0.7-1.01) or those with a CPS of 10 or higher (median, 5.8 months vs. 6.2 months; HR = 0.71; 95% CI, 0.52-0.96).
Grade 3 to grade 5 treatment-related adverse events occurred in 17.3% of those assigned pembrolizumab, 73.2% of those assigned pembrolizumab plus chemotherapy and 69.3% among those assigned chemotherapy alone.
Implications
First-line pembrolizumab plus chemotherapy will be further examined in KEYNOTE-859, according to Wainberg.
“We are still trying to understand the characteristics of the patients who achieved the most benefit from pembrolizumab compared with chemotherapy,” Wainberg told Healio. “The landscape continues to change with more biomarker refinement, which we expect to continue during the next few years.”
For more information:
Zev A. Wainberg, MD, can be reached at UCLA Health, Santa Monica Cancer Care, 2020 Santa Monica Blvd., Suite 600, Santa Monica, CA 90404; email: zwaiberg@mednet.ucla.edu.
Perspective
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Follow up results of the KEYNOTE-062 trial again showed significant promise for pembrolizumab in first-line treatment of PD-L1-positive advanced gastric and gastroesophageal junction malignancies.
The current data, including an additional 25 months of follow up, reinforced the initial findings from KEYNOTE-062 — pembrolizumab was noninferior to chemotherapy among patients with a PD-L1 CPS of 1 or higher, but the addition of pembrolizumab to chemotherapy provided no added benefit.
Researchers also reported a clinical OS benefit for those with a CPS of 10 or higher. This study was not designed to test the statistical significance of this finding, and this is an area that would benefit from additional investigation. It would be important to know if pembrolizumab is superior for patients with higher PD-L1 scores, as this would certainly change front-line management.
It is unclear why the addition of pembrolizumab to chemotherapy conferred no added benefit. Hopefully results of KEYNOTE-859, a phase 3 trial looking at pembrolizumab plus chemotherapy in gastric/gastroesophageal junction adenocarcinoma, will shed more light on this. Bone marrow suppression and its cytotoxic effect on T-cell activity are logical explanations, but the role of immune checkpoint inhibitors in lung cancer treatment suggests otherwise. If bone marrow suppression is a reason for the lack of efficacy of combination therapy, perhaps this suggests pembrolizumab should be used as front-line therapy for those with a CPS of 1 or greater before cytotoxic chemotherapy is introduced and subsequent bone marrow suppression occurs.
Although the results of combination therapy are disappointing, the noninferiority of pembrolizumab to chemotherapy is exciting as it allows for initial avoidance of morbidity associated with traditional chemotherapy. It may also pose an avenue for patients who are hesitant to receive chemotherapy, as many are, or for those who are unlikely to tolerate cytotoxic chemotherapy. Immune checkpoint inhibitors pose a unique set of treatment-related adverse events; however, patients often experience none of these. This contrasts with the invariable side effects that occur as a result of cytotoxic chemotherapy. Furthermore, this study showed pembrolizumab monotherapy resulted in fewer grade 3 to grade 5 treatment-related adverse events than chemotherapy or the combination of chemotherapy plus pembrolizumab. Another area of interest would be whether those with a lower performance status [ECOG 2] have similar results. One may expect such a population to better tolerate immune checkpoint inhibitors than traditional chemotherapy and thus have better outcomes.
Continued investigation into optimizing the selection of patients for front-line pembrolizumab will be important going forward. As we gain better understanding of who will benefit most from pembrolizumab, we will be better able to individually tailor our treatment regimens.
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Wainberg ZA, et al. Abstract 243. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.