2 Clarke Drive
Cranbury, NJ 08512
© 2022 MJH Life Sciences™ and OncLive - Clinical Oncology News, Cancer Expert Insights. All rights reserved.
Manish A. Shah, MD, FASCO, discusses key clinical trials that have evaluated the utility of pembrolizumab and nivolumab in the gastric/gastroesophageal junction cancer, and esophageal squamous cell carcinoma paradigms.
Immunotherapy has offered an alternative option to traditional chemotherapy, with improved responses, for certain subsets of patients with pretreated gastrointestinal (GI) cancers. And, as PD-1 inhibitors continue to be evaluated in the frontline and later-line settings, their utility as up-front immunotherapy remains uncertain, but promising.
“[Immunotherapy] is very different from most cytotoxic therapies that we [use],”
, explained. “The target cell for cytotoxic therapies is the cancer cell. We target DNA or pathways. For immunotherapy, the target is the interaction between the immune microenvironment, the tumor cell, and the cytotoxic T cells.”
“There are positive and negative signals that are integrated by the T cell. If we can turn off the negative signals, we can potentially activate the T cell against the cancer; that is what the immunotherapies we are using do,” Shah continued.
During the 2020 OncLive® Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Shah, who is chief of the Solid Tumor Service and the Bartlett Family Professor of Medicine at Weill Cornell Medical College of Cornell University, as well as an associate attending physician at NewYork-Presbyterian Hospital, discussed key clinical trials that have evaluated the utility of pembrolizumab (Keytruda) and nivolumab (Opdivo) in the gastric/gastroesophageal junction (GEJ) cancer, and esophageal squamous cell carcinoma (ESCC) paradigms.
Findings from the phase 2 KEYNOTE-059 trial provided an “important early clue,” according to Shah, on the potential utility of pembrolizumab as a treatment option for patients with gastric/GEJ cancer.1 Pembrolizumab demonstrated an objective response rate (ORR) of 11.6% (95% CI, 8.0%-16.1%), with a complete response (CR) rate of 2.3% (95% CI, 0.9%-5.0%) among 259 patients with previously treated gastric/GEJ cancer.
Patients with recurrent or metastatic gastric/GEJ adenocarcinoma who had received 2 or more prior lines of therapy were given 200 mg of pembrolizumab every 3 weeks for 24 months or until progressive disease, intolerable toxicity, or withdrawal from the study.
Further subset analyses revealed that patients with PD-L1–positive disease (n = 148) achieved an ORR of 15.5% (95% CI, 10.1%-22.4%) versus 6.4% (95% CI, 2.6%-12.8%) in those with PD-L1–negative disease (n = 109). The CR rates were 2.0% (95% CI, 0.4%-5.8%) and 2.8% (0.6%-7.8%), respectively.
Patients who were in their third line of therapy (n = 134) had an ORR of 16.4% (95% CI, 10.6%-23.8%), with a CR rate of 3.0% (95% CI, 0.8%-7.5%). Conversely, the ORR was 6.4% (95% CI, 2.8%-12.2%) among patients who were in their fourth or later line of therapy (n = 125). The CR rate was 1.6% (95% CI, 0.2%-5.7%) in this population.
Among patients with PD-L1–positive disease who were in their third line of therapy (n = 75), the ORR was 22.7% (95% CI, 13.8%-33.8%), with a 2.7% CR rate (95% CI, 0.3%-9.3%). Patients who were PD-L1 negative and in their third line of therapy (n = 58) had an ORR of 8.6% (95% CI, 2.9%-19.0%), with a CR rate of 3.4% (95% CI, 0.4%-11.9%).
Patients with microsatellite instability (MSI)–high disease (n = 7) obtained the greatest ORR at 57.1%. Comparatively, patients with non–MSI-H disease (n = 167) had an ORR of 9.0%.
Overall, the median duration of response (DOR) among all patients was 8.4 months (95% CI, 1.6+ to 17.3+). Patients with PD-L1–positive gastric/GEJ cancer had a median DOR of 16.3 months (1.6+ to 17.3+) versus 6.9 months (95% CI, 2.4-7.0+) in PD-L1–negative patients.
In the second-line setting, the international phase 3 KEYNOTE-061 trial randomized patients with unresectable, metastatic, or locally advanced gastric/GEJ cancer to receive 200 mg of pembrolizumab every 3 weeks for up to 35 cycles (n = 296) or 80 mg/m2 of paclitaxel on days 1, 8, and 15 of 4-week cycles (n = 296).2
Patients had to have progressive disease following first-line platinum- and fluoropyrimidine-based therapy and an ECOG performance status of 0 or 1. Additionally, the first 489 patients could have any PD-L1 combined positive score (CPS), and the final 103 patients had to have a PD-L1 CPS of 1 or more.
The majority of patients (69%) had a primary stomach tumor and 67% had a PD-L1 CPS of 1 or more.
The median overall survival (OS) was 9.1 months with pembrolizumab (n = 196; 95% CI, 6.2-10.7) versus 8.3 months with paclitaxel (n = 199; 95% CI, 7.6-9.0; HR, 0.82; 95% CI, 0.66-1.03; P = .0421). This did not translate to a significant difference in OS between arms.
The median progression-free survival (PFS) was 1.5 months with pembrolizumab (95% CI, 1.4-2.0) versus 4.1 months with paclitaxel (95% CI, 3.1-4.2; HR, 1.27; 95% CI, 1.03-1.57).
Although the KEYNOTE-061 study was negative, post-hoc subgroup analyses revealed that pembrolizumab improved OS in patients with PD-L1 CPS of 10 or more (HR, 0.64) and MSI-H (HR, 0.42) disease compared with paclitaxel.
“[In the KEYNOTE-061 trial], chemotherapy was perhaps better than pembrolizumab early on, but in the end, some patients had a better durable benefit with pembrolizumab,” said Shah. “A tenet of immunotherapy, at least in GI cancers, is that the response rate isn’t so high. However, when [patients] respond, [they] have a longer, much more durable response.”
The phase 3 KEYNOTE-062 trial randomized patients with previously untreated, unresectable, metastatic, or locally advanced gastric/GEJ adenocarcinoma to 200 mg of pembrolizumab every 3 weeks for up to 35 cycles (n = 256), pembrolizumab with cisplatin plus 5-fluorouracil or capecitabine (n = 257), or the same chemotherapy options plus placebo (n = 250).3
Seven percent of patients had MSI-H disease, and 37% had a PD-L1 CPS of 10 or greater.
Patients with a CPS of 1 or greater who received pembrolizumab and chemotherapy derived the greatest median OS (12.5 months; 95% CI, 10.8-13.9). The median OS was 10.6 months (95% CI, 7.7-13.8) in patients who received pembrolizumab alone and 11.1 months (95% CI, 9.2-12.8) in those who received chemotherapy alone. The median PFS durations were 6.9 months, 2.0 months, and 6.4 months, respectively. The ORRs were 48.6%, 14.8%, and 37.2%, respectively.
Patients with a CPS of 10 or greater who received pembrolizumab monotherapy (n = 92) had a 17.4-month median OS (95% CI, 9.1-23.1) versus 12.3 months (95% CI, 9.5-14.8) and 10.8 months (95% CI, 8.5-13.8) with pembrolizumab plus chemotherapy (n = 99) and chemotherapy plus placebo (n = 90), respectively. The median PFS durations were 2.9 months, 5.7 months, and 6.1 months, respectively. The median ORRs were 25% with pembrolizumab, 52.5% with the combination, and 37.8% with chemotherapy plus placebo.
Patients with a CPS score of 10 or greater who received pembrolizumab alone derived the longest duration of response, at 19.3 months (95% CI, 1.4+to 33.6+).
Similar to pembrolizumab, moving nivolumab up into earlier lines of treatment has been an area of exploration in gastric/GEJ cancer.
“The PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors turn off the negative signals to the T cell, and therefore potentially can activate the T cell against the cancer. By doing that we can [potentially induce] a durable response to therapy,” said Shah. “As is typical in GI malignancies or any solid tumor, [we] examine a drug in more advanced settings and then move it earlier where patients may get more benefit.”
The ATTRACTION-2 trial was a multicenter, randomized, double-blind, placebo-controlled, phase 3 study in which patients with previously treated unresectable advanced or recurrent gastric/GEJ adenocarcinoma received 3 mg/kg of intravenous nivolumab every 2 weeks (n = 330) or placebo (n = 163).4
Twenty percent of patients treated received 2 prior therapies, 40% received 3, and 40% received 4.
Findings revealed that the median OS was 5.26 months with nivolumab versus 4.14 months with placebo (HR, 0.63; 95% CI, 0.51-0.78; P < .0001). At 12 months, the median OS rates were 26.2% and 10.9%, respectively.
The median PFS was 1.61 months with nivolumab versus 1.45 months with placebo (95% CI, 0.49-0.75; P < .0001). The ORR was significantly improved with nivolumab over placebo (11% versus 0%, respectively).
In the second-line ESCC setting, nivolumab was compared with investigator’s choice of chemotherapy in the international, phase 3 ATTRACTION-3 trial.5 Patients in the study had unresectable disease and were refractory/intolerant to 1 prior fluoropyrimidine-based and platinum-based therapy. Patients had a life expectancy of 3 months or longer.
Patients who received nivolumab (n = 210) had a median OS of 10.9 months (95% CI, 9.2-13.3) versus 8.4 months (95% CI, 7.2-9.9) with chemotherapy (HR, 0.77; 95% CI, 0.62-0.96; P = .019), meeting the primary end point of the study.
However, the median PFS was not improved with nivolumab (1.7 months versus 3.4 months with chemotherapy; HR, 1.08; 95% CI, 0.87-1.34). The ORRs were 19% and 22%, respectively.
Novel combinatorial approaches are being investigated with nivolumab in GI cancers as well. For example, at Weill Cornell Medicine, a phase 2 study of frontline FOLFOX plus nivolumab with or without radiation therapy is ongoing in patients with metastatic or unresectable gastroesophageal cancers (NCT04021108).6 The primary end point is 1-year PFS rate, with secondary end points of ORR, DOR, PFS, and OS.