Marshall Highlights Durable Benefits of Pembrolizumab in GI Cancers

John L. Marshall, MD

Immunotherapy has arrived in the gastrointestinal cancer landscape, and while not all patients will benefit from these agents, those who do are likely to have long-lasting responses, explained John L. Marshall, MD.

Pembrolizumab (Keytruda), for example, has induced durable responses in certain subsets of patients with gastric and colorectal cancer (CRC), but many patients still do not respond to this type of therapy. Future research will be focused on achieving benefit in these other patients, Marshall said.

“This is a little bit of a gold rush,” said Marshall, professor of medicine and oncology, director of the Otto Reusch Center for the Cure of GI Cancer, Medstar Georgetown University Medical Center. “Our patients very much want to try one of these immunotherapy drugs, and in all of our patients with metastatic disease, we want to try one—because when they work, they work big.”

During the 2018 School of Gastrointestinal Oncology Annual Meeting, Marshall, who chaired the event, highlighted some of the promising data reported with pembrolizumab in gastric cancer, as well as microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) CRC.

Marshall cited results from the phase II KEYNOTE-059 study, which led to the September 2017 approval of pembrolizumab for the treatment of patients with PD-L1—positive recurrent, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and HER2/neu-targeted therapy when appropriate.¹

The multicenter, nonrandomized, open-label, multicohort trial enrolled 259 patients, 143 of which had PD-L1—positive tumors (combined positive score ≥1) and microsatellite stable tumor status or undetermined MSI or mismatch repair status. All patients received pembrolizumab at a standard 200-mg dose every 3 weeks.

The median age of patients on the trial was 64 years and 77% were male. The patients primarily had an ECOG performance status of 0 (43%) and 1 (57%). Overall, 51.7% of patients had received 2 prior lines of therapy, and 29% and 19.3% had received 3 or ≥4 prior lines of therapy, respectively.

Among the 143 patients with PD-L1—positive tumors, the overall response rate (ORR) was 13.3% (95% CI, 8.2-20.0), with a complete response (CR) rate of 1.4% and a partial response (PR) rate of 11.9%. Among these patients, 11 (58%) had a response of 6 months or longer, and 5 (26%) had a response of 12 months or longer. The median duration of exposure to the agent was 2.1 months (range, 1 day-21.4 months). “When you benefit, you benefit for a while, so the responding patients stay for a long period of time,” said Marshall. “We use the term ‘swinging for the fences’ in our clinic, [which means] that this is worth a try. If you hit, you hit big, and if you don't then you're moving onto something different. The responses are there.”

Adverse events (AEs) in these patients were similar to the AEs occurring in patients with melanoma and non—small cell lung cancer (NSCLC) who were treated with pembrolizumab. In 2799 patients enrolled across 3 randomized, open-label, active-controlled clinical trials of pembrolizumab, including patients with melanoma and NSCLC, the most common all-grade immune-related AEs were pneumonitis in 3.4% of patients (94), colitis in 1.7% of patients (48), and hepatitis in 0.7% of patients (19), he noted.

Marshall also highlighted data from 5 clinical trials that evaluated the efficacy of pembrolizumab in MSI-H or dMMR solid tumors, including CRC: KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158.² A total of 149 patients were enrolled across these single-arm trials. The median age was 55 years, and 56% were male. Of the 149 patients, 98% had metastatic disease and 2% had locally advanced unresectable disease. Ninety patients had CRC and the remaining 59 patients had 1 of 14 other tumor types.

Based on these data, the FDA approved pembrolizumab in May 2017 for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

MSI-H or dMMR status was determined prospectively with immunohistochemistry (IHC) assays for dMMR or laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status in the majority of patients (n = 135). For the remaining patients, MSI-H status was determined through a retrospective evaluation of 415 tumor samples using a central laboratory-developed PCR test. Overall, 47 patients had dMMR cancer identified by IHC, 60 patients had MSI-H identified by PCR, and 42 patients were identified using both tests.

Among all patients with MSI-H/dMMR cancers, the ORR was 39.6% (95% CI, 31.7-47.9), the CR rate was 7.4%, and the PR rate was 32.2%, with 78% of patients achieving response for longer than 6 months. In patients with CRC, the ORR was 36%; in other solid tumors, the ORR was 46%.

“We have a subset of patients clearly who are benefitting, and when they benefit, they benefit a lot, but there are still a lot of folks [who] aren't benefitting from these treatments. That's where all the research is going forward,” Marshall said.

References

1. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Previously Treated Patients with Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer Whose Tumors Express PD-L1 (CPS Greater Than or Equal to 1). Merck. Published September 22, 2017. https://bit.ly/2jprDCM. Accessed May 2, 2018.
2. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Adult and Pediatric Patients with Unresectable or Metastatic, Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer. Merck. Published May 23, 2017. https://bit.ly/2rzdPYQ. Accessed May 2, 2018.