Pembrolizumab doubles PFS for certain patients with metastatic colorectal cancer
First-line pembrolizumab extended PFS vs. chemotherapy for patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer, according to findings to be presented during the ASCO20 Virtual Scientific Program.
The agent also appeared associated with fewer treatment-related adverse events.
“Pembrolizumab should be considered a new standard of care for these patients,” Thierry André, MD, professor of medical oncology at University Sorbonne and head of the medical oncology department at Hôpital Saint Antoine in Paris, said during a presentation. “These data represent another step forward for biomarker-driven studies and will help bring this approach to target microsatellite instability-high tumors into the adjuvant and neoadjuvant settings.”
An estimated 5% of patients with metastatic colorectal cancer have high microsatellite instability, characterized by a high level of mutations.
In microsatellite instability-high/mismatch repair-deficient disease, DNA repair is compromised, leading to an even higher number of mutations. This subgroup of patients is less likely to respond to conventional chemotherapy and, therefore, prognosis typically is poor.
Phase 2 studies showed pembrolizumab improved response and prolonged survival for patients with microsatellite instability-high metastatic colorectal cancer refractory to chemotherapy. The FDA approved pembrolizumab for treatment of adults and children with previously treated microsatellite instability-high metastatic tumors regardless of tumor type or site.
The randomized, phase 3 KEYNOTE-177 trial assessed the efficacy and safety of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) vs. standard chemotherapy as first-line treatment for patients with microsatellite instability-high, mismatch repair-deficient metastatic colorectal cancer.
All 307 patients had measurable disease and an ECOG performance status of 0 or 1.
Researchers randomly assigned 153 patients to pembrolizumab dosed at 200 mg every 3 weeks. The other 154 patients received investigator’s choice of one of six standard chemotherapy regimens selected prior to randomization. These included modified FOLFOX-6, which consists of 5-FU, leucovorin and oxaliplatin; modified FOLFOX-6 plus bevacizumab (Avastin, Genentech); modified FOLFOX-6 plus cetuximab (Erbitux, Eli Lilly); FOLFIRI, which consists of leucovorin, 5-FU and irinotecan; FOLFIRI plus bevacizumab; or FOLFIRI plus cetuximab.
Treatment continued until disease progression, unacceptable toxicity, patient or investigator decision to withdraw, or — in the case of pembrolizumab — completion of 35 cycles. Patients assigned chemotherapy who developed confirmed progressive disease could cross over to pembrolizumab for up to 35 cycles.
PFS by blinded independent central review and OS served as primary endpoints. Key secondary endpoints included overall response rate and safety.
André presented results of the final PFS analysis, based on median follow-up of 32.4 months (range, 24-48.3).
Results showed a near-doubling of median PFS with pembrolizumab (16.5 months vs. 8.2 months; HR = 0.6; 95% CI, 0.45-0.8). A higher percentage of patients assigned pembrolizumab remained progression free at 12 months (55.3% vs. 37.3%) and 24 months (48.3% vs. 18.6%).
Researchers also reported a higher ORR in the pembrolizumab group (43.8% vs. 33.1%), as well as higher rates of complete response (11.1% vs. 3.9%) and partial response (32.7% vs. 29.2%).
Median response duration was not reached with pembrolizumab (range, 2.3+ months to 41.4+ months) and was 10.6 months (range, 2.8-37.5+) with chemotherapy. More than twice as many patients assigned pembrolizumab remained in response for 2 years or longer (83% vs. 35%).
The majority of patients in each group experienced treatment-related adverse events (80% for pembrolizumab vs. 99% for chemotherapy). However, a considerably lower percentage of patients assigned pembrolizumab experienced grade 3 to grade 5 treatment-related adverse events (22% vs. 66%).
The most common adverse events reported among pembrolizumab-treated patients included diarrhea (any grade, 25% for pembrolizumab vs. 52% for chemotherapy; grade 3 or higher, 2% vs. 10%), fatigue (any grade, 21% vs. 44%; grade 3 or higher, 2% vs. 9%), nausea (any grade, 12% vs. 55%; grade 3 or higher, 0% vs. 2%), decreased appetite (any grade, 8% vs. 34%; grade 3 or higher, 0% vs. 2%) and stomatitis (any grade, 5% vs. 30%; grade 3 or higher, 0% vs. 4%).
One patient assigned chemotherapy died due to a treatment-related adverse event.
The study will continue so researchers can assess OS outcomes.
“Our hope is that after starting pembrolizumab, some patients will be cured of metastatic disease,” André said. – by Mark Leiser
Reference:
Andre T, et al. Abstract LBA4. Scheduled for presentation at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Perspective
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KEYNOTE-177 provides evidence for what was previously a hypothesis that utilization of PD-1 inhibition earlier in the treatment course of a microsatellite instability-high metastatic colorectal cancer is superior to starting with chemotherapy. Although an OS benefit will be difficult to interpret given the crossover design of this randomized study, an improvement in response rate and PFS in combination with a third of the number of grade 3 to grade 5 adverse events is an ideal outcome for this study. I agree that PD-1 inhibitor therapy in the first line should be a new standard of care for patients with microsatellite instability-high metastatic colorectal cancer.
Perspective
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The results of the KEYNOTE-177 study change clinical practice and place pembrolizumab in the front-line for patients with microsatellite instability high or mismatch repair-deficient (dMMR) metastatic colorectal cancer. The findings also reiterate the critical importance of testing all colon cancers for mismatch repair, for both identification of Lynch syndrome and now initial treatment options in the metastatic setting.
This study also demonstrates that immune therapy is the best therapy for dMMR colorectal cancer. This indicates that we need to look at immunotherapy in earlier settings, such as adjuvant or neoadjuvant immunotherapy for resectable or resected colorectal cancer, respectively. It is critical that clinicians enroll to the ongoing adjuvant randomized clinical trials (ATOMIC and POLEM) so that the answer to using immunotherapy in earlier disease can be obtained quickly.
Beyond colorectal cancer, this study highlights a need to do more tumor-agnostic trials for dMMR cancers. Pembrolizumab is approved as a tumor-agnostic therapy for cancers with dMMR, but most of the current trials focused on dMMR are focused on specific tumor types. We have many patients with dMMR cancers beyond colorectal cancers, and the obvious question is how to best treat them in front-line therapy. We don’t have an answer to that question. As a field, we should design clinical trials that are dMMR tumor-agnostic to enable such advances as seen in KEYNOTE-177 to be available to all patients with dMMR cancers. There are some challenges with the design of large tumor agnostic trials, but the implications would be important for the field.
Finally, it’s important to note that not all patients in this trial benefitted from pembrolizumab. We really need additional translational data to identify those who will not benefit. On the trial, 29% of patients had progression as best response in the pembrolizumab group. Who are those patients who are progressing on the first scan and aren’t benefitting from pembrolizumab? Can we identify that subgroup to define those that will benefit or not? That ongoing work needs to be completed.
Perspective
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This study is practice-changing, and I think it is one of the most important studies that we’ll see at ASCO this year. The data across microsatellite instability-high cancers was incredibly paradigm-changing as we moved [toward FDA approval of pembrolizumab for the tumor-agnostic indication]. Now we are focusing back on a specific group. I believe, based on the PFS benefit, this will become a new standard of care. Should it become the standard of care? It is hard to move oncologists off what they are comfortable with. There is some comfort, obviously, with using pembrolizumab across multiple diseases, so that’s not an issue. It already has been used in the third-line setting in colorectal cancer, so I think this is a fairly low bar to get over as it will avoid chemotherapy in the first line. I don’t think the OS will be meaningful now. Even if it isn’t in the long term, I think the quality-of-life data will be really important.
The biomarker will be the issue, but I think this one is a little easier than some of the other biomarkers that we are still having trouble getting everyone to participate in and get. Pathologists are now used to measuring microsatellite instability or mismatch repair deficiency — usually by immunohistochemistry, but there are multiple methods to measure this, including next-generation sequencing and other molecular methods. But it’s still a little confusing to some people, so I think the barrier will be making sure everybody gets tested for the biomarker.
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Andre T, et al. Abstract LBA4. Scheduled for presentation at: ASCO20 Virtual Scientific Program; May 29-31, 2020.