The U.S. Food and Drug Administration (FDA) has approved Keytruda (pembrolizumab) as a first-line therapy for people with inoperable or metastatic colorectal cancer with specific genetic features that denote a high mutation rate.
The decision comes after promising findings from KEYNOTE-177 (NCT02563002), a Phase 3 trial in which Keytruda more than doubled the time patients lived without signs of disease progression, compared with standard chemotherapy, while lowering the rate of serious adverse events.
With this approval, Keytruda is now the first single-agent immunotherapy — and first alternative to chemotherapy — approved as a first-line treatment for this indication. The decision came less than a month after Merck (known as MSD outside the United States and Canada), the therapy’s developer, submitted a supplemental biologics license application (sBLA) requesting this approval.
“This is the first randomized controlled study to show that first-line immunotherapy is significantly better than chemotherapy at shrinking metastatic bowel cancers with these specific DNA mutations, and delaying the time it takes for the cancer to progress,” Kai-Keen Shiu, PhD, MD, an honorary associate professor of oncology at the UCL Cancer Institute, consultant medical oncologist at UCLH, and chief investigator of KEYNOTE-177, said in a university news story.
“The results from this trial really are game-changing and will almost certainly result in a paradigm shift in our current clinical practice,” Shiu added.
Keytruda is an immune checkpoint inhibitor that works to prevent a mechanism used by cancer cells to evade immune responses. It specifically targets the PD-1 receptor at the surface of immune T-cells, and prevents it from binding to the PD-L1 protein on cancer cells, removing the brakes from immune cells.
Keytruda has been approved in the U.S. and in the EU to treat different types of cancer, including lung, bladder, stomach, esophageal, and liver cancer, lymphoma, melanoma, and cancers with specific genetic features that failed prior therapies.
The KEYNOTE-177 trial is investigating the safety and efficacy of Keytruda, compared with standard chemotherapy, for the first-line treatment of advanced colorectal cancer with specific genetic markers.
The trial enrolled 307 patients with previously untreated inoperable or metastatic colorectal cancer with microsatellite instability high (MSI-H) or mismatch repair deficiency (dMMR). These genetic markers suggest that cancer cells are unable to repair their DNA when damaged, which increases the number of mutations and the likelihood they will be seen by the immune system as threats.
Once enrolled, patients were randomly assigned to either 200 mg of intravenous Keytruda, every three weeks for up to 35 cycles (approximately two years), or to one of six possible standard-of-care chemotherapy regimens selected by the trial investigators, given every two weeks.
Treatment lasted until disease progression, unacceptable toxicity, a patient or investigator’s decision to withdraw, or the completion of 35 treatment cycles in the case of those who had been assigned to Keytruda.
Those receiving chemotherapy were also allowed to switch over to Keytruda for up to 35 cycles after showing signs of disease progression. Tumor status was evaluated in all patients every nine weeks.
The study’s main goals were to assess if Keytruda was superior to chemotherapy at prolonging the time patients lived without any signs of disease progression, and at extending overall survival. Secondary goals included analyses fo safety and treatment response.
Interim data from KEYNOTE-177, presented at the American Society of Clinical Oncology (ASCO) 2020 Virtual Annual Meeting, showed that Keytruda prolonged the time patients lived without disease progression from a median of 8.2 to 16.5 months, lowering the risk of death or disease progression by 40%.
The percentage of patients who were alive and without signs of disease worsening was higher among those on Keytruda, compared with those on chemo, after one year (55.3% versus 37.3%) and two years of treatment (48.3% versus 18.6%).
“Today’s approval has the potential to change the treatment paradigm for the first-line treatment of patients with MSI-H colorectal cancer, based on the important findings from KEYNOTE-177 that showed Keytruda monotherapy demonstrated superior progression-free survival compared to standard of care chemotherapy,” Roy Baynes, senior vice president and head of global clinical development, and chief medical officer of Merck, said in a press release.
At the time of the interim analysis (Feb. 19, 2020), data regarding the effects of treatment on patients’ overall survival was still unavailable.
Keytruda also increased the proportion of patients responding to treatment (44%), compared to that seen with chemo (33%). Both partial (33% vs. 29%) and complete responses (11% vs. 4%) were higher among those given the immunotherapy. Of note, partial and complete responses refer to partial or complete cancer elimination, respectively.
Treatment responses also lasted longer among those treated with Keytruda — with 43% of the patients responding for more than two years, compared with 18% for those on chemo.
“Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options,” said Luis A. Diaz, MD, head of the division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center.
“This approval helps address the unmet need to provide a new monotherapy treatment option for patients,” Diaz added.
Adverse events reported in patients with MSI-H or dMMR colorectal cancer were similar to those previously seen in patients with melanoma or non-small cell lung cancer treated with Keytruda in other clinical trials. Serious treatment-related adverse events were also found to be less common among those on Keytruda (22%) than among those receiving chemo (66%).
“It is very encouraging that the side effects of pembrolizumab are significantly less than with chemotherapy, so not only the quantity but also the quality of life of these patients is better on immunotherapy,” Shiu said.
The company’s sBLA was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program and Project Orbis. RTOR aims to improve the efficiency of the review process, with the final goal of making safe and effective medications available to patients as soon as possible.
Project Orbis is an initiative created to allow simultaneous submission and review of cancer medications among international regulatory partners. Keytruda’s submission was reviewed by the FDA, in collaboration with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic.
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