When compared to chemotherapy with or without bevacizumab (Avastin) or cetuximab (Erbitux), patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with frontline pembrolizumab (Keytruda) monotherapy experienced significant improvement in the time from treatment randomization to progression on the next line of therapy or any cause death, according to an updated analysis of the pivotal phase 3 KEYNOTE-177 trial.
In a presentation at the 2021 ASCO Gastrointestinal Cancers Symposium, Kai-Keen Shiu, FRCP, PhD, reported that pembrolizumab induced superior progression-free survival (PFS) and improved health-related quality of life (HRQoL).
Pembrolizumab reduced the risk for progression on next-line therapy (PFS2) by 37% (HR, 0.63; 95% CI). Moreover, in the pembrolizumab arm, median PFS2 was not reached, compared with 23.5 months (range, 16.6-32.6) with chemotherapy. The 12- and 24-month PFS2 rates with pembrolizumab were 76% and 65%, respectively, compared with 67% and 50% with chemotherapy.
Patients treated with pembrolizumab monotherapy also experienced better HRQoL, including improvements in global health status/QOL, physical functioning, role functioning, emotional functioning, and social functioning, as well as improvements in symptoms like fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.
“[Data from this trial] support pembrolizumab as a new standard of care for first-line therapy in patients with MSI-high, mismatch repair deficient metastatic colorectal cancer,” Shiu, University College London Hospital and NHS Foundation Trust, said during a virtual presentation of the data. “We also look forward to upcoming studies both in the neoadjuvant and adjuvant setting.”
In the KEYNOTE-177 trial (NCT02563002), investigators randomized patients 1:1 to receive either 200 mg pembrolizumab every 3 weeks for up to 2 years (n = 153) or investigator’s choice of mFOLFOX6 (5-Fluorouracil, leucovorin, and oxaliplatin [Eloxatin]) or FOLFIRI (folinic acid, fluorouracil, and irinotecan) every 2 weeks, with or without bevacizumab or cetuximab (n = 154). Patients were treated until progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles with pembrolizumab only.
Patients in the chemotherapy arm could crossover to pembrolizumab treatment for up to 35 cycles after confirmed progressive disease.
Primary end points included PFS per RECIST v1.1, per blinded independent central review (BICR), and overall survival (OS). Secondary end points were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Duration of response (DOR) per RECIST v1.1 by BICR, PFS2, and HRQoL served as exploratory end points. In addition, tumor response per RECIST v1.1 by BICR was assessed at week 9 and every 9 weeks thereafter.
Data cutoff was February 19, 2020 and included 307 patients with locally-determined MSI-H/dMMR mCRC and an ECOG performance score of 0 or 1.
Patients treated with pembrolizumab monotherapy were a median age of 63 years (range, 24-93), and the majority were diagnosed with a right-sided tumor (n = 102) and had no prior systemic therapy (n = 115).
After a median follow-up of 32.4 months (range, 24.0-48.3), pembrolizumab demonstrated superior PFS (median, 16.5 months vs 8.2 months), compared with chemotherapy (HR, 0.60; 95% CI, 0.45-0.80; P = 0.0002). Moreover, the 12- and 24-month PFS rates were 55.3% and 48.3%, respectively, with frontline pembrolizumab monotherapy, compared with 37.3% and 18.6% with chemotherapy. By patient subgroup, PFS benefit with pembrolizumab was still seen regardless of age, gender, ECOG performance score, geographic region, stage, and tumor site.
OS analysis of the study is ongoing.
Pembrolizumab also induced superior confirmed ORR ([43.8%; 95% CI, 35.8-52.0] vs [33.1%; 95% CI, 25.8-41.4]), compared with chemotherapy. With frontline pembrolizumab, 11.1% of patients experienced a complete response, 32.7% with a partial response, 20.9% with stable disease, and 29.4% with progressive disease, compared with 1.9%, 29.2%, 42.2%, and 12.3%, respectively, with chemotherapy.
DOR was not reached with pembrolizumab (median range, 2.3+ to 41.4+) versus 10.6 months (median range, 2.8 to 37.5+) with chemotherapy. The rates of response at 24 months or more were 83% and 35%, respectively, with pembrolizumab and chemotherapy. The median time to response was 2.2 months (range, 1.8-18.8) with pembrolizumab and 2.1 months (range, 1.7-24.9) with chemotherapy.
In total, 56 patients (36%) of those treated with chemotherapy crossed over to receive pembrolizumab after confirmed disease progression. In addition, 35 more patients in the chemotherapy arm received anti-PD-1/PD-L1 therapy outside of the study, inducing an effective crossover rate of 59% in the intent-to-treat population.
Fewer patients treated with pembrolizumab, compared with chemotherapy, experienced a grade 3 TRAE (22% vs 66%); however, 10% and 6%, respectively, discontinued treatment. TRAEs in the pembrolizumab and chemotherapy arms included diarrhea (25% vs 52%, respectively), fatigue (21% vs 44%), nausea (12% vs 55%), decreased appetite (8% vs 34%), stomatitis (5% vs 30%), alopecia (3% vs 20%), vomiting (3% vs 28%), decreased neutrophil count (1% vs 23%), neutropenia (0% vs 21%), and peripheral sensory neuropathy (0% vs 20%).
Grade 3 or higher immune-mediated AEs occurred in 9% of the pembrolizumab arm, compared with 2% in the chemotherapy arm. All grade immune-mediated AEs included hypothyroidism (12%), colitis (7%), hyperthyroidism (4%), pneumonitis (4%), adrenal insufficiency (3%), hepatitis (3%), infused reactions (2%), hypophysitis, myositis, nephritis, pancreatitis, severe skin reaction, thyroiditis, and Type 1 diabetes mellitus (1% each).
“We have a lot of work to do. We wait for the overall survival analysis of this trial eagerly later this year, because there’s a lot of biomarker work we have to do. And I also think in a lot of upcoming trials, in the same setting, but also in the earlier setting, the agent will keep on giving us more answers. I think it’s really important from a patient perspective looking at this data,” Shiu said in prerecorded commentary of the presentation.
“And then it’s in our remit as clinicians to make sure that not only once they get access to therapy, we really think hard about making sure they get the best way and integrate that with the standard of care pathways and to make sure they get the best outcomes as demonstrated in this trial,” he added.
Shiu KK, Andre T, Kim TW, et al. KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; January 15-17, 2021; Virtual. J Clin Onco.l 39;2021:suppl 3;abstr 6.