When compared with chemotherapy with or without bevacizumab (Avastin) or cetuximab (Erbitux), patients with high / inappropriate microsatellite-instability deficiency (MSI-H / dMMR) metastatic colorectal cancer (mCRC) a treated with pembrolizumab monotherapy (Keytruda) face improvement in the period from randomized treatment to progression on the next line of treatment or death of any cause, according to an updated study of phase 3 trial KEYNOTE-177.
In a presentation at ASCO’s 2021 Gastrointestinal Cancers Symposium, Kai-Keen Shiu, FRCP, PhD, reported that pembrolizumab promoted progressive survival (PFS) and improved health-related quality of life (HRQoL).
Pembrolizumab reduced the risk for progression to next-line therapy (PFS2) by 37% (HR, 0.63; 95% CI). Moreover, in the pembrolizumab arm, moderate PFS2 was not reached, compared with 23.5 months (range, 16.6–32.6) with chemotherapy. 12- and 24-month PFS2 levels with pembrolizumab were at 76% and 65%, respectively, compared with 67% and 50% with chemotherapy.
Patients treated with pembrolizumab monotherapy also experienced improved HRQoL, including improvements in global health status / QOL, physical activity, occupational activity, emotional activity, and social activity, as well as improvements in symptoms such as obesity, nausea and vomiting, pain, insomnia, desire. loss, constipation, diarrhea, and financial difficulties.
“[Data from this trial] supports pembrolizumab as a new standard of care for first-line treatment in patients with high MSI, improper repair of metastatic colorectal cancer, ”said Shiu, University College London Hospital and NHS Foundation Trust, during a keynote presentation of the data. “We are also looking forward to forthcoming studies in both an underdeveloped and conclusive context. ”
In the KEYNOTE-177 trial (NCT02563002), researchers randomized patients 1: 1 to receive either 200 mg pembrolizumab every 3 weeks for up to 2 years (n = 153) or mFOLFOX6 (5-) tester option. 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, inappropriate poisoning, patient / examiner decision to withdraw, or completion of 35 cycles with pembrolizumab alone.
Patients in the arm of chemotherapy could switch to pembrolizumab treatment for up to 35 cycles after diagnosis of advanced disease.
Key endpoints included SDP per RECIST v1.1, all blinded independent review (BICR), and total survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 with BICR and safety. Response time (DOR) of each RECIST v1.1 with BICR, PFS2, and HRQoL used as checkpoints. In addition, tumor response of each RECIST v1.1 with BICR was assessed at week 9 and every 9 weeks thereafter.
The data cut was February 19, 2020 and included 307 patients with locally diagnosed MSI-H / dMMR mCRC and an ECOG performance score of 0 or 1.
Patients treated with pembrolizumab monotherapy had a median age of 63 years (range, 24–93), and most were diagnosed with right sided immersion (n = 102) and had no prior systemic treatment. their hand (n = 115).
After a median follow-up of 32.4 months (range, 24.0–48.3), pembrolizumab showed positive 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 levels were 55.3% and 48.3%, respectively, with face pembrolizumab monotherapy, compared with 37.3% and 18.6% with chemotherapy. According to a subgroup of patients, the benefit of PFS with pembrolizumab was still evident regardless of age, sex, ECOG performance score, geographic area, stage, and tumor location.
OS analysis of the study continues.
Pembrolizumab also contained advanced proven ORR ([43.8%; 95% CI, 35.8-52.0] vs. [33.1%; 95% CI, 25.8-41.4]), compared with chemotherapy. With face pembrolizumab, 11.1% of patients received a total response, 32.7% with a complementary response, 20.9% with persistent disease, and 29.4% with advanced disease, compared with 1.9%, 29.2%, 42.2%, and 12.3% , separately, with chemotherapy.
DOR was not reached with pembrolizumab (medium range, 2.3+ to 41.4+) versus 10.6 months (medium range, 2.8 to 37.5+) with chemotherapy. Response rates at 24 months or more were at 83% and 35%, respectively, with pembrolizumab and chemotherapy. The median response time 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 went over to receive pembrolizumab after confirmed disease progression. In addition, an additional 35 patients in the chemotherapy arm received out-of-study anti-PD-1 / PD-L1 treatment, resulting in an effective referral rate of 59%. in the intended population.
Fewer patients treated with pembrolizumab, compared with chemotherapy, experienced a level 3 TRAE (22% vs. 66%); however, 10% and 6%, respectively, stopped treatment. TRAEs in the arms pembrolizumab and chemotherapy 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%).
Level 3 or higher intermediate AEs occurred in 9% of the pembrolizumab arm, compared with 2% in the chemotherapy arm. All intermediate-level 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 are eagerly awaiting the full survival analysis of this test later this year, as there is a lot of biomarker work to be done. And I also think in a lot of upcoming tests, in the same scenario, but also in the earlier scenario, the surrogate will continue to give us more answers. I think it’s very important from a patient’s perspective looking at this data, ”Shiu said in a pre-recorded statement about the show.
“And then we have a responsibility as clinicians to make sure that it’s not just when they have access to treatment, that we really think hard about making sure they get the way. best and integrate them with the level of care pathways and to ensure they get the best results as seen in this test, ”he said.
References:
Shiu KK, Andre T, Kim TW, et al. KEYNOTE-177: A Phase III randomized study of pembrolizumab versus chemotherapy for advanced colorectal microsatellite instability. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; January 15-17, 2021; Virtually. J Clin Onco.l 39; 2021: solair 3; abstr 6.