Merck & Co. released detailed results from both the Phase III KEYNOTE-716 and KEYNOTE-826 trials, building up evidence to support introducing its PD-1-blocking antibody Keytruda (pembrolizumab) earlier in the treatment course for patients with melanoma and cervical cancer. Data from both studies were presented Saturday at the European Society for Medical Oncology (ESMO) congress.
Last month, Merck said KEYNOTE-716 had achieved its primary endpoint of recurrence-free survival, prompting the FDA to assign a priority review to the company's filing for adjuvant Keytruda in patients 12 and older with stage II melanoma following complete resection. A target action date has been set for December 4. At the moment, Keytruda's melanoma indication includes treating advanced disease, or for use as an adjuvant therapy in patients with lymph node involvement following complete resection.
The KEYNOTE-716 study recruited 976 adult and paediatric patients with complete resection of cutaneous-stage IIB or IIC melanoma and no lymph node involvement, who were randomised to adjuvant Keytruda or placebo for up to one year. Researchers said Keytruda cut the risk of recurrence by 35%, compared to placebo, with 54 patients on Merck's drug experiencing recurrence during the 14-month follow-up period, versus 82 in the placebo arm. There were also 23 and 38 cases of distant recurrences, respectively, in the two groups.
"There has been a belief that early-stage melanoma doesn't recur very fast and that these patients don't develop metastatic disease," commented study author Jason Luke, but the KEYNOTE-716 data "clearly disprove that, and show that patients with high-risk stage II melanoma recur quickly and distantly, just the same as patients with stage IIIA and IIIB." Still, despite an equivalent risk of recurrence and death, an observation approach is typically used for stage II melanoma patients, whereas stage III patients receive adjuvant therapy.
Luke said side effects may have held back use of adjuvant treatment in the stage II setting, but "when the only available therapies were high-dose interferon and ipilimumab (Bristol Myers Squibb's CTLA-4 inhibitor Yervoy), both of which were associated with more than 50% rates of severe [adverse events (AEs)], that just wasn't tolerable for patients with early-stage disease." He suggested that anti-PD-1 treatment, however, could offer "a much more attractive risk/benefit scenario."
Discontinuations in KEYNOTE-716 due to drug-related AEs were higher in the Keytruda group at 15.3%, compared to 2.5% for placebo. Immune-mediated AEs were also more common at 36.2%, versus 8.4% for placebo. No deaths due to any-cause AEs or drug-related AEs occurred with Keytruda, versus four in the placebo arm.
Omid Hamid, chair of melanoma and other skin tumours at ESMO, said that aside from longer-term follow-up needed to see if there is any overall survival (OS) benefit, "we also need to determine what giving adjuvant anti-PD-1 therapy in stage II B/C means for stage III patients who recur and would currently receive this treatment." He believes regimens currently used in the metastatic setting will eventually be introduced earlier in stage III disease – highlighting ongoing trials that are testing novel combinations of anti-PD-1 drugs plus VEGF targeted therapies, pegylated IL-2 or anti-LAG-3 antibodies, as potential candidates for stage III melanoma.
Meanwhile, the KEYNOTE-826 study demonstrated that adding Keytruda to standard treatment extended survival in first-line cervical cancer by eight months. Merck's immunotherapy won accelerated approval from the FDA in 2018 to treat cervical cancer in second-line patients whose tumours express PD-L1 with a combined positive score (CPS) ≥1.
KEYNOTE-826, which was top-lined in June, enrolled 617 women with persistent, recurrent or metastatic cervical cancer who had received no prior systemic chemotherapy. Subjects were randomised to Keytruda or placebo, both given concurrently with chemotherapy, while some also received Roche's Avastin (bevacizumab) at their doctor's discretion.
Results showed that the Keytruda combination significantly improved both progression-free survival (PFS) and OS compared to chemotherapy, reducing the risk of death by 33% and the likelihood of disease progression or death by 35% (see table below for further results). Study author Nicoletta Colombo said the benefit was seen regardless of background Avastin therapy, although the study was not powered to compare outcomes in Avastin subgroups. Still, she said that even without Roche's drug, adding Keytruda to chemotherapy "has clinically meaningful benefit."
Merck noted that its drug is the first anti-PD-(L)1 treatment to show an OS improvement in combination with chemotherapy in these patients. Meanwhile, Agenus is also developing an anti-PD-1 antibody as a treatment for cervical cancer. The FDA recently granted a priority review to its filing for balstilimab to treat recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
The submission is based on data presented at last year's ESMO conference showing response rates of 19% in PD-L1 positive tumours, 14% in PD-L1 positive and negative tumours, and a median DoR of 15.4 months. The FDA is expected to make a decision on that application by December 16. The company is also testing balstilimab together with its CTLA-4 inhibitor zalifrelimab and said final results from a Phase II trial, presented at ESMO this weekend, boosted ORR to 33% in patients with recurrent or metastatic cervical cancer expressing PD-L1. The ORR in all patients was 26%, including 9% achieving complete responses, with median DoR not reached with 19.4 months of follow-up.
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