Treatment with pembrolizumab resulted in a statistically and clinically significant improvement in progression-free survival compared with brentuximab vedotin in adults patients with relapsed or refractory classical Hodgkin lymphoma , meeting a dual primary end point of the phase III KEYNOTE-204 trial, according to the interim analysis results announced in press release from Merck.
Jonathan Cheng, MD
Treatment with pembrolizumab (Keytruda) resulted in a statistically and clinically significant improvement in progression-free survival (PFS) compared with brentuximab vedotin in adults patients with relapsed or refractory classical Hodgkin lymphoma (cHL), meeting a dual primary end point of the phase III KEYNOTE-204 trial (NCT02142738), according to the interim analysis results announced in press release from Merck.1
In addition to demonstrating a PFS benefit, there were no new safety signals observed with pembrolizumab in this study. The overall survival data were immature and therefore not included in the interim analysis.
“Patients with classical Hodgkin lymphoma are generally young and when they do not achieve remission following standard treatment, their cancer is challenging to treat,” said Jonathan Cheng, MD, vice president, oncology clinical research, Merck Research Laboratories.
These pivotal phase III data indicate a statistically significant and clinically meaningful improvement in progression-free survival with Keytruda compared, in head to head fashion, with the currently approved therapy of brentuximab vedotin. These data are strongly supportive of Keytruda’s current indication in cHL and we plan to file these data with regulatory authorities as quickly as is possible.”
The interim analysis results follow positive 3-year survival results presented at the 2019 World Conference on Lung Cancer, which showed that pembrolizumab provided a durable long-term OS benefit despite crossover from chemotherapy to pembrolizumab in most study participants.
The data cutoff for the 3-year survival update was February 15, 2019. At a median follow-up of 44.4 months (range, 39.6-52.9), the OS observed in the pembrolizumab arm was 26.3 months (95% CI, 18.3-40.4) versus 14.2 months (95% CI, 9.8-18.3) in the chemotherapy arm (HR, 0.65; 95% CI, 0.50-0.86). The 36-month OS was 43.7% among patients treated with pembrolizumab versus 24.9% among those treated with chemotherapy.2
Treatment-related adverse events (TRAEs) of grade 3 to 5 were less common in patients who received pembrolizumab (31.2%) than chemotherapy (53.3%), despite a longer mean treatment duration in the pembrolizumab arm.
In total, 38 patients in the pembrolizumab finished 2 years (33 cycles) of treatment. Of these patients, 34 were alive, and 31 had an objective response to pembrolizumab, which included 3 complete responses. The median duration of response was not reached at the time of data cutoff (range, 4.2-46.7 months). After 12 months of pembrolizumab treatment, the OS rate was 97.4% (95% CI, 82.8-99.6). Of the 38 responsive patients who completed 2 years of therapy, 13.2% had grade 3/4 TRAEs, but none were fatal. Ten of the patients who completed 2 years of therapy and subsequently were given a second treatment of pembrolizumab. Of these patients, 7 had an objective response and 8 were alive at the time of data cutoff.
Out of 305 patients, there were 210 deaths during the study, 97 of which were in the pembrolizumab arm and 113 in the chemotherapy arm. There were 98 crossovers from chemotherapy to pembrolizumab that occurred either during the study or outside of the study.
The secondary end points of the randomized, open-label study were OS and objective response rate.
In the study, pembrolizumab was administered intravenous (IV) at 200 mg on day 1 of each 21-day cycle for up to 35 cycles. For comparison, patients received either paclitaxel plus carboplatin, pemetrexed plus carboplatin, pemetrexed plus cisplatin, gemcitabine plus carboplatin, or gemcitabine plus cisplatin. Paclitaxel 200 mg/m2plus carboplatin AUC 5 or 6 was administered IV on day 1 of each 21-day cycle for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2. As additional options, IV pemetrexed 500 mg/m2plus carboplatin AUC 5 or 6, IV pemetrexed 500 mg/m2plus cisplatin 75 mg/m2, were given on day 1 of each 21-day cycle for 4 to 6 cycles. Other options included gemcitabine 1250 mg/m2plus carboplatin AUC 5 or 6, or gemcitabine 1250 mg/m2plus cisplatin 75 mg/m2and in these arms, gemcitabine was administered IV on day 1 and 8 of each 21-day cycle whereas carboplatin or cisplatin was administered on day 1 of each 21-day cycle for 4 to 6 cycles.
Patients were eligible to be included in the study if they had a histologically or cytologically confirmed diagnosis of stage IV NSCLC lacking EGFR-sensitizing mutation and/or ALK translocation and had no prior systemic chemotherapy treatment for their disease. Participants were required to have at least 1 radiographically measurable lesion per RECIST 1.1, a life expectancy of at least 3 months, an ECOG performance status of 0 or 1, and adequate organ function. Participants could not have a history of a prior malignancy with some exceptions. Patients were also required to have a PD-L1 strong expressing tumor as determined by immunohistochemistry. The study excluded individuals who did not meet these requirements as well as those with infections, and diseases that may have interfered with treatment.
Pembrolizumab is approved by the FDA for the treatment of patients with refractory cHL, or patients with cHL who have relapsed following 3 or more prior lines of therapy. The approval of pembrolizumab for this indication was based on the phase II KEYNOTE-087 trial (NCT02453594).
The agent is being studied as a potential option for patients with hematologic malignancies. KEYNOTE-024 is ongoing with a target completion date of May 2021.