The Food and Drug Administration (FDA) has approved new treatments for endometrial cancer and Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (Ph-negative BCP ALL). These advancements promise to enhance therapeutic options and improve outcomes for patients with these challenging conditions.
Endometrial Cancer
On June 14th, 2024, the FDA has approved durvalumab with carboplatin plus paclitaxel followed by single-agent durvalumab for adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR).
The approval is based on results from the DUO-E trial, a randomized, multicenter, double-blind, placebo-controlled study. This trial involved patients with primary advanced or recurrent endometrial cancer, stratified by tumor MMR status determined via immunohistochemistry. Participants were randomized into three groups:
- Durvalumab 1,120 mg with carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by durvalumab 1,500 mg every 4 weeks until disease progression.
- Placebo with carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by placebo every 4 weeks until disease progression.
- An additional investigational combination regimen.
The primary measure of efficacy was progression-free survival (PFS), assessed using RECIST v1.1 criteria. The study found a statistically significant improvement in PFS for the durvalumab combination compared to the carboplatin and paclitaxel alone, with notable benefits observed in patients with dMMR tumors. Among 95 patients with dMMR tumors, median PFS was not reached in the durvalumab arm, compared to 7 months in the placebo arm, indicating a hazard ratio of 0.42.
The most common adverse reactions reported in over 25% of patients receiving durvalumab with carboplatin and paclitaxel included peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough.
On June 17th, 2024, the FDA approved the use of pembrolizumab in combination with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.
The approval was based on the results of the KEYNOTE-868/NRG-GY018 trial, a multicenter, randomized, double-blind, placebo-controlled study involving 810 patients. These patients were divided into two cohorts based on their mismatch repair (MMR) status: 222 patients with dMMR and 588 patients with mismatch repair proficient (pMMR) endometrial carcinoma.
Participants were randomly assigned (1:1) to receive either:
- Pembrolizumab 200 mg every 3 weeks, combined with paclitaxel 175 mg/m² and carboplatin AUC 5 mg/mL/min for six cycles, followed by pembrolizumab 400 mg every 6 weeks for up to 14 cycles, or
- A placebo every 3 weeks, combined with the same doses of paclitaxel and carboplatin for six cycles, followed by a placebo every 6 weeks for up to 14 cycles.
The primary measure of efficacy was PFS, assessed according to RECIST 1.1 criteria. In the dMMR cohort, patients receiving pembrolizumab and chemotherapy had a median PFS that was not reached compared to 6.5 months for those receiving placebo and chemotherapy. In the pMMR cohort, median PFS was 11.1 months for the pembrolizumab and chemotherapy group versus 8.5 months for the placebo and chemotherapy group. The safety profile of pembrolizumab in combination with chemotherapy was consistent with known adverse reactions, although a higher incidence of rash was noted.
Ph-Negative BCP ALL
On June 14th, 2024, the FDA also approved blinatumomab for adult and pediatric patients one month and older with CD19-positive Ph-negative BCP ALL in the consolidation phase of multiphase chemotherapy.
Efficacy was first evaluated in Study E1910, a randomized, controlled trial in adult patients with newly diagnosed Ph-negative BCP ALL. Patients in complete or incomplete remission after initial chemotherapy were randomly assigned to receive either blinatumomab combined with intensive chemotherapy cycles or intensive chemotherapy alone. Results demonstrated a significant improvement in 3-year overall survival (OS), with rates of 84.8% for blinatumomab versus 69% for chemotherapy alone. A follow-up analysis at 5 years showed continued benefit with blinatumomab (82.4%) compared to chemotherapy (62.5%).
Efficacy was also evaluated in Study 20120215 a randomized, controlled, open-label, multicenter trial which compared blinatumomab against the IntReALLHR2010 HC3 intensive combination chemotherapy as the third consolidation cycle. Patients were randomized based on age, minimal residual disease status at the end of induction, and bone marrow status after the second block of consolidation chemotherapy. Results showed a significant improvement in 5-year OS with blinatumomab (78.4%) compared to chemotherapy (41.4%). Additionally, blinatumomab demonstrated a superior 5-year relapse-free survival (RFS) of 61.1% versus 27.6% with chemotherapy.
References:
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-chemotherapy-mismatch-repair-deficient-primary-advanced-or-recurrentÂ
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-blinatumomab-consolidation-cd19-positive-philadelphia-chromosome-negative-b-cell
Viktor Grünwald
