SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity. RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov). PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

A phase I/II study of trimetrexate and capecitabine in patients with advanced refractory colorectal cancer.

OBJECTIVE: We tested the hypothesis that the combination of trimetrexate (TMTX) and capecitabine (CAP) would be active in patients with previously treated metastatic colorectal cancer (CRC). Because the optimum dose of this combination was unknown, we used a phase I/II design. METHODS: In the phase I cohort, patients received 110 mg/m2 TMTX intravenously weekly x6 and CAP starting at 750 mg/m2 orally twice daily from days 2 to 15 and 23 to 36 (one cycle). Cycles were repeated every 8 weeks. The phase II doses were 110 mg/m2 TMTX and 1000 mg/m2 CAP orally twice daily. RESULTS: Thirty-two patients were entered. All patients had prior 5-fluorouracil therapy and 94% had prior exposure to irinotecan. Grade 3/4 toxicities included abdominal pain in 4 patients (12.5%) and vomiting in 3 patients (9.4%). Twenty-seven patients were evaluable for response: one patient each had a complete response and a partial response for an overall response rate of 7.4%. The median time to progression was 3.3 months (95% confidence interval [CI], 1.6-3.7 months) and the median overall survival was 5.9 months (95% CI, 5.2-10.2 months). CONCLUSIONS: The combination of TMTX and CAP is well tolerated. However, recent studies have shown more active regimens in the second- and third-line metastatic setting.

A phase II trial of weekly paclitaxel, 5-fluorouracil, and leucovorin as first-line treatment for metastatic breast cancer.

PURPOSE: This phase II multicenter trial evaluated the efficacy and toxicity of weekly paclitaxel, 5-fluorouracil, and leucovorin administered as first-line therapy for metastatic breast cancer. PATIENTS AND METHODS: The study enrolled 155 women with pathologically confirmed and measurable metastatic adenocarcinoma of the breast. Treatment consisted of paclitaxel 80 mg/m2, 5-fluorouracil 425 mg/m2, and leucovorin 20 mg/m2 administered weekly 4 x per 4-week cycle in the first 40 patients enrolled (group 1), and weekly 3 x per 4-week cycle in the subsequent 115 patients (group 2) enrolled. Hematologic growth factor support was not routinely used. Twenty patients with hepatic dysfunction were enrolled to assess the tolerability of the regimen in this population. All therapies were delivered in an outpatient setting. RESULTS: The overall response rate was 48%, with 12-month estimated survival rates of 53% and 65% for treatment groups 1 and 2, respectively. Response rates were not statistically different between the two treatment schedules. Therapy was well tolerated when delivered on the every 3 of 4-week schedule, including patients with hepatic involvement and those age > or = 65. CONCLUSION: Weekly therapy with paclitaxel and 5-fluorouracil with leucovorin is active as first-line therapy for metastatic breast cancer. Use of this regimen should be given consideration, particularly in patients who are not candidates for anthracycline-based therapy.