S1701: A randomized phase II trial of carboplatin-paclitaxel with and without ramucirumab in patients with locally advanced, recurrent, or metastatic thymic carcinoma.
Authors: Tsao Anne S. , Hsieh Ming-Hui , Koczywas Marianna , Tu Janet Chen , Riess Jonathan W. , Tanvetyanon Tawee , Ma Barbara Ting-wen , Zhao Yingqi , Redman Mary Weber , Edelman Martin Joseph , Gandara David R. , Kelly Karen , Gray Jhanelle E. 
Published: June 2024

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Background: Thymic carcinoma, a rare malignancy, presents treatment challenges due to its aggressiveness and poor response to standard chemotherapy. Angiogenic pathway activation is implicated in its pathogenesis. S1701 evaluated the efficacy and safety of ramucirumab, an anti-angiogenic monoclonal antibody, in combination with carboplatin-paclitaxel. Methods: We conducted a randomized phase II trial with patients having histologically confirmed, unresectable thymic carcinoma and no prior therapy for recurrent or metastatic disease. Patients were randomized to receive carboplatin-paclitaxel with or without ramucirumab for 6 cycles, followed by maintenance ramucirumab for patients without progression. The primary endpoint was progression-free survival (PFS), assessed by RECIST 1.1. Secondary endpoints included response rate, safety and toxicity. The primary analysis was done using a 1-sided 10% level log-rank test. Target sample size was 66 patients. Results: Between 2018-2022, 21 patients enrolled to ramucirumab plus carboplatin-paclitaxel (RCP, n = 8) and to the control arm (CP, n = 13). Three patients in the control arm were excluded from the efficacy analysis, as one was ineligible and 2 had non-measurable disease. No grade 4 or higher treatment-related adverse events occurred in the RCP arm, although 50% (4 out of 8) experienced grade 3 adverse events and 2 patients discontinued ramucirumab due to toxicity. There were no grade 3 or higher thromboembolic or bleeding events in the RCP arm. Among 9 evaluable patients for safety in the control arm (3 withdrew consent prior to initiating therapy), 11% encountered grade 4 neutropenia and 11% reported grade 3 thromboembolic events. Response rate favored the RCP arm, with an 88% [80% CI 59% - 99%] partial response rate compared to 40% [80% CI 19%-65%] in the control arm (Figure, p = 0.04). Disease control rate was higher in the RCP arm (100% vs 70%, p = 0.0897). At median follow-up time of 16.7 months, PFS was not different (hazard ratio [80% CI]: 0.51 [0.24 – 1.09]; p = 0.13). Median PFS was 8 months for RCP and 7 months for the control arm. At this time, OS remains immature. Conclusions: The addition of ramucirumab to CP led to higher response rates than CP alone. At this early analysis, PFS was not significantly improved; OS is pending. High-grade adverse events necessitate careful patient selection. Insights from S1701 emphasize the potential of targeting the angiogenic pathway, although larger trials are needed to confirm these findings. Future research should consider exploring larger multicenter trials and other combinations to improve outcomes. Challenges in enrollment emphasize the need for innovative strategies and larger collaborations in rare malignancies like thymic carcinoma. Funding: NIH/NCI/NCTN grant awards U10CA180888 and U10CA180819 and in part by Eli Lilly. Clinical trial information: 03694002.