However, a trend towards OS benefit was observed when treatment with cabozantinib was deferred until after disease progression vs administered upfront.
Administering cabozantinib (Cabometyx) as maintenance therapy led to higher toxicity rates and did not improve disease stabilization or response rates following treatment with doxorubicin with/without ifosfamide when compared with placebo, according to results from the phase 2 EORTC 62113-55115-STBSG-GCG study (NCT01979393).1 These data were presented at the
At median follow-up of 29 months, the median progression-free survival (PFS) was comparable between treatment arms, at 3.7 months (95% CI, 1.9-8.1) with cabozantinib (n = 30) vs 3.7 months (95% CI, 2.0-5.6) with placebo (n = 29; HR, 0.84; 95% CI, 0.43-1.64). The 4-month PFS rates were 43.3% with cabozantinib (70% Exact CI, 32.8%-54.4%) vs 41.4% with placebo (70% Exact CI, 30.8%-52.7%) for a difference of 2% (70% CI, -12% to 16%).
Similarly, the median overall survival (OS) was 27.7 months (95% CI, 10.5-not evaluable [NE]) with cabozantinib and 28.4 months (95% CI, 17.1-33.7) with placebo (HR, 1.54; 95% CI, 0.59-4.00). Best response in the cabozantinib arm (n = 19) vs placebo arm (n = 17) included complete response (CR; 5.3% with cabozantinib vs 0% with placebo), partial response (PR; 15.8% vs 11.8%), stable disease (SD; 42.1% vs 58.8%) or progressive disease (PD; 36.8% vs 29.4%). Combined CR and PR rates were 21% vs 12% with these respective regimens.
“The cabozantinib [regimen] did not [produce] PFS or OS benefits as maintenance. However, [patients who received] cabozantinib post-progression seemed to report promising OS compared with [upfront use],” presenting author Isabelle Ray-Coquard, MD, PhD, HDR, shared with OncLive®. Ray-Coquard is a professor of medical oncology at Université Claude Bernard Lyon 1 and medical oncologist at the Centre Léon Bérard, Lyon, France.
High-grade uterine sarcomas are rare malignancies associated with poor prognosis and a high risk of recurrence, and responses with standard doxorubicin-based chemotherapy remain limited. Prior evidence has shown that angiogenesis plays a key role in the growth and dissemination of high-grade uterine sarcomas and other soft tissue sarcomas, and elevated VEGF expression has been associated with an increased risk of metastases and reduced OS. Given the activity of VEGF-targeting agents in soft tissue sarcomas, the multikinase inhibitor cabozantinib was chosen for evaluation as a maintenance strategy following chemotherapy in the EORTC 62113-55115-STBSG-GCG study.
This randomized, blinded, placebo-controlled phase 2 trial was conducted by the EORTC Soft Tissue Bone Sarcoma Group in cooperation with the EORTC Gyneacological Cancer Group and Clinical Trials Unit Glasgow, and was developed with the International Rare Cancers Initiative framework. At registration, eligible patients were required to be diagnosed with disease relapse after local treatment of the primary tumor, be suitable for doxorubicin with or without ifosfamide, and have histological evidence of either high-grade leiomyosarcoma (HGLMS), high-grade endometrial stromal sarcoma (HGESS), undifferentiated uterine sarcoma (UUS), or high-grade adenosarcoma.1,2 If undergoing adjuvant chemotherapy, patients must have had FIGO stage II or stage III disease; if chosen for first-line chemotherapy, patients must have had FIGO stage IV disease. At the time of randomization, patients must have had central pathological confirmation of disease and have achieved a CR, PR, or SD at the end of standard first-line treatment with 4 to 6 cycles of anthracyclines alone or in combination with ifosfamide. Organ, marrow function, and laboratory values also needed to be within eligible ranges.
A total of 115 patients from 17 institutions across 7 countries were enrolled onto the study between February 2015 and June 2021.1 Of these, 56 patients were considered randomization failures due to PD (39.0%), no central confirmation (27.0%), and patient refusal (13.0%). The remaining 59 patients were randomly assigned to either 60 mg of cabozantinib or placebo as maintenance daily for 2 years or until withdrawal. Following documented PD per RECIST 1.1 criteria, treatment was unblinded.2 Patients received further treatment at the investigator’s discretion. Of note, crossover to cabozantinib was permitted after placebo. Criteria for withdrawal included PD, second malignancy, patient refusal, excessive toxicity, or unblinding.1
The study’s primary end point was PFS at 4 months. Secondary end points included PFS, OS, response rate, duration of response, safety, dose modifications, and quality of life.
The median age of patients across both treatment arms was 57 years. Regarding histologic subtype, most patients had UUS (45.8%) followed by HGLMS (39.0%), HGESS (10.2%), and HG adenosarcoma (5.1%). Most patients had not received first-line ifosfamide (57.6%) or prior radiotherapy (81.4%), had metastatic disease (62.7%), inoperable tumors (62.7%), and had achieved a CR or PR to chemotherapy (55.9%).
Protocol treatment was administered to 94.9% of patients for a median of 4.5 (range, 1-27) treatment cycles for a median of 16.9 weeks. Dose interruptions (48.2%) or reductions (33.9%) occurred due to non-hematologic adverse effects (AEs; 79.5% interruptions; 76.0% reductions), patient decision (6.8%; 16.0%), hematological AEs (2.3%; 4.0%), or other reasons (11.4%; 4.0%).
Of the 29 patients in placebo arm, 72.4% crossed over to receive a median of 8 cycles (range, 1-22) of cabozantinib. The main reason for discontinuation in this cohort included PD (85.7%), toxicity, required radiotherapy, or ongoing treatment (4.8% each). Notably, fewer patients who started crossover had adjuvant disease at randomization (28.6%) than those who did not cross over (62.5%). Age at randomization and response rates at the end of first-line chemotherapy were comparable between cohorts. Histologic subtypes present in the crossover cohort included HGUS (47.6%), HGLMS (47.6%), and HG adenosarcoma (4.8%). In contrast, those who did not start crossover had HGUS (75.0%), HGESS (12.5%) and HGLMS (12.5%).
Deferring treatment with cabozantinib until after PD resulted in a trend towards improved survival compared with its use as upfront maintenance. Among patients who stopped treatment with placebo due to PD and received cabozantinib in the second line (n = 20), the median OS was 19.0 months (95% CI, 11.3-30.6). The respective 6-, 12-, and 18-month OS rates were 95.0% (95% CI, 69.5%-99.3%), 74.6% (95% CI, 45.3%- 89.8%), and 54.3% (95% CI, 27.1%-75.2%).
Conversely, patients who stopped maintenance cabozantinib due to progression and subsequently switched to another anticancer treatment achieved a median OS of 6.9 months (95% CI, 1.7-not evaluable). The 6-month OS rate was 64.8% (95% CI, 25.3%-87.2%); 12- and 18-month OS rates were both 32.4% (95% CI, 5.0%-65.4%).
Treatment discontinuation occurred due to PD (64.3%), normal completion (14.3%), toxicity (12.5%), ongoing treatment (5.4%), unblinding (1.8%), or patient decision (1.8%).
Safety analyses showed that overall toxicity rates were higher with cabozantinib vs placebo as maintenance. The rate of grade 3 or higher AEs was 65.5% vs 14.8% in these respective arms. The most reported AEs were gastrointestinal disorders (any grade, 93.1%; grade 3 or higher, 20.7%) and vascular disorders (79.3%; 41.4%). One death due to pulmonary embolism occurred in the cabozantinib arm.
Disclosures: Dr Ray-Coquard disclosed receiving personal honoraria from AbbVie, Adaptimmune, Agenus, Amgen, AstraZeneca, BMS, Clovis, Corcept, Daiichi Sankyo, Deciphera, Eisai, EQRx, GSK, Genmab, Gilead, Immunocore, Lilly, MacroGenics, Merck Serono, Mersana, Novartis, Onxeo, Roche, Sutro Biopharma, Scorpion, and ITM pharma; institutional honoraria from MSD (translational research); institutional funding from BMS, DSI, and GSK; and travel funding from AbbVie, AstraZeneca, BMS, GSK, and MSD.
