Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial

Author(s): Matthew A. Powell, MD¹; Virginia L. Filiaci, PhD²; Martee L. Hensley, MD³; Helen Q. Huang, MS²; Kathleen N. Moore, MD⁴; Krishnansu S. Tewari, MD⁵

Source: DOI: 10.1200/JCO.21.02050 Journal of Clinical Oncology Published online January 10, 2022. PMID: 35007153

Dr. Lucio Gordan's Thoughts

Many of us have used platinum/paclitaxel in this setting but this study helps to corroborate the clinical practice.

PURPOSE

This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS).

PATIENTS AND METHODS

Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test.

RESULTS

The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant.

CONCLUSION

PC was not inferior to the active regimen PI and should be standard treatment for UCS.

Author Affiliations

¹Washington University School of Medicine, St Louis, MO; ²NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY; ³Memorial Sloan-Kettering Cancer Center, New York, NY; ⁴The Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK; ⁵University of California, Irvine, Division of Gynecologic Oncology, Orange, CA; ⁶Ohio State University, Columbus, OH; ⁷Duke Cancer Institute, Durham, NC; ⁸Washington University, St Louis, MO; ⁹Yale University, Obstetrics and Gynecology, Division of Gynecologic Oncology, New Haven, CT; ¹⁰Cooper Hospital University Medical Center, Camden, NJ; ¹¹Women’s Cancer Center, Las Vegas, NV; ¹²Women and Infants Hospital, Providence, RI; ¹³University of Maryland Medical Center, Baltimore, MD; ¹⁴UT Southwestern Medical Center at Dallas, Dallas, TX

Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial

Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. Adding it to nab-paclitaxel in platinum resistant ovarian cancer pateints had18-m overall survival was 46% and 27%. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16· vs 11·9 months.

Pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer (ENGOT-ov65/KEYNOTE-B96): a multicentre, randomised, double-blind, phase 3 study

Participants (who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum) regime were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator. Overall survival (OS) was significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76
OS was significantly improved in the overall population (median 17·7 m vs 14·0 m, hazard ratio (HR) 0·82

Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial

This is another well-done study that, frankly, confirms what we’ve seen elsewhere—PDL1 inhibition does not seem to meaningfully change outcomes in platinum-resistant ovarian cancer, even when added to chemo + bev.

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201

The ENGOT-OV60/GOG-3052/RAMP 201 phase II trial evaluated avutometinib (a RAF/MEK clamp) plus defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC), showing a confirmed objective response rate (ORR) of 31% (44% in KRAS-mutant, 17% in KRAS wild-type) and a median progression-free survival (PFS) of 12.9 months (22.0 vs 12.8 months for KRAS-mutant vs wild-type). The median duration of response was notably long at 31.1 months, and the disease control rate was 88%. The most common grade ≥3 AEs were elevated creatine phosphokinase (CPK) (24%), diarrhea (8%), and anemia (5%), with a 10% discontinuation rate due to adverse events (AEs); so management of AE’s is key for using this new drug combo. This combination looks like a real contender for a new standard in recurrent LGSOC, especially for KRAS-mutant patients.

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial

Adding Atezo to combination chemotherapy with bevacizumab did not meet the primary end point of PFS. Regardless of the PDL-1 status it was also more toxic. It seems that ovarian cancer is still immune to immunotherapy.