carboplatin

Pembrolizumab in combination with chemotherapy improves progression free survival for women with advanced or recurrent endometrial cancer

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NRG Oncology Phase III clinical trial, NRG-GY018, evaluating pembrolizumab in combination with standard of care chemotherapy (carboplatin and paclitaxel) met its primary endpoint of progression free survival (PFS) for the treatment of patients with stage III-IV or recurrent endometrial carcinoma, regardless of mismatch repair status. A pre-specified interim analysis, conducted by an independent Data Monitoring Committee, demonstrates that pembrolizumab in combination with chemotherapy has a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in both study cohorts, mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR). The full results of this trial will be presented at an upcoming scientific conference.

NRG-GY018, a randomized, blinded, placebo-controlled study, accrued 819 women with stage III-IV or recurrent endometrial cancer. Two independent cohorts were evaluated, patients with endometrial cancers that are dMMR and patients with endometrial cancers that are pMMR. Patients were randomly assigned to receive pembrolizumab combined with carboplatin and paclitaxel (for a planned six, 3-week cycles), followed by pembrolizumab maintenance (for up to fourteen, 6 week cycles) or placebo combined with carboplatin and paclitaxel, followed by placebo maintenance.

Patients with advanced stage or recurrent endometrial cancer, the most common type of gynecologic cancer in the U.S., face a poor prognosis with limited treatment options. This is particularly notable in patients who progress after prior platinum-based adjuvant therapy with disease not amenable to curative surgery or radiation. In this study, pembrolizumab in combination with carboplatin and paclitaxel resulted in a statistically significant and clinically meaningful improvement in PFS in both the dMMR and pMMR study populations. We look forward to presenting these exciting findings at an upcoming scientific congress.”

Ramez Eskander, MD, of the University of California San Diego Moores Cancer Center and the Principal Investigator of the NRG-GY018 trial

This project was supported by the NRG Oncology Operations grant U10CA180868 and the NRG Oncology SDMC grant U10CA180822 from the National Cancer Institute (NCI), part of the National Institutes of Health and conducted by the NCI National Clinical Trials Network. Funding and support were also received from Merck & Co., Inc. through a Cooperative Research and Developmental Agreement with NCI. NRG-GY018 was conducted with funding supplemental to the CRADA from Merck in an Agreement between Merck and The GOG Foundation d/b/a NRG Oncology Philadelphia East.

Paclitaxel plus carboplatin ’preferred regimen of choice’ for gynecologic carcinosarcomas

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Paclitaxel plus carboplatin demonstrated noninferiority to paclitaxel plus ifosfamide and should be a standard treatment for uterine carcinosarcoma, according to results of a phase 3 study published in Journal of Clinical Oncology.

“The better tolerated and more convenient regimen of paclitaxel-carboplatin should be the preferred regimen of choice for gynecologic carcinosarcomas,” Matthew A. Powell, MD, professor of obstetrics and gynecology and chief in the division of and chief gynecologic oncology at Washington University School of Medicine in St. Louis, told Healio.

Survival outcomes among women.
Powell MA, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.02050.

Background

An estimated 66,570 women in the U.S. received a diagnosis of uterine cancer and another 21,410 received a diagnosis of ovarian cancer in 2021, according to study background. A regimen of paclitaxel and carboplatin has been the standard for epithelial ovarian carcinoma for decades and became the standard for endometrial carcinomas within the last 2 years.

Previous studies showed benefits of the paclitaxel-ifosfamide regimen, but the treatment has drawbacks, according to Powell.

Matthew A. Powell, MD

Matthew A. Powell

“The ifosfamide regimen (is associated with) significant toxicity in this often-frail population (and) the 3-day regimen is also very inconvenient for patients and requires growth factor support,” he told Healio. “Also, we learned that molecularly, these cancers are epithelial tumors and not true sarcomas, so perhaps the paclitaxel-carboplatin regimen would be superior.”

Methodology

Powell and colleagues tested the null hypothesis that paclitaxel-carboplatin was inferior to paclitaxel-ifosfamide in an international, open-label study that included 449 adult women with uterine carcinosarcoma. Nearly half (47.9%) had stage III or stage IV disease at enrollment.

Researchers randomly assigned 228 of the women to paclitaxel-carboplatin (median age, 65 years; 65.8% white; 28.9% Black) and 221 to paclitaxel-ifosfamide (median age, 64 years; 60.2% white; 32.6% Black), administered in 3-week cycles for six to 10 cycles.

OS from the date of randomization served as the study’s primary endpoint, with PFS, adverse events, quality of life and neurotoxicity scores as secondary endpoints.

Key findings

Paclitaxel plus carboplatin demonstrated noninferiority to paclitaxel plus ifosfamide. Results showed median OS of 37 months with paclitaxel-carboplatin vs. 29 months with paclitaxel-ifosfamide (HR = 0.87; 90% CI, 0.7-1.07) and median PFS of 16 months vs. 12 months (HR = 0.735; 95% CI, 0.58-0.93).

Researchers observed similar toxicities between the groups, with more hematologic toxicities in the paclitaxel-carboplatin group and more confusion and genitourinary hemorrhaging in the paclitaxel-ifosfamide group.

Among a separate cohort of 90 women with ovarian carcinosarcoma, researchers reported longer OS (30 months vs. 25 months) and PFS (15 months vs. 10 months) with paclitaxel and carboplatin, but the differences did not reach statistical significance.

Implications

The findings establish paclitaxel plus carboplatin as a new standard regimen for uterine carcinosarcomas of all stages, especially among women with stage III disease, researchers wrote. Future areas of study included identifying and targeting molecular aberrations within the tumors, which should lead to further improvements in treatment, they concluded.

Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study.

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Abstract

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.

We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712).

Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group.

Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation.

National Cancer Institute and Eli Lilly and Company.