OS benefit of pembrolizumab regimen ‘great news’ for women with recurrent cervical cancer
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The addition of pembrolizumab to chemotherapy, with or without bevacizumab, significantly improved PFS and OS among women with persistent, recurrent or metastatic cervical cancer, results of the randomized phase 3 KEYNOTE-826 study showed.
The combination, which demonstrated clinically meaningful improvement regardless of PD-L1 tumor expression, may represent a new standard of care for this patient population, according to findings presented at the virtual ESMO Congress 2021.
“This is great news for patients,” Bradley J. Monk, MD, FACS, FACOG, professor at Creighton University School of Medicine and University of Arizona College of Medicine, director of gynecologic oncology research at US Oncology Network and co-director of the Gynecologic Oncology Group, told Healio. “In over 2 decades, we have gone from no chemotherapy, to chemotherapy, to chemotherapy and bevacizumab, and now chemotherapy, bevacizumab and pembrolizumab.”
KEYNOTE-826 included 617 women with persistent, recurrent or metastatic cervical cancer that had not been treated with systemic chemotherapy and was not amenable to curative therapy. Researchers randomly assigned 308 women (median age, 51 years) to 200 mg pembrolizumab (Keytruda, Merck) and 309 women (median age, 50 years) to placebo every 3 weeks for up to 35 cycles. All women also received chemotherapy with paclitaxel and cisplatin or carboplatin, and 63.6% in the pembrolizumab group and 62.5% in the placebo group also received bevacizumab (Avastin, Genentech). Researchers stratified women according to metastatic status at diagnosis, planned use of bevacizumab and PD-L1 combined positive score (CPS).
PFS assessed by investigator review according to RECIST version 1.1 and OS served as primary endpoints, tested sequentially in 548 women with a PD-L1 CPS of 1 or greater, the all-comer population, and 317 women with a PD-L1 CPS of 10 or greater.
Results of the first preplanned interim analysis, presented during ESMO and published simultaneously in The New England Journal of Medicine, showed median PFS of 10.4 months in all three groups with pembrolizumab and chemotherapy vs. 8.2 months with placebo and chemotherapy for women with a PD-L1 CPS of 1 or greater (HR = 0.62; 95% CI, 0.5-0.77) and all women (HR = 0.65; 95% CI, 0.53-0.79) and 8.1 months for women with a PD-L1 CPS of 10 or greater (HR = 0.58; 95% CI, 0.44-0.77). The 12-month PFS rate among all women was 44.7% with pembrolizumab regimen vs. 33.5% with placebo (HR = 0.65; 95% CI, 0.53-0.79), with similar rates among the PD-L1 subgroups.
Median OS in the all-comer population was 24.4 months with pembrolizumab vs. 16.5 months with placebo (HR = 0.67; 95% CI, 0.54-0.84), which Monk described as “a huge incremental jump.” Median OS was not reached in either of the PD-L1 subgroups.
OS rates at 24 months were 53% vs. 41.7% for women with a PD-L1 CPS of 1 or greater, 50.4% vs. 40.4% for all women, and 54.4% vs. 44.6% for women with a PD-L1 CPS of 10 or greater.
Researchers observed the survival benefit regardless of bevacizumab use.
“Bevacizumab should be used when it can,” Monk said. “If you look at the hazard ratio when bevacizumab is added, it’s better enough to justify its use.”
Grade 3 or higher adverse events occurred among 81.8% of the pembrolizumab group and 75.1% of the placebo group and included anemia (30.3% vs. 26.9%) and neutropenia (12.4% vs. 9.7%). Adverse events that led to discontinuation of any treatment occurred in 37.5% of patients in the pembrolizumab group vs. 26.5% of patients in the placebo group, and 5.9% vs. 4.9% for all treatments.
“At the first interim analysis, the sponsor and the data safety monitoring committee said, ‘Wow, this is a big deal.’ You have an improvement in response rate, progression-free survival, overall survival and even patient-reported outcomes are looking more favorable,” Monk told Healio. “So not only are patients living longer ... they might even live better. And these are young women in their late 40s and 50s.”
Monk said KEYNOTE-826 will rapidly launch pembrolizumab as the global standard of care in first-line metastatic cervical cancer.
“Next will be adding checkpoint inhibitors to chemotherapy and radiation in an attempt to cure more patients. That sort of has already been validated in the PACIFIC trial with durvalumab [Imfinzi, AstraZeneca] in lung cancer, so we’re getting there. Ultimately, the real solution — just like in COVID — is to get vaccinated.”
References:
- Colombo N, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
- Colombo N, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2112435.
Perspective
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Mehdi M. Kebria, MD
Over the past few years, significant progress has been made in understanding the immune system’s role in the development of cancer and the use of immune system modulators in management of various types of cancers. Use of PD-1 blockade for reversing tumor-mediated immunosuppression has been one of the most important developments in immuno-oncology. Previous studies had shown use of pembrolizumab as second-line therapy for patients with PD-L1-positive recurrent cervical cancer was associated with improvement in PFS.
KEYNOTE-826 is the first study to show survival benefit of immunotherapy in first-line and recurrent metastatic cervical cancer. This randomized phase 3 trial enrolled patients with persistent, recurrent or metastatic disease who had not been treated previously with systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation therapy. The well-conducted study showed improvement in PFS and OS regardless of biomarker status. Median OS was not reached in the investigational arm of this trial. However, OS at 24 months was 10% to 12% higher than in the placebo group, with over 50% of the patients alive at 2-year follow up. The toxicity profile appears to be acceptable.
I believe this information is management-changing and use of pembrolizumab will become widely approved and standard of care in first-line treatment of metastatic cervical cancer. Future studies should look at role of immunotherapy in the adjuvant setting in locally advanced cervical cancer. It would be important to review quality-of-life data from the KEYNOTE-826 study.
Perspective
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Stephanie V. Blank, MD
KEYNOTE-826 is practice-changing. The study shows an impressive increase in both OS and PFS for these women, who in the past had few options. Adding pembrolizumab to chemotherapy reduced the risk for death by 33%, extended survival by 8 months, and lowered the likelihood of disease progression or death by 35%.
KEYNOTE-826 is notable because it moves immunotherapy earlier in the treatment course for people with advanced or recurrent cervical cancer — to the front line for systemic therapy — and is the first study to show such positive results for anti-PD-L1 therapy plus chemotherapy in this setting. It also confirms the signal seen for pembrolizumab in second-line treatment for advanced or recurrent cervical cancer. Interestingly, PD-L1 was not a predictive biomarker.
It would be ideal if we could answer the question of whether the improvement seen with the addition of pembrolizumab to paclitaxel/carboplatin requires bevacizumab. Bevacizumab may increase the immunogenicity of the tumor, but if it is not adding to the improvements in survival shown in this study, we could avoid using four drugs when three will do. This could mitigate some of the financial toxicity associated with this regimen.
But the take-home message here is that pembrolizumab, when added to chemotherapy with or without bevacizumab as first-line systemic therapy for advanced or recurrent cervical cancer, improves survival and marks an advancement in the field. I applaud and thank the authors as well as the 617 patients and their families.
Perspective
Back to TopMansoor Raza Mirza, MD
[KEYNOTE-826 showed] a statistically significant benefit in the intention-to-treat population, treatment is fairly well-tolerated, and I would say this should be — not may be, as Dr. [Colombo] said — the new standard of care for our patients. However, there are more questions coming up. Is this combination effective in primary metastatic disease? In a biomarker-negative population? In adenocarcinomas? Given without bevacizumab? My take-home message for you would be that pembrolizumab plus chemotherapy with bevacizumab in a biomarker-positive population shall be the new standard of care for women with persistent, recurrent or perhaps primary metastatic cervical cancer.
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Colombo N, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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