Pembrolizumab/Chemo With or Without Bevacizumab Has Potential as New SOC in Metastatic Cervical Cancer

Adding pembrolizumab (Keytruda) to chemotherapy, plus or minus bevacizumab (Avastin), provided clinically meaningful overall survival (OS) and progression-free survival (PFS) improvements and may be a new standard of care for women with persistent, recurrent, or metastatic cervical cancer, according to Nicoletta Colombo, MD, PhD.

Findings from the phase 3 KEYNOTE-826 trial (NCT03635567) demonstrated significant benefits in all protocol-specified primary analysis populations, including patients with a PD-L1 combined positive score (CPS) greater than 1, all-comers, and patients with a CPS greater than 10. The benefits observed were consistent across all protocol-specified subgroups, including the with and without bevacizumab subgroups. However, the addition of pembrolizumab was associated with higher overall response rates (ORR).¹

“These results provide enough data to change the standard of care for patients with persistent recurrent, or metastatic cervical cancer,” Colombo said. “I do believe that this regimen should be considered the new standard of care for this population.”

The European Commission approved pembrolizumab plus chemotherapy with or without bevacizumab for this patient population based on data from KEYNOTE-826 in April 2022.²

In an interview with OncLive^® during the 2021 ESMO Congress, Colombo, associate professor, obstetrics and gynecology, University of Milan-Bicocca, director, Ovarian Cancer Centre, chair, Program of Gynecology, European Institute of Oncology, discussed the practice-changing data to emerge from KEYNOTE-826 and the next steps for the pembrolizumab plus chemotherapy with or without bevacizumab regimen.

OncLive^®: Could you speak to the rationale for this trial?

Colombo: Cervical cancer still represents a [large] burden worldwide, with more than 600,000 new cases and more than 300,000 deaths [per year]. If the treatment of early-stage [disease] is surgery, plus or minus radiotherapy, there is a high unmet need for patients with persistent, recurrent, or metastatic cervical cancer. This is the reason KEYNOTE-826 was designed: to demonstrate the efficacy of pembrolizumab [plus] chemotherapy compared with placebo [plus] chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer.

What were the methods used in the study?

This is a prospective, randomized, phase 3, double-blind and placebo-controlled study. We randomized 617 patients with persistent, recurrent, or metastatic disease to receive pembrolizumab 200 mg [once every] 3 weeks for up to 35 cycles or matching placebo. [Pembrolizumab was combined] with standard chemotherapy based on paclitaxel, [in combination with] the physician choice of cisplatin or carboplatin. Also, patients could receive bevacizumab at the discretion of the investigators. The enrollment went from November 2018 until January 2020. Patients were stratified according to the use of bevacizumab or not, according to their PD-L1 expression, and according to the diagnosis of metastatic disease at the beginning or recurrent and persistent disease.

What were the key takeaways from the study?

This is the first study that demonstrated that PD-1 inhibitors together with chemotherapy improve efficacy in cervical cancer. In fact, we have this very important data because pembrolizumab plus chemotherapy plus or minus bevacizumab demonstrated clinically meaningful survival benefit for these patients. There were 3 populations that we analyzed according to PD-L1 expression. First was the population with a PD-L1 CPS of 1 or more, then we analyzed the all-comer population, or the intended-to-treat population, and finally, the population with a PD-L1 CPS of 10 or more.

The study demonstrated improvement in PFS and OS in all protocol-specified populations, or all primary analysis populations. Also, [the regimen] demonstrated an improvement in ORR and duration of response. To give you an idea of the benefit that we demonstrated, adding pembrolizumab reduced the risk of disease progression by 38% in the PD-L1 CPS of 1 or more population, by 35% in the all-comer population, and by 42% in the CPS of 10 or more population. The risk of death was reduced by 36%, 33%, and 39%, respectively, compared with the standard of care.

The all-comer population, the pembrolizumab plus chemotherapy with or without bevacizumab [group], had a median OS of 24.4 months, while it was only 16.4 months in the control arm. If we look at the population with a PD-L1 score of 1 or more, we see that the median OS was not reached, [as was also the case in] the PD-L1 CPS of 10 or more [population]. The control arm performed similarly, with a median OS of 16.3 and 16.5 months [respectively]. Also, we achieved an improvement in ORR and DOR.

Overall, the treatment was well tolerated. The most common grade 3 and higher adverse events were anemia and neutropenia, but none of these grade 3 adverse events were more frequent in the pembrolizumab arm compared to the standard treatment.

Looking forward, what are the next steps for this regimen?

The ability of pembrolizumab to improve outcomes even earlier in the treatment paradigm is now being assessed in another phase 3 trial, KEYNOTE-A18/ENGOT-cx11/GOG-3047 [NCT04221945]. This is a study of chemo-radiotherapy, with or without concurrent and maintenance pembrolizumab in patients with high-risk, locally advanced cervical cancer.

What was your overall message from this presentation?

Cervical cancer is a disease for which immunotherapy is quite effective. We knew already that immunotherapy or PD-1 inhibitors were effective as monotherapy in this population. Now we have this information that the combination of anti–PD-1 and chemotherapy may improve OS and PFS compared to standard of care. These [regimens] represent a new standard of care for patients with persistent, recurrent, or metastatic cervical cancer and these results are practice changing.

Are there any other noteworthy highlights you want to mention?

The improvement in PFS and OS was seen in both bevacizumab groups. So, we observed a benefit for the addition of pembrolizumab in patients receiving bevacizumab together with chemotherapy, and also in patients not receiving the bevacizumab. Many of these patients with advanced cervical cancer may not be able to tolerate bevacizumab, [such as when] the use of bevacizumab is contraindicated because of possible complications such as bowel perforation or fistula. [Therefore], bevacizumab cannot be administered to all patients with cervical cancer. Our results provide evidence that adding pembrolizumab to chemotherapy, even in patients who cannot tolerate bevacizumab, may provide a benefit in OS and PFS. These [data] represent a very important option for these patients.

Reference

1. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: Randomized, double-blind, phase III KEYNOTE-826 study. Annals of Oncology. 2021;32(5):S1283-S1346. doi:10.1016/annonc/annonc741
2. European Commission approves Merck’s KEYTRUDA® (pembrolizumab) plus chemotherapy, with or without bevacizumab, for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1). News release. Merck. April 29, 2022. Accessed May 20, 2022. https://bit.ly/38CBX79