Novel combination of immunotherapy and tyrosine kinase inhibitor for recurrent cervical cancer: balancing efficacy and toxicity

There is an urgent need for better treatment options to improve the poor prognosis for patients with recurrent and metastatic cervical cancers (1). Approximately 15% of patients with cervical cancer have metastatic disease at initial diagnosis (2), and more than half of patients with cervical cancer will eventually develop metastatic disease (3). The median overall survival (OS) in these settings is 8 to 13 months (4), with a 5-year survival rate as low as 5% to 15% (5,6). Recent studies show that adding immunotherapy to standard palliative chemotherapy with or without bevacizumab (7), an antiangiogenic agent, can slightly improve survival outcomes (8).

Pembrolizumab is a monoclonal antibody that binds to programmed cell death protein-1 (PD-1) and has limited single-agent activity as monotherapy in recurrent programmed death-ligand 1-positive (PD-L1+) cervical cancer. Pembrolizumab in combination with standard platinum-taxane chemotherapy with or without bevacizumab is approved by the US Food and Drug Administration as a first-line therapy for PD-L1+ recurrent and metastatic cervical cancers (9). This approval was based on results of the KEYNOTE-826 trial, which showed a 36% reduction in risk of death [hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.5–0.8] with the addition of pembrolizumab for patients with PD-L1+ cancer.

A second recently published study showed that addition of atezolizumab, an anti-PD-L1 checkpoint inhibitor, to standard chemotherapy and bevacizumab improved survival outcomes for patients with metastatic and/or recurrent cervical cancer. The addition of atezolizumab resulted in a 9-month improvement in OS [HR: 0.68; 32 months (95% CI: 24–37) vs. 23 months (95% CI: 20–28)] and a similar rate of grade ≥3 treatment-related adverse events (TRAEs; 79% vs. 75%) (8).

The use of vascular endothelial growth factor (VEGF) blockade and immunotherapy also has been explored in later lines of therapy. A multicohort, adaptive, open-label, nonrandomized phase 2 study (NCT03827837) conducted in China showed antitumor activity for camrelizumab (CAM; anti-PD-1 antibody) plus famitinib [FAM; antiangiogenic multi-targeted tyrosine kinase inhibitor (TKI) against VEGFR2/3] in patients with recurrent or metastatic cervical cancer (10). This trial enrolled patients between 18 and 75 years of age with cervical squamous cell carcinoma measurable by Response Evaluation Criteria in Solid Tumors (RECIST) who had received one or two prior lines of systemic therapy for recurrent or metastatic disease. Participants who received prior treatment with PD-1 or PD-L1 antagonists or FAM were excluded. Eligible patients were treated with 200 mg of CAM intravenously (IV) on day 1 of a 3-week cycle plus 20 mg of FAM orally once daily. The primary endpoint was objective response rate (ORR). A total of 33 patients were enrolled, with a median follow-up of 13.6 months. The ORR was 39.4% (95% CI: 22.9–57.9%), with a median progression-free survival (PFS) of 10.3 months (95% CI: 3.5–not reached) and a 12-month OS rate of 77.7% (95% CI: 58.9–88.7%). All patients experienced TRAEs, and 79% experienced a grade ≥3 TRAE. The authors concluded their results suggested durable antitumor activity and a manageable safety profile of CAM plus FAM (CAM + FAM) in patients with recurrent or metastatic cervical cancer.

Wu et al. presented the results of their randomized three-arm phase 2 study (11) at the European Society for Medical Oncology (ESMO) Congress 2023. The study explored the combination of antiangiogenic therapy and immunotherapy in immunotherapy-naïve patients with platinum-treated recurrent or metastatic cervical cancer, a group who continues to have a grim prognosis despite recent advances in first-line treatment (1,8,9). The combination of CAM and FAM was compared to two monotherapy arms, CAM and investigator’s choice of single-agent chemotherapy. The investigators hypothesized the combination of an anti-PD-1 immunotherapy with an antiangiogenic agent would enhance the immunoreactivity of the tumor. Patients with cervical cancer who had experienced disease progression following prior platinum-based chemotherapy and who had not previously received prior anti-PD-1/PD-L1/CTLA-4 treatment were assessed for eligibility. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Patients were stratified based on histologic subtyping (squamous cell carcinoma vs. non-squamous cell carcinoma) and PD-L1 expression status [combined positive score (CPS) ≥1 vs. CPS <1].

Patients treated with CAM + FAM (cohort A) received 200 mg of CAM IV every 3 weeks plus 20 mg of FAM orally once daily. Patients treated with CAM (cohort B) received 200 mg of CAM IV every 3 weeks. Patients treated with investigator’s choice of single-agent chemotherapy (cohort C) received either nab-paclitaxel (260 mg/m² on day 1 every 3 weeks or 125 mg/m² on days 1, 8 and 15 every 4 weeks); 500 mg/m² of pemetrexed on day 1 every 3 weeks; or 1,000 mg/m² of gemcitabine on days 1 and 8 every 3 weeks. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, investigator-initiated termination, or loss to follow-up. The primary endpoints at study inception were PFS and OS; however, the endpoint was later modified to ORR. In addition, disease control rate (DCR), which was defined as the number of subjects with a best overall response of complete response (CR), partial response (PR), or stable disease per RECIST version 1.1, was also assessed. The CAM+FAM and CAM cohorts underwent blinded independent central review (BICR) for ORR, DCR, and PFS endpoints, and all patients were evaluated for 12-month OS rate.

A total of 360 patients were assessed for eligibility, of whom 194 patients were enrolled and randomized to one of the three cohorts. The initial study design randomized patients 2:1:2 to the CAM + FAM, CAM, and chemotherapy cohorts, respectively. Following an interim analysis, further enrollment onto the chemotherapy cohort was terminated due to observed limited benefit. Overall, 105 patients were initially assigned to CAM + FAM, 54 to CAM, and 35 to chemotherapy, of whom 105, 53, and 30 underwent the assigned treatment, respectively.

Some baseline characteristics, including median age and ECOG score, were balanced among the three cohorts, with two-thirds of patients having an ECOG score of 1 at study enrollment. Participants in the CAM+FAM cohort, however, received more “radical” prior treatment, with prior “radical” surgery reported in 62%, 57%, and 46% of patients in the CAM + FAM, CAM, and chemotherapy cohorts, respectively; concurrent chemoradiotherapy reported in 31%, 37%, and 40% of patients, respectively; and “radical” treatment in 89%, 85%, and 74% of patients, respectively. The interval from completion of prior treatment to the most recent recurrence was ≤1 year in 46%, 41%, and 34% of participants in the CAM + FAM, CAM, and chemotherapy cohorts, respectively. For prior systemic treatment, patients who received CAM + FAM were less heavily pretreated and were less likely to have received prior targeted therapy. Although all patients in the study had received prior platinum, 81% (CAM + FAM), 74% (CAM), and 74% (chemotherapy) of participants had received only one prior line of systemic therapy, with the remaining patients having received two lines. Overall, 26% (CAM + FAM), 39% (CAM), and 34% (chemotherapy) of patients had received prior targeted therapy, including bevacizumab, anlotinib, apatinib, and nimotuzumab.

There were also some discrepancies in baseline disease characteristics, including PD-L1 status and extent of disease. PD-L1 status was reported as positive in 62%, 63% and 71% of patients, in the CAM + FAM, CAM, and chemotherapy cohorts, respectively, representing a slightly lower percentage of patients with PD-L1 tumors in the immunotherapy arms. Similarly, patients who received immunotherapy (CAM + FAM and CAM) appeared to have less widespread disease at study entry, with 55% (CAM + FAM), 52% (CAM), and 77% (chemotherapy) of patients having more than one site of metastatic disease.

The revised primary endpoint of ORR (CR or PR), which was reported at the ESMO Congress 2023, was assessed by BICR. The ORR was highest in the CAM + FAM cohort (41%); 9% of patients achieved CR and 32% achieved PR. An ORR of 24% was observed in the CAM cohort; 6% of patients achieved CR and 19% achieved PR. The DCR was also higher in the CAM + FAM than the CAM cohort (75% vs. 56%). The median time to response was 2.1 months for all cohorts, and the median duration of response was 16 months for the CAM + FAM cohort. At a median follow-up of 9.9 months at the time of data cut-off, the median PFS was 3 months longer for the CAM + FAM cohort compared to the CAM cohort (7.2 vs. 4 months). Although no statistically significant difference in OS was found between the CAM + FAM and CAM cohorts, both had better survival outcomes compared to the chemotherapy cohort.

While higher response rates were observed among patients who received CAM + FAM, there was also a significant increase in toxicity in this cohort; 85% of patients experienced a grade ≥3 TRAE despite the reported “tolerable safety profile”. Although TRAEs of any grade were reported in almost every patient enrolled on trial [100% (CAM + FAM), 94.3% (CAM), and 100% (chemotherapy)], the percentage of grade ≥3 TRAEs was significantly higher for patients treated with CAM + FAM (85%) vs CAM (15%) and chemotherapy (60%). Two patients who received CAM + FAM experienced treatment-related death (1.9%) from acute coronary syndrome and sepsis, respectively; no deaths were reported in the other two cohorts. The most common TRAEs were myelosuppression and hypertension. At the time of data cutoff, 35 (33%) of 105 patients in the CAM + FAM cohort and 11 (21%) of 53 patients in the CAM cohort were still receiving treatment, whereas all patients in the chemotherapy cohort had discontinued treatment. The rate of dose discontinuation due to adverse events was also considerably higher in the CAM + FAM cohort (19%) compared to the CAM (6%) and chemotherapy (0%) cohorts.

In the palliative setting, morbidity of the investigational treatment regimen must be considered. Any incremental benefits in survival need to be carefully weighed against the negative impact on quality of life in the event of treatment-related toxicity. Patients with recurrent cervical cancer often face clinically challenging disease and treatment-related complications, including severe pain and/or fistulae, and therefore assessments of quality of life are critical when trying to improve outcomes for this vulnerable patient population. Similar to other studies comparing anti-PD-1 monotherapy to single-agent chemotherapy, the CAM monotherapy arm in Wu et al.’s study (11) had a more favorable toxicity profile. The addition of a TKI to the anti-PD-1 antibody did not translate to improved OS or investigator-assessed CR rates, despite a substantial increase in toxicity.

Great progress has been made to eradicate cervical cancer globally with focused efforts on universal human papillomavirus vaccination programs and screening, and efforts to improve treatment options for patients with advanced disease are ongoing. Although the TKI/anti-PD-1 combination showed favorable radiographic response rates in Wu et al.’s study (11), this combination did not result in significant improvement in OS.

In conclusion, while the study by Wu et al. (11) presents the combination of CAM plus FAM as a valid option for patients not amenable to local therapy, the observed safety profile and adverse event rates, warrant careful consideration and thorough review with a need for additional investigation before adopting this drug combination in clinical practice. The potential impacts on patients’ quality of life, given the challenges they already face, emphasize the need for a balanced evaluation of the risk and benefits associated with the combination of CAM plus FAM for the treatment of recurrent and metastatic cervical cancers.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-8/prf

Funding: This research was funded in part by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-8/coif). R.E.O.C. reports institutional research grants from ArsenalBio, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Therapeutics, OnCusp Therapeutics, Regeneron, Sellas Life Sciences, Stemcentrx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Immunogen, Miltenyi, Loxo, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; and travel fees from Hitech Health. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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