Efficacy results from Phase I/II (Checkmate 358) of nivolumab ± ipilimumab in subjects with R/M cervical cancer

Cervical cancer is the fourth most common cancer among women worldwide. Cervical cancer focuses more on primary and secondary prevention. Primary prevention is the best method to decrease the burden of cervical cancer and decrease mortality. In the United States and other developing countries, most screening and diagnostic efforts are directed toward the early identification of high-risk human papillomavirus (HPV) lesions through HPV testing and Pap smears. Currently, pembrolizumab is used for PD-L1 positive or MSI high, and a lot of drugs have been studied through the Gynecologic Oncology Group (GOG). They include gemcitabine, mitomycin, and nab-paclitaxel. The response rates and survival rates related to these drugs and fairly low, which is why filling this gap is the need of the hour. Outside the US, there is a lack of treatment options for patients with metastatic or recurrent disease, when they progress on the first line of treatment. There is currently no standard of care in the second line with patients given chemotherapies with very little benefit or just the best supportive care. The treatment of recurrent cervical cancer remains challenging, and the prognosis of recurrent cervical cancer remains poor, with a 5-year overall survival (OS) rate of less than 5% despite intensive therapy, particularly for those who experience a recurrence in a previously irradiated field. The poor prognosis of recurrent cervical cancer is attributed to several factors, including the biological behavior of the tumor, contraindication of repeated radiotherapy for the same field, limited response to systemic chemotherapy or targeted therapy, and the uncertain role, indication, and extent of surgical therapy.

The ORR was found to be 26% in the nivolumab monotherapy group versus 31%, 39%, and 26% in all, 1L and ≥2L nivolumab3 + ipilimumab1 (N3+I1) patient pool, versus 38%, 41%, 35% in all, 1L and ≥2L N1+I3 patient pool. As expected, more responses were noted in the first- vs second-or-later-line setting. Also, N1 + I3 showed a higher response rate than N3 + I1 in both the first- and second-or-later-line settings. Durable responses were observed regardless of the tumor PD-L1 status across all treatment arms, and there are fewer responses seen in patients with PD-L1 < 1% treated with nivolumab monotherapy compared with patients with PD-L1 < 1% treated with nivolumab and ipilimumab. The median duration of response (mDoR) was not reached in the nivolumab monotherapy arm while N3 + I1 arm achieved the best mDoR among other arms. The median overall survival (mOS) was found to be 21.6, 15.2, and 20.9 months. Median progression-free survival (mPFS) was 5.1, 3.8, and 5.8 months for the nivolumab, N3 + I1, and N1 + I3 arms. No new safety signals were observed and also the incidence of toxicity appeared to be higher in patients with N1 + I3 compared with either N3 + I1 or nivolumab monotherapy.

Conclusion- As already stated, the treatment of recurrent cervical cancer is quite challenging and also has limited treatment options. Also, currently, there is no standard of care in the second line with patients given chemotherapies with very little benefit or just the best supportive care. So, these data with nivo + ipi are of strong clinical interest and warrant further investigation in this patient population. The PD-1 inhibitor pembrolizumab is approved by the FDA for the treatment of R/M cervical cancer post-chemotherapy but its approval is limited to those patients whose tumors express PD-L1 (combined positive score ≥1). Upregulation of PD-1 and PD-L1 expression has been reported in cervical cancer, which suggests that this tumor type is likely to respond to PD-1/PD-L1-based therapy. CTLA-4 is another inhibitory checkpoint that plays a key role in regulating adaptive immunity, offering the possibility of response to agents that target this protein receptor.

Expert Opinion: “These data indicate that chemotherapy-free immunotherapy with nivolumab alone or in combination with ipilimumab can provide a durable tumor regression with manageable toxicity in patients with R/M cervical cancer, regardless of tumor PD-L1 expression.”

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