More Research Needed to Improve on Current Immunotherapy Progress in Gynecologic Cancers

Ursula Matulonis, MD

Patients with gynecologic cancers have received benefit from immunotherapy, but these treatments have not yet yielded significant response rates in both the newly-diagnosed and recurrent settings. According to Ursula Matulonis, MD, more exploration regarding molecular subtypes in gynecologic cancers may be the next step toward achieving more promising outcomes in patients with certain histologies.¹

In a presentation during the 38th Annual Chemotherapy Foundation Symposium® virtual conference, Matulonis, chief of the Division of Gynecologic Oncology and Brock-Wilson Family Chair at the Dana-Farber Cancer Institute, and professor of Medicine at Harvard Medical School, took stock of the role for immunotherapy agents in treatment landscape for ovarian, recurrent/advanced endometrial, and recurrent/advanced cervical cancers.

Immune Checkpoint Inhibitors Fail to Move the Needle in Ovarian Cancer

Investigators have found that adding immunotherapy to platinum chemotherapy in the up-front setting for patients with newly diagnosed disease does not show any benefit. This was exemplified in 2 clinical trials: JAVELIN OVARIAN 100 (NCT02718417) and IMagyn050 (NCT03038100).

Specifically, patients enrolled to JAVELIN OVARIAN 100 received either carboplatin, paclitaxel, and avelumab (Bavencio) with or without maintenance avelumab or chemotherapy alone. Those enrolled to IMagyn050 received either carboplatin, paclitaxel, and bevacizumab (Avastin) plus bevacizumab maintenance, or carboplatin, paclitaxel, atezolizumab (Imfinzi), and bevacizumab with bevacizumab and atezolizumab maintenance.

“When you add avelumab as a maintenance therapy, you actually see a worsening of outcomes,” Matulonis explained. Notably, JAVELIN OVARIAN 100 was terminated due to lack of efficacy demonstrated during planned interim analysis. She added, “There is no [improvement in] progression-free survival nor [observed] overall survival benefit with the addition of avelumab or atezolizumab, respectively.”

Investigators have also examined the efficacy of immunotherapy agents in patients with recurrent disease. Matulonis pointed to data from 3 studies in which reported response rates were 15.0% (n = 20) for nivolumab (Opdivo; UMIN000005714), 9.6% (n = 125) for avelumab (JAVELIN Solid Tumor; NCT01772004), and 8.0% (n = 376) for pembrolizumab (Keytruda; KEYNOTE-100; NCT02674061).2-4 Although the response rate in patients treated with nivolumab was promising, patients treated with avelumab and pembrolizumab displayed only modest response.

Further, data from the phase 3 NINJA trial (NCT01844986) showed a small difference in median overall survival (OS) for single agent nivolumab compared with chemotherapy in patients with platinum resistant ovarian cancer (10.12 vs 12.09 months, respectively).⁵ Median progression-free survival (PFS) was not improved in those who received nivolumab (2.04 vs 3.84 months, respectively).

“There were higher risks of toxicities with chemotherapy, but the efficacy results do not support the general use of checkpoint inhibition for recurrent platinum-resistant ovarian cancer,” Matulonis said.

“There are other trials ongoing, but we’re not making much headway with the use of immune checkpoint inhibitors in recurrent ovarian cancer,” Matulonis said. “Some new strategies are really necessary.”

Pantumor Approvals Pave a Path Forward

The American Society of Clinical Oncology guidelines for germline and somatic tumor testing in epithelial ovarian cancer recommend women with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing in order to detect mismatch repair deficiency (dMMR). Although dMMR is rare in high-grade serous ovarian cancer, it appears to occur more commonly in nonserous ovarian cancer, according to Matulonis.⁶

In 2017, the FDA approved pembrolizumab for patients with microsatellite instable (MSI) high and mismatch repair deficient cancers. This was followed by the 2020 approval of the agent for the treatment of patients with tumor mutational burden (TMB) high cancers (≥ 10 mutations/megabase).⁷

Although pantumor approvals with single agent immune checkpoint inhibitors have demonstrated clinical activity in patients with dMMR or MSI-high cancer navigating molecular-based treatments remains an uphill battle. Various agents have shown reasonable response rates in patients with endometrial cancer, including dostarlimab (TSR 042), durvalumab (Imfinzi), pembrolizumab, and avelumab. Matulonis said that up to 30% of patients with endometrial cancer have dMMR or MSH-high disease. However, Matulonis indicated that there is an unmet need for patients with MMR proficient disease.¹

“Response rates are much lower, sometimes 0%, in MMR [mismatch repair] proficient disease [with these agents] and [they] are not approved,” she said. Notably, pembrolizumab is approved in combination with lenvatinib (Lenvima) for patients with MMR-proficient recurrent endometrial cancer.

“It’s important to remember the toxicities of this regimen. [The rate of] patients who had treatment-related adverse effects leading to steady drug discontinuation was 18.5% for both drugs,” Matulonis said. “About 9.3% of patients had to stop both drugs, around 15.7% of patients had to stop lenvatinib, and 13% had to stop pembrolizumab. Almost 64.8% of patients had to have some kind of dose reduction of lenvatinib, so just remember that when you’re starting [the regimen.”

Immunotherapy for PD-L1–Positive Cervical Cancer

Data for patients with cervical cancer have shown benefit for those treated with a PD-1 inhibitor. In 2018, the FDA approved pembrolizumab for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (combined positive score ≥ 1).⁷

Although the single agents have shown modest improvement, combination strategies provide a mixed bag of results. In a phase 2 study (NCT02921269) the combination of atezolizumab and bevacizumab failed to meet its primary end point and yielded an overall response rate (ORR) of 0% (n = 10).⁸

Investigators of CheckMate 358 (NCT02488759) examined the combination of nivolumab and ipilimumab at 2 doses: 3 mg/kg nivolumab and 1 mg/kg ipilimumab, and 1 mg/kg nivolumab and 3 mg/kg of ipilimumab.9 In the first cohort, patients with no prior systemic treatments had an ORR of 31.6% (n = 19) and patients who were heavily pretreated had an ORR of 23.1% (n = 26). In the second cohort, patients with no prior treatment had an ORR of 45.8% (n = 24) and patients who were heavily pretreated had an ORR of 36.4% (n = 22).

In the first cohort, investigators noted a median PFS of 13.8 months (95% CI, 2.1-NR) in patients who had not received prior treatment compared with 3.6 months (95% CI, 1.9-5.1) in those who had. The second cohort had a median PFS of 8.5 months (95% CI, 3.7-NR) and 6.8 months (95% CI, 3.5-17.2), respectively. Further, the duration of response was not reached in those patients who did not receive prior systemic therapy for relapsed or metastatic disease in both the first and second cohorts.

“Higher response rates were observed in patients who had no prior systemic treatments. The less heavily pretreated patients had better response rates,” said Matulonis. “There was some suggestion that response rates were higher in 1 mg/kg nivolumab and 3 mg/kg of ipilimumab but this [study] was not meant to take a look at that.”

A notable success in combination therapy came In March 2020, when the FDA granted a fast track designation to the PD-1 inhibitor balstilimab and the CTLA-inhibitor zalifrelimab for the treatment of patients with relapsed or refractory metastatic cervical cancer. The combination showed durable responses in an all-comer, nonbiomarker selected population of patients with refractory cervical cancer who progressed following prior platinum-based chemotherapy with or without bevacizumab.¹⁰

In data presented at the European Society for Medical Oncology, the combination demonstrated a 22% ORR (n = 143), with 8 complete responses and 23 partial responses. Data was also reported for single-agent balstilimab and showed a 14% ORR, which included 3 complete responses and 20 partial responses. A rolling submission of a biologics license application to the FDA has been initiated for single-agent balstilimab for the treatment of patients with recurrent/metastatic cervical cancer.

_References

1. _{Matulonis UA. Immunotherapy for Gynecologic Cancers. Presented at: 38th AnnualCFS®; November 4-6, 2020.}
2. _{Hamanish J, Mandai M, Ikedo T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015-4022. doi:10.1200/JCO.2015.62.3397.}
3. _{Disis ML, Taylor MH, Kelly K, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol. 2019;5(3):393-401. doi:10.1001/jamaoncol.2018.6258}
4. _{Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30(7):1080-1087. doi:10.1093/annonc/mdz135}
5. _{Omatsu K, Hamanishi J, Katsumata N, et al. Nivolumab versus gemcitabine or pegylated liposomal doxorubicin for patients with platinum-resistant (advanced or recurrent) ovarian cancer: open-label, randomized trial in Japan (NINJA trial). Ann Oncol. 2020;31(suppl 4):S551-S589. doi:10.1016/annonc/annonc276}
6. _{Konstantinopoulos PA, Norquist B, Lacchetti C, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(11):1222-1245. doi:10.1200/JCO.19.02960}
7. _{Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated October 26, 2020. Accessed November 5, 2020. https://bit.ly/32yemyX}
8. _{Friedman CF, Charen AS, Zhou Q, et al. Phase II study of atezolizumab in combination with bevacizumab in patients with advanced cervical cancer. J ImmunoTherapy Can. 2020;8:e001126. doi:10.1136/jitc-2020-001126.}
9. _{Naumann RW, Oaknin A, Meyer T, et al. Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: results from CheckMate 358. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394.059}
10. _{O'Malley DM, Oaknin A, Monk B, et al. Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): preliminary results of two independent phase II trials. Ann Oncol. 2020;31(suppl 4):S1142-S1165). doi:10.1016/j.annonc.2020.08.2264}