Immunotherapy has especially demonstrated broad activity in cervical cancer, fueling development in this area and providing further signs of hope for new treatment options to come into the landscape with greater efficacy and manageable safety profiles.
Recent advances in cervical cancer have provided new options for treating patients with advanced forms of the disease, fulfilling a significant unmet medical need. Two agents, one of which is an immune checkpoint inhibitor, have recently been FDA approved for cervical cancer. Immunotherapy has especially demonstrated broad activity in cervical cancer, fueling development in this area and providing further signs of hope for new treatment options to come into the landscape with greater efficacy and manageable safety profiles.
Nearly all cervical cancer results from human papillomavirus (HPV) infection.1 Prophylactic HPV vaccines have resulted in reduction of HPV prevalence and HPV-related diseases, and research supports that vaccination with appropriate screening protocols has the greatest opportunity to reduce cervical cancer incidence.2 According to Dmitriy Zamarin, MD, PhD, “The best treatment for cervical cancer is prevention.”
Yet access to health care and vaccines is a global concern. In an interview with Targeted Therapies in Oncology™, Krishnansu S. Tewari, MD, added, “The biggest deficiency is lack of access to health care for many women in the United States who are at risk for cervical cancer and can’t be screened with Pap smears and/or high-risk HPV DNA testing. These are likely the same patients who do not have access to the HPV vaccine.”
A population impact of vaccination is only achieved when coverage rates exceed 50%.3 Due to lack of access and a percentage of women opting out of vaccination, cervical cancer will likely remain an issue for many years to come.
Metastatic disease will develop in 15% to 61% of women diagnosed with early cervical cancer, and the 5-year survival rate for women with recurrent disease is less than 5%.4 Currently, the best treatment regimen for advanced cervical cancer is the combination of cisplatin, paclitaxel, and bevacizumab (Avastin).5 This protocol results in an overall response rate of 48% with a median survival of 17 months, but there remains no consensus on the benefits of second-line chemotherapy in recurrent cervical cancer.6
Oncologists are desperate for greater variety and more efficacious options for the treatment of patients with advanced cervical cancer.
On October 13, 2021, the FDA approved pembrolizumab (Keytruda) in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent, or metastatic cervical cancer with PD-L1 tumor expression (combined positive score [CPS] ≥1) as determined by an FDA-approved test.7 The FDA also granted regular approval for pembrolizumab as a single agent for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy with tumors expressing PD-L1 (CPS≥1).7 Pembrolizumab is a highly selective, fully humanized monoclonal antibody that prevents the interaction between PD-1 and its ligands, PD-L1 and PD-L2.8
Approval was based on results from the double-blind phase 3 KEYNOTE-826 trial (NCT03635567), in which pembrolizumab was evaluated in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab.7 A total of 617 patients with persistent, recurrent, or first-line metastatic cervical cancer were enrolled irrespective of PD-L1 status.8
A total of 548 patients had a PD-L1 CPS of 1 or higher, and the median progression-free survival (PFS) in this population was 10.4 months in the pembrolizumab group vs 8.2 months in the placebo group (HR, 0.62; 95% CI, 0.50-0.77; P <.001). The overall survival (OS) rate was 53.0% at 24 months in the pembrolizumab group and 41.7% in the placebo group. The median OS was not reached (NR) in the pembrolizumab arm but showed a trend toward improvement over placebo (HR, 0.64; 95% CI, 0.50- 0.81; P<.001). This trend was observed across all PD-L1 expression subgroups (TABLE).8
Confirmed responses were reported in 68.1% of patients in the pembrolizumab group and in 50.2% of patients in the placebo group among patients with a PD-L1 CPS of 1 or higher. The most common grade 3 to 5 AEs were anemia (30.3%, pembrolizumab; 26.9%, placebo) and neutropenia (12.4% and 9.7%, respectively).8
“[These data serve] as an indication that earlier incorporation of immune checkpoint inhibitors into therapy may improve long-term outcomes for these patients,” Zamarin said. However, he mentioned additional challenges this approval may bring. “The approval is limited to patients with PD-L1–positive cancers; thus, we still have no effective therapies for patients with PD-L1–negative cancers. We don’t have effective strategies for patients who progress on pembrolizumab.”
Numerous trials evaluating pembrolizumab in combination with other agents are currently underway and could help determine treatment alternatives.
On September 20, 2021, the FDA granted accelerated approval to tisotumab vedotin-tftv (Tivdak; tiso-v) for adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.9,10 Approval for the antibody-drug conjugate was based on results from the open-label phase 2 innovaTV 204 trial (NCT03438396). A total of 101 patients with advanced cervical cancer who received at least 2 prior lines of systemic therapy received tiso-v.10 The confirmed objective response rate (ORR) was 24% (95% CI, 16%-33%), with 7% complete response (CR) and 17% partial response (PR) rates with a median follow-up time of 10.0 months. Duration of response (DOR) was 8.3 months (95% CI, 4.2-NR), with the study ongoing.11
Treatment-related adverse events (TRAEs) grade 3 or higher occurred in 28% of patients and included neutropenia (3%), fatigue (2%), and ulcerative keratitis (2%). Serious TRAEs occurred in 13% of patients, with peripheral sensorimotor neuropathy (2%) and pyrexia (2%) being most common. A single death from septic shock was considered related to therapy. Clinically meaningful and durable antitumor activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer led to tiso-v’s approval.11
The confirmatory phase 3 innovaTV 301 trial (NCT04697628) for the accelerated approval is currently underway and will enroll approximately 482 patients with recurrent or metastatic cervical cancer who have received 1 or 2 prior lines of systemic therapy.
Zamarin, director of translational research for gynecologic medical oncology and an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, noted, “Tisotumab vedotin presents a new and excellent treatment option for patients with cervical cancer, and trials exploring tisotumab vedotin for frontline therapy of cervical cancer have already been initiated.”
One of those trials is the phase 1b/2 innovaTV 205 trial (NCT03786081) evaluating tiso-v in combination with carboplatin in the first-line setting and in combination with pembrolizumab in the second-line or third-line setting. In the first-line setting, the ORR was 55%, with a median time to response of 1.4 months, a median DOR of 8.3 months, and a median follow-up of 7.9 months. The median PFS was 9.5 months, and the median OS was NR. Grade 3 or higher AEs occurred in 78.8% of patients (26/33), with 57.6% (19/33) related to tiso-v.12
In the second-line or beyond combination group, ORR was 38% with a median time to response of 1.4 months, a median DOR of 13.8 months, and a median follow-up of 13.0 months. The median PFS was 5.6 months, and the median OS was NR.12
Cemiplimab
On September 28, 2021, the FDA granted priority review to a supplemental biologics license (sBLA) for cemiplimab-rwlc (Libtayo) for treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Support for the sBLA comes from the phase 3 EMPOWER-Cervical 1 trial (NCT03257267).13 Interim results show cemiplimab is superior in the overall and squamous cell carcinoma (SCC) populations in all end points.14
A total of 608 patients were included in the 1:1 randomization, 477 of whom had SCC. In the overall population, the median OS was 12 months for the cemiplimab group and 8.5 months for the chemotherapy group (HR, 0.69; 95% CI, 0.56-0.84, P <.001). Among patients with positive PD-L1 expression on tumor cells, the median OS with cemiplimab treatment was 13.9 months vs 9.3 months with chemotherapy (HR, 0.70; 95% CI, 0.46- 1.05). For patients with SCC, the median OS was 11.1 months with cemiplimab and 8.8 months with chemotherapy (HR, 0.73; 95% CI, 0.58-0.91; 1-sided P= .00306).14
In the intention-to-treat (ITT) population, the median PFS was similar between the cemiplimab and chemotherapy arms. The ORR in the cemiplimab arm was 16.4% compared with 6.3% in the chemotherapy arm (odds ratio, 2.98; 95% CI, 1.71-5.22).14
AEs were lower with cemiplimab vs chemotherapy with the most common of any grade being anemia (25% vs 45%, respectively), nausea (18% vs 33%), and vomiting (16% vs 23%). Discontinuation due to AEs occurred in 8% of patients receiving cemiplimab and 5% of patients receiving chemotherapy.14
“Among the most striking data is that cemiplimab significantly improved overall survival in the second-line setting in both the squamous cell carcinoma subpopulation and in the intent-to-treat overall population,” said Tewari, a professor and director of the Division of Gynecological Oncology at University of California, Irvine.
Cemiplimab is the first immunotherapy to demonstrate an improvement in OS, PFS, and ORR compared with chemotherapy in advanced cervical cancer.15 The target action date for the FDA’s decision is January 30.13
Balstilimab
Earlier this year, Agenus, Inc submitted a biologics license application (BLA) to the FDA for accelerated approval of balstilimab, an anti–PD-1 antibody in patients with recurrent or metastatic cervical cancer.16 Submission was based on data from a phase 2 trial (NCT03894215) in which balstilimab exhibited promising results as monotherapy in patients with advanced cervical cancer. The ORR was 14% (95% CI, 10%-21%) in the modified ITT population (n=160) and 13.0% (95% CI, 8%-20%) in patients who had received 1 or more prior lines of chemotherapy (n=138). In the modified ITT population, the median duration of response was 15.4 months (range, 1.1+ to 15.4). Immune-related AEs were reported in 30% of patients, and AEs were severe in 8%; 13.7% of patients discontinued treatment.17
Due to the approval of pembrolizumab, however, Agenus withdrew the BLA for balstilimab per the FDA’s recommendation on October 22, 2021.18
Balstilimab in combination with other agents is still being explored for the treatment of cervical and other gynecologic malignancies. Balstilimab and zalifrelimab (formerly AGEN1884), an anti–CTLA-4 antibody, in patients with advanced cervical cancer produced promising results in a phase 2 trial (NCT03495882). An ORR of 25.6% was reported in 125 patients evaluable for efficacy and 32.8% in 67 patients with positive PD-L1 expression. The median DOR was NR, with a 6-month DOR rate of 86.4% and 12-month DOR rate of 66.7%. The 6-month OS rate was 69.0%, and the 12-month rate was 52.7%. Grade 3 or higher AEs were observed in 21.3% of patients and 9.7% of patients discontinued treatment.19
A phase 2 trial (NCT05033132) evaluating balstilimab alone or in combination with zalifrelimab in patients with advanced cervical cancer who have relapsed or progressed after receiving first-line platinum-based chemotherapy recently launched, with an estimated enrollment of 160 patients. Although accelerated approval will not be achieved for balstilimab, it still holds promise for treating patients with solid tumors, including those with cervical cancer.
Camrelizumab
Camrelizumab is another anti–PD-1 antibody that was recently assessed in combination with apatinib in patients with advanced cervical cancer. The open-label phase 2 CLAP trial (NCT03816553) enrolled 45 patients with advanced cervical cancer who had progressed after at least 1 prior line of systemic therapy. Ten patients (22.2%) had previously received bevacizumab, and 57.8% of patients had previously received 2 or more lines of chemotherapy. The ORR was 55.6% (95% CI, 40%-70.4%), with 2 CRs and 23 PRs; the disease control rate (DCR) was 82.2% (95% CI, 67.9%-92.0%). The median PFS was 8.8 months (95% CI, 5.6-not estimable), and the PFS rate at 6 months was 57.0%. Both the median DOR and OS were NR. Grade 3 or 4 TRAEs occurred in 71.1% of patients, with the most common events being hypertension (24.4%), anemia (20.0%), and fatigue (15.6%).20
A single-center, open-label prospective study (2019-S1071) is evaluating the combination of camrelizumab, apatinib, and nabpaclitaxel (Abraxane) in patients with advanced cervical cancer as a second-line therapy. A total of 22 patients were enrolled with a median follow-up of 13.0 months. The ORR was 71.43% (95% CI, 47.82%-88.72%), with 5 CRs and 10 PRs, and the DCR was 85.7% (95% CI, 70.0%-100.00%). Median PFS was 10.9 months (95% CI, 7.29-14.5), with median DOR and median OS both NR. Grade 3 or 4 TEAEs were mostly hematologic, including neutropenia, thrombocytopenia, and anemia.21
These results warrant larger trials. An open-label phase 2 clinical trial (NCT04974944) is evaluating camrelizumab in combination with apatinib vs chemotherapy with bevacizumab as first-line treatment of patients with advanced cervical cancer. The estimated enrollment is 172 patients, and the estimated completion date is December 2024.
The combination of camrelizumab with apatinib holds promise for treatment of patients with advanced cervical cancer. “While the mechanism of synergy for such combination is unknown, the high response rate and durability are exciting and prompt further studies,” Zamarin said.
Nivolumab Plus Ipilimumab
Previously, the combination of nivolumab (Opdivo), an anti–PD-1 antibody, with ipilimumab (Yervoy), an anti–CTLA-4 antibody, provided durable clinical activity in patients with recurrent or metastatic cervical cancer. The CheckMate 358 study (NCT02488759) indicated efficacy of the combination of nivolumab and ipilimumab was superior in patients without prior systemic therapy vs with systemic therapy.22 A total of 91 patients with SCC of the cervix who received 2 or fewer prior systemic therapies for recurrent or metastatic disease were randomized.22
In the nivo1-ipi3 arm, the median PFS was 8.5 months (95% CI, 3.7-NR) for patients with no prior systemic therapy and 5.8 months (95% CI, 3.5-17.2) in those who had received prior systemic therapy. The 6-month PFS rate was 60.9% for patients with no prior systemic therapy for advanced disease and 47.6% for those with prior treatment; at 12 months, the PFS rates were 43.5% and 38.1%, respectively. For the nivo3-ipi1 group, median OS was NR for patients with no prior systemic therapy and 10.3 months for those with prior systemic treatment.22
The rate of gastrointestinal TRAEs was higher in the nivo1-ipi3 arm than the nivo3- ipi1 arm, as well as the rate of TRAEs leading to treatment discontinuation.22
The CheckMate 358 trial is ongoing, but another interventional trial, COLIBRI (NCT04256213), is evaluating the effects of the combination of ipilimumab and nivolumab on tumor and immune response.23 Included patients have histologically confirmed cervical SCC stage IB3 to IVA. Study completion is expected in early 2022.23
The future holds promise for immuno-oncology treatments for patients with cervical cancer. R. Wendel Naumann, MD, says: “With the KEYNOTE-826 data, the combination of pembrolizumab and chemotherapy with or without bevacizumab has become the standard of care for patients with PD-L1–positive cervical cancer.”
Naumann, professor and director of gynecologic oncology research and associate medical director of clinical trials at Levine Cancer Institute in Charlotte, North Carolina, also pointed out the use of atezolizumab (Tecentriq) in patients with recurrent cervical cancer is being evaluated in a similar fashion in the phase 3 BEATcc trial (NCT03556839).
“Overall, we are looking at moving immunotherapy with PD-1 inhibitors to the up-front setting,” he said. “The big question is: What do we do for patients with recurrent cervical cancer who have been treated with a PD-1 inhibitor? Unfortunately, none of the current trials will address this issue.”
Naumann mentioned other immunooncology combinations with treatment potential for cervical cancer, including targeting TIGIT, TIM3, and LAG3, but these all require further evaluation. “There is a lot going on in cervical cancer now that is very exciting,” Naumann said.
References:
1. WalboomersJM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol.1999;189(1):12-19. doi:10.1002/(sici)1096-9896(199909)189:1<12::Aid-path431>3.0.Co;2-f
2. Harper DM, DeMars LR. HPV vaccines -areview of the first decade. Gynecol Oncol. 2017;146(1):196-204. doi:10.1016/j.ygyno.2017.04.004
3. Drolet M, Bénard É, Boily MC, et al. Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis. 2015;15(5):565-580. doi:10.1016/s1473-3099(14)71073-4
4. Pfaendler KS, Tewari KS. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol. 2016;214(1):22-30. doi:10.1016/j.ajog.2015.07.022
5. Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med.2014;370(8):734-743. doi:10.1056/NEJMoa1309748
6. Wendel Naumann R, Leath CA 3rd. Advances in immunotherapy for cervical cancer. Curr Opin Oncol. 2020;32(5):481-487. doi:10.1097/cco.0000000000000663
7. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. FDA. Updated October 13, 2021. Accessed December 1, 2021. https://bit.ly/3G5r6yd
8. Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385(20):1856-1867. doi:10.1056/NEJMoa2112435
9. FDA grants accelerated approval to tisotumabvedotin-tftv for recurrent or metastatic cervical cancer. FDA. Updated September 21, 2021. Accessed December 3, 2021. https://bit.ly/3EjT4WA
10. Seagen and Genmab announce FDA accelerated approvalfor Tivdak(tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Genmab A/S and Seagen Inc. September 20, 2021.Accessed December 16, 2021.https://bit.ly/31UaZoJ
11. Coleman RL, Lorusso D, Gennigens C, et al; innovaTV 204/GOG-3023/ENGOT-cx6 Collaborators. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619. doi:10.1016/s1470-2045(21)00056-5
12. Vergote IB, Monk BJ, O’Cearbhaill RE, et al. Tisotumab vedotin (TV) + carboplatin (carbo) in first-line (1L) or + pembrolizumab (pembro) in previously treated (2L/3L) recurrent or metastatic cervical cancer (r/mCC): interim results of ENGOT-Cx8/GOG-3024/innovaTV 205 study. Presented at: European Society for Medical OncologyCongress2021; September 16-21, 2021; virtual.
13. FDA accepts Libtayo (cemiplimab-rwlc) for priority reviewfor advanced cervical cancer. News release. Regeneron.September 28, 2021.Accessed December 16, 2021.https://bit.ly/31OMLfL
14. Tewari KS, Monk BJ, Vergote I, et al. VP4-2021: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: interim analysis of phase III trial of cemiplimab vs. investigator’s choice (IC) chemotherapy (chemo) in recurrent/metastatic (R/M) cervical carcinoma. Ann Oncol. 2021;32(7):940-941. doi:10.1016/j.annonc.2021.04.009
15. Positive phase 3 Libtayo (cemiplimab) results in advanced cervical cancer presented at ESMO Virtual Plenary. News release. Sanofi.May 12, 2021.Accessed December 16, 2021.https://bit.ly/3pZ7kxZ
16. Agenus submits balstilimab biologics license applicationto the U.S. FDA for patients with recurrent or metastatic cervical cancer. News release. Agenus Inc. April 19, 2021. Accessed December 16, 2021. https://bit.ly/31o7dn8
17. O'Malley DM, Oaknin A, Monk BJ, et al. LBA34 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):S1164-S1165. doi:10.1016/j.annonc.2020.08.2264
18. Agenus provides update on balstilimab development. News release. Agenus Inc. October 22, 2021.Accessed December 16, 2021.https://bit.ly/3oR9pwz
19. O'Malley D, Neffa M, Monk BJ, et al. 724MO balstilimab(anti-PD-1) in combination with zalifrelimab (anti-CTLA-4): final results from a phase II study in patients (pts) with recurrent/metastatic (R/M) cervical cancer (CC). Ann Oncol.2021;32(suppl 5):S727. doi:10.1016/j.annonc.2021.08.1167
20. Lan C, Shen J, WangY, et al. Camrelizumab plus apatinib in patients with advanced cervical cancer (CLAP): a multicenter, open-label, single-arm, phase II trial. J Clin Oncol. 2020;38(34):4095-4106. doi:10.1200/JCO.20.01920
21. Li G, Zhao Y, Jiang Y, et al. 777P a prospective, single-arm, open-label study of camrelizumab, apatinib and nab-paclitaxel in patients with advanced cervical cancer. Ann Oncol.2021;32(suppl 5):S753-S754. doi:10.1016/j.annonc.2021.08.1219
22. Naumann RW, Oaknin A, Meyer T, et al. LBA62 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):v898-v899. doi:10.1093/annonc/mdz394.059
23. Ray-Coquard IL, Kaminsky-Forrett MC, Joly F, et al. 819TiP COLIBRI trial (GINECO-CE108b): amulticenter, window study evaluating immune impact and safety of nivolumab in combination with ipilimumab before initial radio-chemotherapy (RTCT) treatment for locally advanced cervix cancer. Ann Oncol.2021;32(suppl 5):S770. doi:10.1016/j.annonc.2021.08.1261
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