Coleman Looks Forward to a Big Year for New Cervical Cancer Therapies

Five new therapies for the treatment of patients with cervical cancer are in late-stage development that could potentially change clinical practice and set the stage for 2021 to be a banner year for FDA approvals for this malignancy, according to Robert L. Coleman, MD.

“This is going to be really exciting,” said Coleman, noting that there have been only 2 new drug approvals for cervical cancer in recent years: bevacizumab (Avastin) plus chemotherapy in 2014 and pembrolizumab (Keytruda) for PD-L1 positive disease in 2018.^1,2

Coleman, a 2020 Giants of Cancer Care^® award winner in the gynecologic malignancies category, identified the following therapies as among the most promising in the cervical cancer pipeline: lifileucel; balstilimab as a single agent and in combination with zalifrelimab; tisotumab vedotin; cemiplimab-rwlc (Libtayo); and pembrolizumab (Keytruda) in combination with chemotherapy (Table).

Table. Emerging Therapies for Cervical Cancer

In an interview with OncLive®, Coleman discussed key data for these therapies and touched on emerging developments concerning new therapies in ovarian and endometrial cancers. Coleman, a longtime clinical investigator and leader of the Gynecologic Oncology Group Foundation, became chief scientific officer of The US Oncology Network in March 2020.

Late-Stage Cervical Cancer Candidates

Lifileucel, formerly known as LN-145, uses autologous tumor-infiltrating lymphocytes (TILs) harvested from tumor fragments to create a patient-specific immunotherapy. In November 2020, Iovance Biotherapeutics, Inc, which is developing the adoptive cell transfer therapy, said the last patient has been dosed in the pivotal cohort of the phase 2 C-145-04 trial (NCT03108495) in patients with recurrent, metastatic, or persistent cervical cancer. The company is discussing assays to define TILs with the FDA and plans to submit a biologics license application (BLA) to the agency this year.³

In early findings from the pivotal trial, lifileucel demonstrated a 44% objective response rate (ORR) among 27 patients, including 3 complete responses (11%) and 9 partial responses (33.3%), for an 85% disease control rate, according to data presented at the 2019 American Society of Clinical Oncology Annual Meeting.⁴ TIL persistence was observed at 6 months in the peripheral blood mononuclear cells of 20 participants available for analysis, suggesting that memory T cells in the TIL therapy can be long lived, investigators said in a poster presented at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020).⁵

Another treatment moving forward in the regulatory process is balstilimab, an anti– PD-1 monoclonal antibody. In September 2020, Agenus Inc, the drug’s developer, started a rolling BLA with the FDA for use of balstilimab in recurrent or metastatic cervical cancer based on findings from a single-arm phase 2 trial (NCT03104699).⁶ The study enrolled patients with squamous cell, adenosquamous, or adenocarcinoma of the cervix who had relapsed or progressed on or after platinum-based treatment.

Balstilimab monotherapy resulted in a 14% ORR among 160 patients in the intentionto-treat population, with a median duration of response (DOR) of 15.4 months (range, 1.1+ to 15.4), according to findings presented at ESMO 2020. The ORR was 19% among participants with PD-L1–positive tumors (19 of 99 patients).⁷

In a separate phase 2 trial (NCT03495882), balstilimab administered in combination with zalifrelimab, a CTLA-4 inhibitor, resulted in an ORR of 22% among 143 patients, with the median DOR not reached (range, 1.3+ to 16.6+ months). The ORR was 27% among those with PD-L1–positive disease (21 of 79 patients).⁷ The combination is being developed under an FDA fast track designation.⁸

Tisotumab vedotin, another therapy on the horizon, is an antibody-drug conjugate that targets tissue factor, part of the coagulation network, which is highly prevalent in cervical cancer and other solid tumors. Coleman and colleagues presented data at ESMO 2020 from the phase 2 innovaTV 204 trial (NCT03438396) evaluating tisotumab vedotin as monotherapy, if appropriate, in patients with recurrent or extrapelvic metastatic cervical cancer that progressed during or after doublet chemotherapy with bevacizumab.⁹

The ORR was 24% (95% CI, 15.9-33.3) among 101 patients who received tisotumab vedotin, including 7 patients (7%) with a complete response and 17 patients (17%) with a partial response. After a median follow-up of 10 months, the median DOR was 8.3 months (95% CI, 4.3-not reached). The median time to response was 1.4 months (range, 1.1-5.1), with activity generally observed within the first 2 treatment cycles.⁹

Plans call for the phase 3 innovaTV 301 trial (NCT04697628) to start enrolling patients in January 2021. The study will evaluate tisotumab vedotin monotherapy versus physician’s choice of 1 chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) as second- or third-line treatment for patients with recurrent or metastatic cervical cancer. The trial aims to enroll 482 participants.

Several immune checkpoint inhibitors approved in other indications also are being investigated for cervical cancer. Cemiplimab, a PD-1 inhibitor approved for patients with metastatic or locally advanced cutaneous squamous cell carcinoma, is being evaluated in a phase 3 trial (NCT03257267) as monotherapy versus physician’s choice of chemotherapy in patients with recurrent or metastatic platinum-refractory cervical cancer with squamous cell histology.

In November 2020, investigators reported data from expansion cohorts from a phase 1 trial (NCT02383212) that evaluated cemiplimab as a monotherapy or in combination with hypofractionated radiation therapy in patients with recurrent or metastatic cervical cancer. One of the 10 patients in each cohort achieved a partial response for an ORR of 10% (95% CI, 0.3%-44.5%); both responders had squamous histology. The DOR was 11.2 months and 6.4 months in the monotherapy and combination cohort, respectively.¹⁰

“In cervix cancer recurrence, if the cemiplimab trial is positive, that would replace chemotherapy with an immune checkpoint inhibitor. We’re monitoring these phase 3 studies that could be reporting in 2021,” Coleman said.

These studies include the phase 3 KEYNOTE-826 trial (NCT03635567), which is testing the PD-1 inhibitor pembrolizumab in combination with investigator’s choice of chemotherapy (paclitaxel plus either cisplatin or carboplatin) with bevacizumab, if appropriate, versus chemotherapy with bevacizumab alone as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer. Pembrolizumab currently is approved for PD-L1–positive recurrent or metastatic cervical cancer that has progressed on or after chemotherapy.²

Other Malignancies

In the ovarian cancer space, Coleman said, the results of the TRUST trial (NCT02828618) could be practice changing. The trial is comparing primary debulking surgery followed by 6 cycles of standard chemotherapy versus 3 cycles of neoadjuvant chemotherapy followed by interval debulking surgery in patients with newly diagnosed invasive stage IIIB to IVB epithelial ovarian cancer. The study, which is designed for an enrollment of nearly 800 patients, is taking place at 20 centers with a high level of surgical expertise in ovarian cancer.

“This trial is going to be really important from a practice-changing standpoint because if it validates that there is no difference between those 2 modalities, then neoadjuvant chemotherapy will become an even bigger standard. If it refutes it, then it is going to change the way people look at surgical candidacy in ovarian cancer, and that will be practice changing,” Coleman said.

Coleman also is anticipating the results of the phase 3 ATHENA trial (NCT03522246), which is testing the combination of the PD-1 inhibitor nivolumab (Opdivo) plus the PARP inhibitor rucaparib (Rubraca) as maintenance therapy for patients who have responded to frontline platinum-based chemotherapy and have completed cytoreductive surgery. The study, which aims to enroll 1000 patients, has 4 arms: intravenous (IV) nivolumab plus oral rucaparib or placebo, rucaparib plus IV placebo, and an oral placebo plus an IV placebo. The primary end point is progression-free survival, and secondary end points include overall survival, ORR, and DOR.

“There are a lot of drug combinations that are working their way through [the pipeline], as well as novel treatments, including tumor treatment fields to novel biologics to gene therapy. PARP inhibitors will continue to roll out. We’ll have OS data starting to emerge on some of the mature trials. The exciting story for PARP inhibitors in 2021 is combinations,” Coleman said.

In endometrial cancer, Coleman hopes to see data this year from the phase 3 LEAP-001 trial (NCT03884101), which is studying the combination of pembrolizumab plus lenvatinib (Lenvima) versus the chemotherapy regimen of paclitaxel plus carboplatin.

“This will be important to see if we can replace chemotherapy in the metastatic, recurrent space,” he said.

References

1. Bevacizumab solution. FDA. Updated September 1, 2015. Accessed January 14, 2021. https://bit.ly/3srYmJS
2. FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. FDA. Updated June 13, 2018. Accessed January 15, 2021. https:// bit.ly/3qnCXQf
3. Iovance Biotherapeutics reports third quarter and year-to-date 2020 financial results and corporate updates. News release. Iovance Biotherapeutics Inc. November 5, 2020. Accessed December 8, 2020. https://bit.ly/2JF681I
4. Jazaeri AA, Zsiros E, Amaria RN, et al. Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma. J Clin Oncol. 2019;37(suppl 15):2538. doi:10.1200/JCO.2019.37.15_suppl.2538
5. Jazaeri AA, Gontcharova V, Blaskovich M, et al. In vivo persistence of Iovance tumor-infiltrating lymphocytes LN-145 in cervical cancer patients. Ann Oncol. 2020;31(suppl 4):S642. doi:10.1016/j. annonc.2020.08.1012
6. Agenus initiates rolling BLA submission of balstilimab for recurrent/ metastatic cervical cancer. News release. Agenus Inc. September 18, 2020. Accessed December 8, 2020. https://bit.ly/39NQuM2
7. O’Malley DM, Oaknin A, Monk BJ, 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-S1215. https://www.annalsofoncology.org/article/ S0923-7534(20)42346-4/pdf
8. Agenus receives fast track designation for balstilimab & zalifrelimab in advanced cervical cancer. News release. Agenus, Inc. March 12, 2020. Accessed December 8, 2020. https://bit.ly/3lZnUtm
9. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/j. annonc.2020.08.2262
10. Rischin D, Gil-Martin M, González-Martin A, et al. PD-1 blockage in recurrent or metastatic cervical cancer: data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer. Gynecol Oncol. 2020;159(2):322-328. doi:10.1016/j.ygyno.2020.08.026