Data Show Potential Survival Improvement With IO in Advanced Cervical Cancer

Deanna Teoh, MD, MS

Women with recurrent or metastatic cervical cancer who fail prior treatment are known to have a poor prognosis, but immunotherapy may extend their survival, according to a presentation by Deanna Teoh, MD, MS, at the 2019 SGO Annual Winter Meeting.¹

Bevacizumab (Avastin) offers the best results to date with a median overall survival (OS) of 7.3 months for these patients. Clinical trial data suggests that immunotherapeutic agents can demonstrate equivalent or superior median OS.

“Immunotherapy is promising for the treatment of advanced or recurrent cervical cancer, but I think that we really have to figure out which patients or which tumors are best suited for different therapies,” said Teoh, assistant professor in the Division of Gynecologic Oncology at the University of Minnesota Medical School and medical director of gynecologic oncology at Regions Cancer Care Center in St. Paul, Minnesota.

In phase II data presented at the 2014 ASCO Annual Meeting, axalimogene filolisbac (AXAL)—a live attenuated Listeria monocytogenes immunotherapy agent bioengineered to induce antitumor T-cell immunity and break immune tolerance in the tumor microenvironment—improved median OS among 110 Indian women with recurrent cervical cancer who had previously received chemotherapy, radiotherapy or both. Treatment resulted in a median OS of 8.28 months, with a 12-month OS rate of 30.9% and an overall response rate of 17.1%. The addition of cisplatin did not result in a significant improvement in OS (P= .9981) in 69 evaluable patients.²

Axalimogene filolisbac was further evaluated in this patient population in the phase II GOG/NRG-0265 study. The immunotherapy agent induced an unprecedented 1-year survival rate of 38%, a 52% improvement over the calculated survival. The median OS was 6.2 months and 32% of patients achieved disease control based on investigator assessment of best response of the 50 evaluable patients.³

In a January 2018 interview withTargeted Oncology, Sharad Ghamande, MD, director for gynecological oncology at Augusta University, said cervical cancer is the most attractive target for immunotherapy among gynecologic cancers.

“If you look at the genesis of cervical cancer, there is always an HPV infection. The immune system in most cases, especially when we are younger, takes care of the infection,” he said. “However, if it is persistent as we get older, it then causes cancerous changes. HPV is a target that is always expressed, making it a very potent target that we can exploit either by a vaccine or checkpoint inhibition.”

Teoh said that one of the most exciting things about immunotherapeutic agents is that they are generally well tolerated. The only grade ≥3 treatment-related adverse event (TRAE) recorded in GOG/NRG-0265 was grade 3 anemia in 10% of patients.

Based on these findings, axalimogene filolisbac is now being investigated in the ongoing global phase III AIM2CERV (NCT02853604) trial as adjuvant monotherapy to prevent recurrence in patients with locally advanced cervical cancer treated with chemoradiation.

Patients are randomly assigned 2:1 to axalimogene filolisbac or placebo. The experimental cohort will receive 3 doses of axalimogene filolisbac every 3 weeks during the primary phase, followed by a maintenance phase where the drug is administered every 2 months for 1 year.

The current trial design has a planned sample size of 450 patients to maintain adequate statistical power over a broader range of survival outcomes, as well as a preplanned interim analysis (IA) of safety and efficacy. Advaxis, the developer of axalimogene filolisbac, is considering accelerating the IA timeline and establishing a more stringent futility boundary. The company expects to finalize the redesign in the next few months.

The FDA lifted a clinical hold on a phase I/II study for axalimogene filolisbac in combination with durvalumab (Imfinzi) for the treatment of patients with advanced, recurrent, or refractory cervical cancer and HPV-associated head and neck cancer in July 2018. The agency applied the hold in March following a report of a patient who died of acute respiratory failure after 9 months of combination therapy. Advaxis agreed to new guidelines for the early detection and treatment of such rare adverse events.

Immune Checkpoint Inhibitors

Enrollment in AIM2CERV was not affected by the clinical hold.Investigators are evaluating immune checkpoint inhibitors (ICIs) for the treatment of cervical cancer in several clinical trials including CheckMate 358 and KEYNOTE-028 and -158. Results are also pending for the phase II GY-007 trial evaluating nivolumab (Opdivo) for persistent, recurrent, or metastatic cervical cancer.

The multicohort phase I/II CheckMate 358 study evaluated nivolumab and nivolumab-based combination therapy in patients with virus-associated tumors, including a cohort of 24 patients with recurrent or metastatic cervical, vaginal, and vulvar cancers. Nineteen patients with cervical cancer had received up to 2 prior treatment regimens for recurrent or metastatic disease.

The objective response rate (ORR) was 20.8% overall and 26.3% in the patients with cervical cancer. It was higher in treatment-naïve patients at 28.6%, compared with 17.6% in previously treated patients. The overall median progression-free survival (PFS) was 5.5 months.⁴

In June, the FDA granted an accelerated approval for the treatment of patients with advanced, PD-L1—positive cervical cancer with disease progression on or after chemotherapy based on the results of the phase II KEYNOTE-158 trial. The global, open-label, nonrandomized, multicohort, multicenter study evaluated pembrolizumab (Keytruda) in patients with multiple types of advanced solid tumors who progressed on standard of care therapy.

At a median follow-up of 11.7 months (range, 0.6-22.7), the ORR was 14.3% (95% CI, 7.4%-24.1%) in 77 PD-L1—positive patients (CPS ≥1) previously treated with ≥1 line of chemotherapy in the metastatic setting. The ORR included a complete response rate of 2.6% and a partial response rate of 11.7%. The median duration of response was not reached (range, 4.1-18.6+), and 91% of responders had a response duration of 6 months or longer.⁵

In KEYNOTE-158, pembrolizumab was discontinued in the cohort of women with recurrent or metastatic cervical cancer due to adverse reactions in 8% of 98 patients. Thirty-nine percent of patients experienced serious adverse reactions.

KEYNOTE-028 is a multicenter, phase Ib, single-arm trial evaluating the safety and efficacy of pembrolizumab in 20 different PD-L1—positive advanced solid tumors. These results come from an analysis of 24 women with PD-L1–positive advanced cervical cancer. Eighteen (75%) patients expressed PD-L1 in the tumor only and 6 (25%) were PD-L1–positive in the tumor and stroma.

Four women had confirmed partial responses (PRs), for an ORR of 17% (95% CI, 5%-37%). Three patients had stable disease (13%; 95% CI, 3%-32%), and 16 (67%) had progressive disease (95% CI, 45%-84%) as best response.⁶

The median PFS in all patients was 2 months (95% CI, 2-3). PFS was 21% at 6 months and 4% at 12 months. The median OS in all patients was 11 months (95% CI, 4-15). The OS rate was 67% at 6 months and 40% at 12 months.

Investigators are currently recruiting patients for the phase I NRG-GY017 (NCT03738228) trial evaluating atezolizumab (Tecentriq) in combination with chemoradiation, and for the phase II UVA-LACC-PD201 trial (NCT02635360) evaluating pembrolizumab in combination with chemoradiation.

“We know from other tumor types that, especially with the checkpoint inhibitors, a lot of times you see a lot more activity when combined with cytotoxic therapies, possibly PARP inhibitors or another checkpoint inhibitor, something like a CTLA-4 inhibitor,” Teoh said. “We also have to look at, if we're getting improved responses, are we also increasing the toxicity?

“There's a lot of excitement in this area and I look forward to see where it's going.”

References:

1. Teoh D. Immunotherapy in cervical cancer. Presented at: the 2019 SGO Annual Winter Meeting; January 17-19, 2019; Lake Tahoe, CA.
2. Basu P, Mehta AO, Jain MM, et al. ADXS11-001 immunotherapy targeting HPV-E7: Final results from a phase 2 study in Indian women with recurrent cervical cancer.J Clin Oncol. 2014;32(suppl 5; abstr 5610).
3. Huh W, Brady WE, Dizon DS, et al. A prospective phase II trial of the listeria-based human papillomavirus immunotherpay axalimogene filolisbac in second- and third-line metastatic cervical cancer: A NRG oncology group trial. Presented at: 2017 SGO Annual Meeting; March 12-15, 2017; National Harbor, MD. LB-3.
4. Hollebecque A, Meyer T, Moore KN, et al. An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers.J Clin Oncol. 2017;35(suppl; abstr 5504).
5. Chung HC, Schellens JHM, Delord JP, et al. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study.J Clin Oncol. 2018;36(suppl; abstr 5522).
6. Frenel JS, Le Tourneau C, O’Neil B, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial.J Clin Oncol. 2017;35(36):4035-4041. doi: 10.1200/JCO.2017.74.5471.