The treatment of recurrent or metastatic cervical cancer has not changed much in recent years, but according to preliminary trials presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, checkpoint inhibitors and antibody-drug conjugates may become new options.

In the multicenter phase II innovaTV 204 trial of the antibody-drug conjugate tisotumab vedotin, 24 of 101 patients responded, with 7 being complete responders.¹ In two phase II studies also presented at ESMO 2020, the investigative PD-1 inhibitor balstilimab as a single agent and combined with the CTLA-4 inhibitor zalifrelimab also yielded promising response rates, regardless of PD-L1 expression.²

Tisotumab Vedotin in innovaTV 204

Tisotumab vedotin comprises an antibody directed at tissue factor and covalently linked to the microtubule disruptor monomethyl auristatin E (MMAE). Tissue factor is commonly found in cervical cancer and is associated with a poor prognosis.

Robert L. Coleman, MD

“Tisotumab vedotin demonstrated compelling and durable antitumor activity in recurrent or metastatic cervical cancer previously treated with doublet chemotherapy,” reported Robert L. Coleman, MD, of Texas Oncology in the Woodlands, Texas. Thus, the antibody-drug conjugate is “a potential novel treatment” for women with recurrent or metastatic cervical cancer, for whom there is no established second-line option.

In innovaTV 204, single-agent tisotumab vedotin was given to 101 patients (median age of 50) with recurrent or extrapelvic metastatic cervical cancer that had progressed during or after doublet chemotherapy with bevacizumab (if eligible). No more than two prior lines of therapy were allowed; most patients had received cisplatin-containing chemoradiation therapy. The primary endpoint was objective response rate, as determined by independent imaging review.

After a median follow-up of 10 months, objective responses were observed in 24%, and stable disease was seen 49% (four patients were yet to be evaluated). The median duration of response was 8.3 months, and 79% of patients had some tumor shrinkage.

“Most responses were rapid, with activity observed within the first two treatment cycles. Clinically meaningful responses were observed regardless of histology subtype, tissue factor expression level or prior therapy, including use of doublet chemotherapy with bevacizumab as a first-line treatment,” Dr. Coleman said. “Of note, the objective response rates in patients with nonsquamous histology (25%) and in those previously treated with bevacizumab (19%) were encouraging, as only limited data currently exist in these populations.”

Median progression-free survival was 4.2 months, and 30% of patients were alive without disease progression at 6 months. Median overall survival was 12.1 months, with 79% alive at 6 months. One-third of the treatment cohort is still being followed for overall survival.

Safety Profile

Most treatment-related adverse events were grade 1 or 2, most commonly alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (24%), and dry eyes (23%). Treatment-related adverse events grade ≥ 3 occurred in 28% of patients; one death due to septic shock was considered to related to the study drug.

Prespecified adverse events of interest included ocular toxicities, bleeding, and peripheral neuropathy. Conjunctivitis and dry eye effects were mostly mild to moderate, resolved, and were manageable with an eye care plan. Most bleeding events were grade 1 epistaxis, of which the majority resolved. Most peripheral neuropathy events (a known MMAE-related toxicity) were grade 1 and manageable with dose modifications; resolution was limited by the follow-up period.

New Checkpoint Inhibitors Under Study

Two phase II trials evaluated the novel checkpoint inhibitors balstilimab alone or with the novel anti–CTLA-4 agent zalifrelimab. They included patients with squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma with relapse following platinum-based therapy. The single-agent trial included 160 patients, 138 of whom had received at least one prior line of chemotherapy. The combination cohort included 155 patients, of whom 119 had received one line.

“This is, by far, the largest reported study of checkpoint inhibitors in recurrent or metastatic cervical cancer reported to date. We demonstrated responses in both PD-L1–positive and PD-L1–negative tumors in patients treated with single-agent balstilimab and with the combination of balstilimab and zalifrelimab,” said David O’Malley, MD, Professor of Obstetrics and Gynecology at The Ohio State University College of Medicine.

David O’Malley, MD

Single-agent balstilimab elicited a 14% response rate overall; of 20 responses, 3 were complete responses. With the combination of balstilimab and zalifrelimab, response rates increased to 22%; of 23 responses, 8 were complete responses. The median duration of response was 15.4 months with balstilimab and was not reached with the combination, he reported.

In the single-agent cohort, by PD-L1 status, responses were seen in 19%, 10%, and 0% of patients with PD-L1–positive disease (≥ 1%), PD-L1–negative disease, and unknown PD-L1 status, respectively. In the combination study, these rates were 27%, 11%, and 21%, respectively.

Treatment was well tolerated in both studies, and no new safety signals were identified, with all-grade endocrine disorders being more common with the combination than with single-agent balstilimab (20.6% vs 9.3%, respectively). As expected, more immune-related adverse effects were also seen with the combination, but few were grade ≥ 3. 

DISCLOSURE: The innovaTV 204 study was supported by Genmab. Dr. Coleman disclosed relationships with AbbVie, Aravive, Curio Science, Geistlich, Genmab, More Health, AstraZeneca, Genentech, GlaxoSmithKline, Janssen, Merck, Myriad, Novocure, Roche, Tarveda Therapeutics, Tempus Labs, Tesaro, Clovis Oncology, OncoMed, and the National Cancer Institute. Dr. O’Malley’s study was funded by Agenus, and he disclosed personal financial relationships with AstraZeneca, Clovis, Immunogen, Ambry, Jansen/J&J, AbbVie, Regeneron, Amgen, and Novacure.

REFERENCES

1. 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. ESMO Virtual Congress 2020. Abstract LBA32. Presented September 21, 2020.

2. 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 cervical cancer: Preliminary results of two independent phase II trials. ESMO Virtual Congress 2020. Abstract LBA34. Presented September 18, 2020.