Focusing on ADCs, Immodulators in Cervical and Endometrial Cancers

Ursula A. Matulonis, MD

The field of gynecologic cancer continues to leverage the role of immunotherapy and novel treatments to treat patients who have new diagnoses or who have recurrent disease. That focus is emphasized throughout the 13th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ conference scheduled for May 14, 2022.¹ The virtual conference allows for greater international involvement as faculty, presenters, and attendees will learn about key clinical topics in cervical, ovarian, and endometrial malignancies.

The presentations are stratified by disease setting, said Ursula A. Matulonis, MD, cochair of this year’s conference, during an interview with Targeted Therapies in Oncology™. Presentations that focus on cervical cancer will kick off the meeting, with cochair Bradley J. Monk, MD, professor, clinical scholar track at the University of Arizona College of Medicine and medical director, gynecologic oncology research at US Oncology, addressing the role of biomarkers for immunotherapy in cervical cancer.

Targeted Antibodies

“We devote a significant portion of presentations on targeted antibodies and immunomodulating agents,” said Matulonis, professor of medicine, Harvard Medical School and chief, Division of Gynecologic Oncology and the Brock-Wilson Family Chair at Dana-Farber Cancer Institute, both in Boston, Massachusetts.

Robert L. Coleman, MD, FACOG, FACS, cochair of the conference and chief scientific officer for US Oncology Research, will address antibody-drug conjugates (ADCs) in the cervical cancer setting and will touch on tisotumab vedotin (Tivdak).

On September 20, 2021, the FDA approved tisotumab vedotin for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.² Accelerated approval for the antibody-drug conjugate was based on the findings of the phase 2 innovaTV 204 clinical trial (NCT03438396), updated data from which were published in the Lancet and previously presented during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.³

The innovaTV 204 trial is a single-arm, global, multicenter study of tisotumab vedotin in patients with recurrent or metastatic cervical cancer who had progressed during or following doublet chemotherapy with bevacizumab (Avastin). Twenty-four percent of patients had an objective response rate (ORR) (95% CI, 15.9%-33.3%) that included 7% of patients experiencing a complete response and 17% with a partial response to tisotumab vedotin.^3,4 Target lesions were reduced in 79% of patients after at least 1 post-baseline scan. Researchers also found that 49% of patients had stable disease and 24% had progressive disease after a median follow-up of 10 months.

ORR was the primary end point of the study, and secondary end points included overall survival (OS), duration of response (DOR), time to response (TTR), progression-free survival (PFS), and safety. Median DOR was 8.3 months (95% CI, 4.2-not reached [NR]) with most responses considered rapid with a median TTR of 1.4 months (range, 1.1-5.1 months) and activity observed within the fi rst 2 treatment cycles.

In another study, the addition of bevacizumab (Avastin) to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer resulted in an increase of 3.7 months in median OS (NCT00803062). Findings were published in the New England Journal of Medicine.⁵

Investigators used a 2 × 2 design to randomize 452 patients to receive chemotherapy with or without bevacizumab delivered at a dose of 15 mg/kg. The chemotherapy regimen included cisplatin at 50 mg/m² plus paclitaxel at 135 mg/m² or 175 mg/m² or topotecan at 0.75 mg/m² on days 1 to 3, plus paclitaxel at 175 mg/m² on day 1. With the data for the 2 chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased OS (17.0 months vs. 13.3 months; HR, 0.71; 98% Cl, 0.54-0.95; P = .004 in a 1-sided test) and higher response rates (48% vs. 36%, P = .008).

Immunomodulators

On the immunotherapy front for cervical cancer, the FDA granted an accelerated approval to dostarlimab-gxly (Jemperli), a programmed cell death receptor-1 blocking antibody, for the treatment of adult patients with mismatch repair-deficient recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.⁶

The efficacy of dostarlimab was evaluated in the GARNET trial (NCT02715284), a non-randomized, multicenter, open-label, multi-cohort trial. The overall response rate was 41.6%, with a 9.1% complete response rate and a 32.5% partial response rate. Median DOR was 34.7 months, with 95.4% of patients with duration greater than or equal to 6 months.

For a subset of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 and a combined positive score (CPS) greater than 1 or more, pembrolizumab (Keytruda) in combination with chemotherapy, with or without bevacizumab has been approved by the FDA.⁷ Results from the randomized, placebo-controlled KEYNOTE-826 trial (NCT03635567) examined pembrolizumab with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab. The trial enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy. Patients were randomized 1:1 to pembrolizumab 200 mg plus chemotherapy with or without bevacizumab or placebo plus chemotherapy with or without bevacizumab. Pembrolizumab was continued until disease progression, unacceptable toxicity, or 24 months of treatment.

The main efficacy outcome measures were OS and PFS assessed by the investigator using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional outcome measures were ORR and DOR. For patients with tumors expressing PD-L1 (CPS ≥ 1, n = 548), the median OS was NR (95% CI, 19.8-NR) in the pembrolizumab arm and was 16.3 months (95% CI, 14.5-19.4) in the placebo arm (HR, 0.64; 95% CI, 0.50-0.81; P = .0001). Median PFS was 10.4 months (95% CI, 9.7-12.3) in the pembrolizumab arm and 8.2 months (95% CI, 6.3-8.5) in the placebo arm (HR, 0.62; 95% CI, 0.50-0.77; P < .0001). The ORRs were 68% (95% CI, 62-74) and 50% (95% CI, 44-56) with median DOR of 18.0 and 10.4 months in the pembrolizumab and placebo arms, respectively.

Endometrial Cancer

Results of KEYNOTE-775 (NCT03517449) led to significantly longer PFS and OS for patients who received lenvatinib (Lenvima) plus pembrolizumab compared with chemotherapy in patients with advanced endometrial cancer.⁸

Investigators reported that 827 patients were randomly assigned to receive lenvatinib plus pembrolizumab (n = 411) or chemotherapy (n = 416). Baseline characteristics revealed 697 patients with proficient mismatch repair gene expression (pMMR) disease and 130 patients with mismatch repair–deficient disease. The median PFS was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 months vs. 3.8 months; HR for progression or death, 0.60; 95% CI, 0.50-0.72; P < .001; overall: 7.2 months vs. 3.8 months; HR, 0.56; 95% CI, 0.47-0.66; P < .001). The median OS was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 months vs. 12.0 months; HR for death, 0.68; 95% CI, 0.56-0.84; P < .001; overall: 18.3 months vs. 11.4 months; HR, 0.62; 95% CI, 0.51-0.75; P < .001).

Matulonis will present on the role of ADCs in endometrial cancer. ADCs have emerged as a promising approach in this setting because they combine the selectivity of a targeted treatment with the payload of cytotoxicity of chemotherapy agents.

Although gemtuzumab ozogamicin (Mylotarg) was approved in 2000 and subsequently pulled from the market, it nonetheless paved the way for additional ADCs: brentuximab vedotin (Adcetris), ado-trastuzumab emtansine (Kadcyla), and inotuzumab ozogamicin (Besponsa). These approaches and other emerging trends across all gynecologic malignancies will be explored during the conference.

REFERENCES

1. 13th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™. May 14, 2022. Accessed February 21, 2022. https://bit.ly/3JICJgd

2. Seagen and Genmab announce FDA accelerated approval for Tivdak (tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Seagen, Inc. September 20, 2021. Accessed September 20, 2021. https://bwnews.pr/3hSbILN

3. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; virtual. Abstract LBA32.

4. Coleman RL, Lorusso D, Gennigens C, et al. Effi cacy 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

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. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated February 1, 2022. Accessed February 22, 2022. https://bit.ly/3t0tAsQ

7. FDA approves pembrolizumab combination for the fi rst-line treatment of cervical cancer. FDA. Updated October 13, 2021. Accessed February 22, 2022. https://bit.ly/3HbP9Mb

8. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38(26):2981-2992. doi:10.1200/JCO.19.0262