Immuno-Oncology Therapies Make Slow But Steady Gains in Gynecologic Cancers

Thomas J. Herzog, MD

Thomas J. Herzog, MD

Although the emergenceof immuno-oncology therapies have demonstrated promise in some solid and hematologic malignancies, their benefit in gynecologic cancers is lagging behind a bit. That doesn’t discourage experts in the field: “This is an exciting time in gynecologic cancers,” said Thomas J. Herzog, MD, during the 14th Annual New Orleans Summer Cancer Meeting.

Herzog, the Paul & Carolyn Flory Professor of Obstetrics and Gynecology and deputy director of the University of Cincinnati Cancer Institute in Ohio, provided an overview of clinical research in cervical, endometrial, and ovarian cancer settings that covered cancer vaccines, adoptive T-cell transfer therapy, and immune checkpoint inhibitors (ICIs).¹

Cervical Cancer

“Cervical cancer is a preventable disease because of screening and vaccination,” Herzog said. “Because the human papillomavirus [HPV] is the causative agent of many cases of cervical cancer, it makes sense to target this cancer with immune strategies.”

Herzog noted that HPV vaccines fall into the prophylactic or therapeutic categories. In particular, therapeutic approaches have enjoyed renewed clinical activity in the past 3 to 5 years.

A greater understanding of adaptive immune resistance, in which cancer cells evade the immune response, has paved the way for the emergence of ICIs, immune-activating cytokines, and chimeric antigen receptor (CAR) T cells, Herzog said.²The antitumor T-cell response has been particularly notable.³

Stevanović et al³used a personalized immunogenomic approach in patients with HPV associated metastatic cervical cancer after tumor-infiltrating adoptive T-cell therapy. “I want to emphasize the prolonged regression that was observed in these patients who were without any other treatment available. Their next stop was hospice,” Herzog told the audience. He noted that the response was not seen in every patient, raising the questions, “What makes these patients different, and why did this happen?”

“Expect to see more of this type of research as we move forward,” Herzog said. “I think it will be important.”

A number of trials involving checkpoint inhibitors have made inroads in cervical cancer, according to Herzog.

KEYNOTE-029 (NCT02054806) involved pembrolizumab for PD-L1—positive advanced cervical cancer in patients who had received prior lines of therapy including platinum and bevacizumab (Avastin). The investigators reported an objective response rate (ORR) of 17%, with 13% of patients exhibiting stable disease. Herzog pointed out that the length of response in those who responded was exceptional, but elucidating these responses would be particularly interesting.⁴

Results from KEYNOTE-158 (NCT02628067) led to the eventual approval of pembrolizumab (Keytruda) in cervical cancer in June 2018. In the pivotal trial, ORR was 14.3% (95% CI, 7.4%-24.1%), with a 2.6% complete response and an 11.7% partial response rate.⁵

KEYNOTE-826 is an ongoing trial that is determining the efficacy and safety of pembrolizumab plus 1 of 4 platinum-based chemotherapy regimens compared with the efficacy and safety of placebo plus 1 of 4 platinum-based chemotherapy regimens. The primary endpoints are progression-free survival (PFS) per RECIST 1.1 as assessed by blinded independent central review or overall survival (OS).⁶

Endometrial Cancer

In the endometrial cancer arena, Herzog emphasized the importance of determining microsatellite instability (MSI) status. “Endometrial cancer has a high percentage of patients who are MSI high [MSI-H], especially in recurrent or metastatic cases,” he said.

KEYNOTE-028 (NCT02054806) evaluated the safety and efficacy of pembrolizumab in patients with PD-L1—positive advanced solid tumors. Of 75 patients screened, 36 (48.0%) had PD-L1–positive tumors and 24 (32.0%) were enrolled. Of these 24 patients, 15 (62.5%) had received at least 2 previous lines of therapy for advanced disease. Three patients (13.0%) achieved confirmed partial response (95% CI, 2.8% to 33.6%); the median duration of response (DOR) was not reached. Two patients were still receiving treatment and exhibiting continued response at the time of data cutoff. Three additional patients (13.0%) achieved stable disease, with a median duration of 24.6 weeks.⁷

Herzog noted that pembrolizumab has been evaluated in patients with MSI-H or deficient mismatch repair (dMMR) status across various cancer types including colorectal, gastric, bladder, breast, esophageal, and biliary. The agent was evaluated in KEYNOTE trials -016 (NCT01876511), -164 (NCT02460198), -012 (NCT01848834), -028 (NCT02054806), and -158 (NCT02628067).

In May 2017, the FDA subsequently awarded pembrolizumab an accelerated approval for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors progressing following prior treatment and who have no satisfactory alternatives.⁸

ICIs have also been evaluated in combination with chemotherapy and other targeted agents. In KEYNOTE-146, lenvatinib (Lenvima) and pembrolizumab were evaluated in patients with mismatch repair—proficient (MMRp) tumors. The primary endpoint was ORR at 24 weeks, which was calculated only for evaluable patients who had 24 weeks of follow-up or discontinued treatment prior to 24 weeks.⁹

The researchers reported that ORR was 36.7% (95% CI, 23.4%—51.7%). Median DOR had not yet been reached (not estimable [NE], 95% CI, 4.1-NE) and median PFS was 10.1 months (95% CI, 5.3-NE). Of the 3 MSI-H patients, 1 achieved partial response, 1 had stable disease, and 1 had progressive disease. For non–MSI-H/ MMRp patients, ORR at 24 weeks was 50.0% (95% CI, 29.9%–70.1%).⁹

Another ongoing combination trial in the endometrial cancer setting is NRG GY018 (NCT03914612), a phase III trial in patients with known MMR immunohistochemical status. Patients will be randomized to receive paclitaxel/ carboplatin plus pembrolizumab versus paclitaxel/carboplatin plus placebo and stratified by dMMR status (yes or no), performance status (0 or 1), and prior chemotherapy (yes or no). The trial’s primary endpoint is PFS, and secondary endpoints are tumor response and DOR.

Ovarian Cancer

Immuno-oncology agents in the ovarian cancer setting have demonstrated response rates in the 10% to 15% range for single agents, Herzog said. A number of different trials have played a role in the treatment paradigm, including JAVELIN Ovarian 100 and 200, ENGOT-OV24, and TOPACIO.

JAVELIN Ovarian 100 (NCT02718417) and 200 (NCT02580058) involved avelumab (Bavencio) in the treatment of first- or second-line ovarian cancer. Herzog noted that both trials were terminated after failing to meet primary endpoints in 2018 and 2019, respectively.

JAVELIN Ovarian 100 looked at previously untreated patients with stage III/IV ovarian cancer who were randomized to receive chemotherapy or chemotherapy and avelumab in 3 arms: Arm A received chemotherapy and observation; B, chemotherapy plus avelumab every 2 weeks; and C, chemotherapy plus avelumab every 3 weeks, then avelumab every 2 weeks.

According to the investigators, the primary endpoint was PFS, and secondary endpoints were maintenance PFS, OS, ORR, and DOR.

JAVELIN Ovarian 200, which examined avelumab alone or in combination with pegylated liposomal doxorubicin (PLD), failed to provide a statistically significant improvement in OS or PFS versus PLD alone in patients with platinum-resistant/refractory ovarian cancer, missing its primary endpoint. The ORR for the combination was 13.3% compared with 3.7% for avelumab monotherapy and 4.2% for PLD alone.

“What was interesting was [that] the investigators did not use a biomarker in either of these trials. When the post hoc analysis was conducted, hypothesis generating only, investigators found that there were statistical significance in terms of efficacy if they had used the biomarker,” Herzog said.

The ENGOT-OV24 (NCT02354131) trial involved the combination of the PARP inhibitor niraparib (Zejula) plus bevacizumab. Investigators observed a significant increase in PFS for the combination arm versus niraparib alone in patients with platinum-sensitive recurrent ovarian cancer. Although no difference in treatment-emergent grade 3/4 adverse events was observed, patients developed hypertension (26% vs 0%) and neutropenia (12% vs 2%).¹⁰

In the phase I/II TOPACIO (NCT02657889) study, women with platinum-resistant/refractory ovarian cancer were assigned to the combination of niraparib and pembrolizumab. Among 36 patients with platinum-resistant disease, 6 had a partial response and 12 had stable disease.¹¹

“These combination trials are probably the most promising approach that we see going forward,” Herzog said. “There are multiple studies that are going on in parallel that are looking at agents including antiangiogenic agents, PARP inhibitors, as well as immuno-oncology to determine whether or not we’re going to be able to identify a winning combination. As we continue to use next-generation sequencing and better understand the epigenetic effect, as well, I think we’re going to best predict who benefits from these immuno-oncology therapies.”

References

1. Herzog TJ. Immunotherapies in gynecologic malignancies. Presented at: 14th Annual New Orleans Summer Cancer Meeting; July 19-21, 2019; New Orleans, LA.
2. Ribas A. Adaptive immune resistance: how cancer protects from immune attack.Cancer Discov. 2015;5(9):915-919. doi: 10.1158/2159- 8290.CD-15-0563.
3. Stevanović S, Pasetto A, Helman SR, et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer.Science. 2017;356(6334):200-205. doi: 10.1126/science. aak9510.
4. Frenel J-S, Le Tourneau C, O’Neil BH, et al. Pembrolizumab in patients with advanced cervical squamous cell cancer: preliminary results from the phase Ib KEYNOTE-028 study.J Clin Oncol.2016;34(suppl 15; abstr 5515). ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.5515.
5. Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co Inc, 2014.
6. Efficacy and safety study of first-line treatment with pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy in women with persistent, recurrent, or metastatic cervical cancer (MK- 3475-826/KEYNOTE-826). bit.ly/2lzgsMa. Updated August 22, 2019. Accessed August 22, 2019.
7. Ott PA, Bang YJ, Berton-Rigaud D, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 Study.J Clin Oncol.2017;35(22):2535-2541. doi: 10.1200/JCO.2017.72.5952.
8. FDA grants accelerated approval to pembrolizumab for first tissue/ site agnostic indication. FDA website. bit.ly/2lDQSG0. Updated May 30, 2017. Accessed August 22, 2019.
9. Makker V, Rasco DW, Vogelzang NJ, et al. Lenvatinib + pembrolizumab in patients with advanced endometrial cancer: updated results.J Clin Oncol. 2018;36(suppl 15; abstr 5596). doi: 10.1200/JCO.2018.36.15_ suppl.5596.
10. Mirza MR, Avall-Lundqvist E, Birrer MJ, et al. Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: a randomized controlled chemo- therapy-free study—NSGO-AVANOVA2/ENGOT-OV24.J Clin Oncol.2019;37(suppl 15; abstr 5505). doi: 10.1200/JCO.2019.37.15_suppl.5505.
11. Niraparib in combination with pembrolizumab in patients with triple- negative breast cancer or ovarian cancer (TOPACIO). bit.ly/2ktR36g. Updated February 12, 2018. Accessed August 22, 2019.