Targeted Therapy, Immunotherapy Are Replacing Chemotherapy in Endometrial Cancer

Shannon Westin, MD

Researchers and practicing physicians have done as much as possible with chemotherapy as a systemic treatment for endometrial cancers, and other modalities—alone and in combination—are likely to become standard of care in the coming years, Shannon N. Westin, MD, MPH, said during a presentation at the 2020 SGO Winter Meeting.

“The therapeutic ceiling for chemotherapy is reached,” said Westin, an associate professor at The University of Texas MD Anderson Cancer Center. “Now we need to understand how these different pathways are interacting and how we might be able to turn them off to best impact tumor reduction.”

Westin said investigators saw promise with hormonal agents in preclinical studies and began exploring the potential of targeting the PI3K/AKT/mTOR pathway with the combination of the mTOR inhibitor everolimus (Afinitor) and the nonsteroidal aromatase inhibitor letrozole (Femara). That combination was evaluated in the phase II GOG 3007 trial comparing everolimus/letrozole versus hormonal therapy with tamoxifen plus megestrol acetate in women with advanced, persistent or recurrent endometrial carcinoma.

In the study, the overall response rate (ORR) was 53% in the everolimus/letrozole arm compared with 43% with hormonal therapy. The median progression-free survival (PFS) also favored the experimental arm (6.3 vs 3.8 months), as did the median overall survival (OS; not reached vs 16.6 months).¹

“The next step is to say, 'Can we eliminate chemotherapy in that frontline? Can we move toward everolimus and letrozole in that population?’” Westin said.

She noted that only women with endometrial cancer were included in the study. “They were not selected by progesterone receptor, but [investigators] are basically picking patients who are more likely to have that aberration.”

Antiangiogenic Agents

Initial studies of antiangiogenic agents as monotherapy in endometrial cancers produced a handful of singles, but no home runs, noted Westin. In results from the 229-E trial, bevacizumab (Avastin) was associated with a complete response (CR) rate of just 2%, but 40% of patients were progression-free for >6 months.² The 229-J study, published in 2015, evaluated cediranib for patients with recurrent or persistent endometrial cancer after receiving 1 or 2 prior cytotoxic regimens. The 6-month PFS rate was 33.3%.³

Historically, PFS in this population is 3 months, Westin said. She called the results “a signal” suggesting these agents could have a role to play in this disease. “Certainly, not the home runs we're looking for, but definitely some idea that antiangiogenics make sense in endometrial cancer.”

However, it is not yet clear that these agents can improve PFS in endometrial cancer.

The randomized phase II GOG 86P trial (N = 349) compared paclitaxel and carboplatin plus bevacizumab, versus paclitaxel and carboplatin plus temsirolimus (Torisel), versus ixabepilone (Ixempra) and carboplatin plus bevacizumab in patients with chemotherapy-naïve stage III/IVa and stage IVb or recurrent endometrial cancer. None of the treatment arms showed an improvement in PFS compared with historical controls.⁴

In the phase II MITO END-2 trial, patients with advanced or recurrent disease were randomly assigned to carboplatin and paclitaxel with or without bevacizumab. The median PFS in the bevacizumab arm was 13.7 months compared with 10.5 months in the control arm (HR, 0.846; 95% CI, 0.5-1.3; P = .437).⁵

However, the addition of bevacizumab did improve ORR (74.4% vs 53.1%), which may be enough to show that the combination should be explored further.

Targeting the HER2 Pathway

Westin said attacking endometrial cancer through HER2 is one of the great successes of recent years. Although early results with trastuzumab (Herceptin) monotherapy were disappointing, combining the drug with chemotherapy produced promising results.

Investigators conducting a multicenter, randomized phase II trial assigned 61 women with primary stage III or IV or recurrent HER2/neu-positive disease to carboplatin/paclitaxel with or without intravenous trastuzumab. Fader et al observed 40 PFS events among 58 evaluable participants.⁶

The median overall PFS was 12.6 months versus 8.0 months in favor of the experimental arm (HR, 0.44; 90% CI, 0.26-0.76; P = .0052). The median PFS with trastuzumab was 17.9 months compared with 9.3 months (HR, 0.40; 90% CI, 0.20-0.80; P = .013) among 41 patients with stage III or IV disease undergoing primary treatment. Among 17 patients with recurrent disease, the median PFS again favored the experimental arm (9.2 vs 6.0 months; HR, 0.14; 90% CI, 0.04-0.53; P = .0029).

The study investigators reported that toxicity was not different between treatment arms and there were no unexpected safety signals.

“We had a clear benefit in PFS,” Westin said. “[We saw] a 60% reduction in the risk for progression in patients who had trastuzumab added to chemotherapy. When we broke it out by primary advanced disease versus recurrent, we saw consistent benefit across the 2. Of course, the more impressive curve is that patient population that was primary, because they generally do better.”

She added that OS data is scheduled to be presented at the 2020 SGO Annual Meeting in March.

Immunotherapy

Westin also pointed to success with immunotherapy. In findings from the ongoing phase I/II GARNET trial presented at the 2019 SGO Annual Meeting, patients with recurrent or advanced endometrial cancer assigned to dostarlimab (TSR-042) demonstrated an ORR of 29.6% (95% CI, 21.8-38.4).⁷ Moreover, these responses were durable in both microsatellite instability—high (MSI-H; 48.8%) and microsatellite stable (MSS; 20.3%) cohorts.

In KEYNOTE-146/Study 111, investigators evaluated the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) for patients with advanced endometrial carcinoma who had disease progression following prior systemic therapy but were ineligible for curative surgery or radiation. The investigator-assessed ORR in the total study population was 38.9%, including a CR rate of 7.4%. Among patients whose tumors were not MSI-H or mismatch repair deficient (dMMR), the ORR was 37.2%. In patients with tumors that were MSI-H or dMMR, the ORR was 63.6%.

“Nearly every single patient had some kind of benefit on this trial. The majority of them were MSS and it didn't correlate with PD-L1,” Westin said. “[These results] were really exciting.”

Based on the results from KEYNOTE-146/Study 111, the FDA granted an accelerated approval to the combination in September 2019 for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, and who have disease progression following prior systemic therapy but are ineligible for curative surgery or radiation.

References

1. Slomovitz BM, Filiacic VL, Coleman RL, et al. GOG 3007, a randomized phase II (RP2) trial of everolimus and letrozole (EL) or hormonal therapy (medroxyprogesterone acetate/tamoxifen, PT) in women with advanced, persistent or recurrent endometrial carcinoma (EC): A GOG Foundation study. Presented at: 49th Annual Meeting of the Society of Gynecologic Oncology; March 24-27, 2018; New Orleans, LA. Abstract 1.
2. Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29:2259-2265. doi: 10.1200/JCO.2010.32.6397.
3. Bender D, Sill MW, Lankes HA, et al. A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;138(3):507—512. doi:10.1016/j.ygyno.2015.07.018.
4. Aghajanian C, Filiaci V, Dizon DS, et al. A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol. 2018;150(2):274-281. doi: 10.1016/j.ygyno.2018.05.018.
5. Lorusso D, Ferrandina G, Colombo N, et al. Carboplatin-paclitaxel compared to Carboplatin-Paclitaxel-Bevacizumab in advanced or recurrent endometrial cancer: MITO END-2 - A randomized phase II trial. Gynecol Oncol. 2019;155(3):406-412. doi:10.1016/j.ygyno.2019.10.013.
6. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol. 2018;36(20):2044-2051. doi: 10.1200/JCO.2017.76.5966.
7. Oaknin A, Duska LR, Sullivan RJ, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti—PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H and MSS endometrial cancer. Presented at: 2019 SGO Annual Meeting; March 16-19, 2019; Honolulu, HI. Abstract 33.
8. Final Study Results Evaluating KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Combination Treatment in Advanced Endometrial Cancer Presented at ESMO 2019 Congress. Merck (MSD). Published September 29, 2019. https://bit.ly/376Q9PE. Accessed February 7, 2020.

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