Immunotherapy Combinations Launch Into Earlier Lines and Signal Success in Metastatic Solid Tumors

Omid Hamid, MD

Across lung, skin, genitourinary, and gastrointestinal (GI) cancers, successful immunotherapies that have been approved for use in the metastatic setting, notably ipilimumab (Yervoy) plus nivolumab (Opdivo), are rapidly moving forward into the adjuvant and neoadjuvant settings, whereas newer combinations, such as cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) in renal cell carcinoma (RCC), are arising for later lines.

At an OncLive^® Institutional Perspectives in Cancer webinar on immunotherapy, chaired by Omid Hamid, MD, director of the Melanoma Program, director of Melanoma Therapeutics, director of the Phase I Immuno-Oncology Program, and chief of Translational Research and Immunotherapy at The Angeles Clinic and Research Institute at Cedars-Sinai, highlighted the benefits of ipilimumab plus nivolumab in non–small cell lung cancer (NSCLC) and BRAF-mutant melanoma, as well as the positive role of adjuvant pembrolizumab (Keytruda) in clear cell RCC. The presenters also discussed immunotherapies on the horizon in early-stage GI cancers and how immunotherapeutic advances can be sequenced with or replace chemotherapy.

Hamid was joined by the following colleagues:

• Ani Balmanoukian, MD, director, Thoracic Oncology; associate director, the Phase I Immuno-Oncology Program; leader; the Lung Cancer Clinical Program, The Angeles Clinic and Research Institute at Cedars-Sinai
• Inderjit Mehmi, MD, physician, Hematology Oncology, The Angeles Clinic and Research Institute at Cedars-Sinai
• Vi K. Chiu, MD, PhD, director, Gastrointestinal Oncology; director, Molecular Precision Programs, The Angeles Clinic and Research Institute at Cedars-Sinai
• Kristopher P. Wentzel, MD, leader, the Genitourinary Cancer Clinical Program, The Angeles Clinic and Research Institute at Cedars-Sinai

Below, Balmanoukian, Mehmi, Chiu, and Wentzel summarize the main messages from their presentations.

Updates in Immunotherapy in NSCLC

Balmanoukian: In the recurrent and metastatic setting in NSCLC, the [phase 3] CheckMate 227 trial [NCT02477826] is studying ipilimumab plus nivolumab for patients with NSCLC with a PD-L1 expression of greater than 1%. We see a 5-year overall survival [OS] rate of 24% in the group that received ipilimumab plus nivolumab vs 14% in the group that received chemotherapy alone.

In the [phase 3] CheckMate 9LA trial [NCT03215706], which included newly diagnosed patients with metastatic or recurrent NSCLC, regardless of PD-L1 expression, we now have 3-year OS data showing an OS rate of 27% in the group that received limited chemotherapy plus ipilimumab and nivolumab vs 19% in the group that received chemotherapy alone. In the [phase 3] EMPOWER-Lung 3 trial [NCT03409614] investigating the combination of cemiplimab-rwlc [Libtayo], a PD-1 inhibitor, plus chemotherapy in the newly diagnosed setting, we see a median OS of 21.9 months with the combination vs 13 months with chemotherapy alone.

Now, in the neoadjuvant setting, the [phase 3] CheckMate 816 trial [NCT02998528], which studied the combination of chemotherapy plus nivolumab, noted a pathologic complete response rate of 24% with [chemotherapy plus nivolumab] vs 2.2% with chemotherapy alone; the event-free survival was 31.6 months in the group that received chemotherapy plus nivolumab vs 20.8 months in the group that only received chemotherapy.

We’ve made substantial progress regarding all treatment options that are available for patients, and I can only see the field moving forward and patients doing better overall.

Melanoma Therapeutics: State of the Art in 2022

Mehmi: I talked about the adjuvant setting for node-negative and node-positive melanoma applications, as well as treatment sequencing for BRAF-mutant melanoma, where ipilimumab plus nivolumab [should be used], unless it’s contraindicated.

My goal was to emphasize 2 main trials. The [phase 2/3] RELATIVITY-047 study [NCT03470922] is a promising metastatic melanoma treatment–naïve study in the first-line setting. The biggest point from that study was the reduced burden of toxicity [with relatlimab plus nivolumab (Opdualag)] compared with other available regimens. The second study, the [phase 3] DREAMseq trial [NCT02224781], [gives us options for] patients who have BRAF-mutated melanoma.

I also touched on some of the other options available in the clinical trial setting for uveal, mucosal, and cutaneous melanoma. For example, I discussed tebentafusp-tebn [Kimmtrak] in uveal melanoma, its ongoing studies, and its applications in cutaneous melanoma. I also talked about ALKS 4230, a mutant of interleukin 2 in mucosal melanoma; adoptive T-cell therapy; and how to manage brain metastases from melanoma.

In the first-line setting, patients who might not be good candidates for ipilimumab plus nivolumab, should be considered for nivolumab plus relatlimab rather than PD-1 inhibition alone, because the combination is better than PD-1 inhibitors alone. Additionally, once we run out of standard-of-care treatments, there are so many more options within the clinical trial setting.

We’re moving that needle, continuing to improve the OS rate for metastatic melanoma beyond 5 years. Right now, we’re at about 50%, and we want to make it better. The only way to do that is through clinical trials.

Immunotherapy in GI Cancers

Chiu: There is current evidence [to support] immunotherapy efficacy in some GI cancers, [not including] pancreatic cancer, [where data with this approach have] been negative so far. There will be a transition of immunotherapy exposure to earlier-stage tumors prior to the development of increased immune resistance.

There’s also an unmet need for predictive biomarkers, and we’re trying to identify synergistic immunotherapy combinations. At The Angeles Clinic and Research Institute, we’re looking at many of these combinations in clinical trials to improve their efficacy.

Current and Future Considerations in RCC and Urothelial Carcinoma

Wentzel: [In the phase 3 KEYNOTE-564 trial (NCT03142334)], adjuvant pembrolizumab demonstrated a significant disease-free survival benefit following nephrectomy for patients with clear cell RCC with intermediate-to-high risk of recurrence after surgery. The benefit was greater in [those with] higher-risk disease, as well as in those with sarcomatoid features. With additional follow-up, there was no increase in adverse effects (AEs) or the use of steroids to treat AEs, and there were no deaths related to pembrolizumab.

The [phase 3] JAVELIN Bladder 100 study [NCT02603432] is a practice-changing trial that used avelumab [Bavencio] maintenance after chemotherapy in patients who had at least stable disease after their first line of chemotherapy. [The benefit of avelumab maintenance] has been shown regardless of PD-L1 status, which platinum-based chemotherapy was used, and what response they achieved, as long as they achieved stable disease with the chemotherapy.

In terms of studies to have on our radar, the [phase 1b] COSMIC-021 trial [NCT03170960] is investigating the combination of cabozantinib and atezolizumab. It’s demonstrating encouraging results with a reasonable and expected safety profile in multiple cohorts, even metastatic castration-resistant prostate cancer.

The [phase 1] STELLAR-001 trial [NCT03845166] is still upcoming; it’s the sister trial to COSMIC-021 and is looking at XL 092, the next-generation oral TKI after cabozantinib. The thought is that since XL 092 has a shorter half-life [than cabozantinib], it could potentially be less toxic or at least [allow patients] to recover from toxicities quicker.