Luke Breaks Down Key Clinical Trial Updates From the 2023 ASCO Annual Meeting

Updated data from the phase 3 KEYNOTE-716 (NCT03553836) presented at the 2023 ASCO Annual Meeting highlighted the continued evolution of the adjuvant treatment setting for patients with melanoma, according to Jason Luke, MD, FACP.

Results from final distant metastasis­–free survival (DMFS) analysis of the phase 3 study showed that at a median follow-up of 39.4 months, patients with stage IIB or IIC melanoma treated with adjuvant pembrolizumab (Keytruda) and those given placebo experienced a median DMFS that was not yet reached (HR, 0.59; 95% CI, 0.44-0.79). The 36-month DMFS rate was 84.4% in the pembrolizumab arm compared with 74.7% in the placebo arm.¹

“At the 2023 ASCO Annual Meeting, for melanoma, it was the year of adjuvant therapy. There were several updates for clinical trials for stage III [and] stage II melanoma that look very promising,” Luke explained in an interview with OncLive® News Network: On Location during the meeting.

In the interview, Luke, expanded on the key takeaways from KEYNOTE-716, detailed data reported from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881), and highlighted other key updates from across the melanoma landscape presented at the 2023 ASCO Annual meeting. Luke is an associate professor of medicine in the Division of Hematology/Oncology and the director of the Cancer Immunotherapeutic Center, Immunology and Immunotherapy Program, at UPMC Hillman Cancer Center, in Pittsburgh Pennsylvania.

OncLive: What were the key takeaways from the updated data from KEYNOTE-716 presented at the 2023 ASCO Annual Meeting?

Luke: My presentation [was] the long-term update of the phase 3 KEYNOTE-716 trial. We previously reported the primary end point [recurrence-free survival], showing that it was a positive trial, and [this] led to FDA and European Medicines Agency approval of [adjuvant] pembrolizumab for stage IIB/C melanoma.

What we updated [at the 2023 ASCO Annual Meeting] was the long-term DMFS, which is a very important landmark that emphasizes that the treatment is durable over a long period of time. What we've seen is that the trial is getting better over time. The hazard ratio [for DMFS] is expanding, and it looks like the impact is [improving], with no changes to the safety signal.

We saw the DFS results from the open-label, randomized mRNA-4157-P201/KEYNOTE-942 trial with the addition of mRNA-4157 to pembrolizumab in patients with high-risk, resected melanoma.² What could these data potentially mean for the melanoma treatment landscape?

These data start a new epoch in oncology—not just in melanoma, but in all of cancer. The difference is that these new vaccination approaches with individualized neoantigen therapy rely on a personalized approach of targeting the differences in the genomic characteristics of the tumor, and that's never been tried before. Whereas, previous vaccines were against shared antigens and didn't generate responses. What we see in this clinical trial is an enormous benefit in terms of improvement in RFS and now DMFS.

One of the idiosyncrasies of the trial is that in PD-1–based combinations in the past, we've always seen a very close relationship with RFS and DMFS. That has not, to date, translated into overall survival [OS]. What we've seen for possibly the first time with the individual neoantigen therapy is that the DMFS is even better than the RFS. That makes us very excited about the phase 3 results, as this may be a transformative agent initially in melanoma, and then, more broadly, this concept might apply to basically every cancer.

We also saw the findings with the combination of fianlimab and cemiplimab (Libtayo) in a phase 1 trial (NCT03005782) in patients with advanced melanoma who were naïve to a PD-L1 inhibitor.³ How does this combination distinguish itself from other checkpoint blockade combinations currently available?

These data look really promising. This will be the second PD-1/LAG-3 combination coming forward. It is early [to consider] differentiation, but the data are very strong. The response rate looks very high, and in subsets of patients who have high-risk features, such as liver metastases, [the benefits are] maintained in the early data. That looks really good.

How would you compare this LAG-3 combination vs another LAG-3 combination? Well, we're not there yet to be able to do that. However, these data look very promising, and they are leading to a phase 3 trial for metastatic disease and an adjuvant clinical trial for stage III [disease], so we're going to see more from this combination.

Primary results from the phase 3 RELATIVITY-047 trial (NCT03470922) were promising. This year, we saw the 2-year follow-up with the combination of nivolumab and relatlimab-rmbw (Opdualag).⁴ What are your thoughts on the durability of response with this combination?

The LAG-3 combination that is in clinic is nivolumab/relatlimab. [Initial data from inhibiting] the third checkpoint with LAG-3 [were exciting], albeit with some caution that the initial results reported needed to mature. We needed to be more confident that this was going to turn into something [beneficial]. That's what we're starting to see with these 2-year durability results.

One of the big questions in the field has been: which patients should get nivolumab and relatlimab, and which should get ipilimumab [Yervoy] and nivolumab? These kinds of long-term data make us more confident that perhaps even in higher-risk patients, it would be okay to use nivolumab and relatlimab and not risk losing the opportunity to give ipilimumab and nivolumab.

[These data] are very important. As with any new therapy, we need to see what happens over time, but this only further cements that this is going to be a useful regimen in our treatment of melanoma.

Navitoclax (ABT-263) was studied in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) in a phase 1/2 trial (NCT01989585) in patients with BRAF-mutant metastatic melanoma.⁵ What's the basis for this work and what did the results show?

This stems from work dating back more than 10 years. In targeted therapy, we go after the genomic change, but [one] of the things that happen to the cancer cell after you hit with a targeted therapy [is] they can modulate their death response. That death response is mediated by BCL-2 family members, and we know about that from leukemias and such. However, it turns out in solid tumor cancer cells, similar proteins are involved. This led to the hypothesis that giving a BCL-2/BCL-XL inhibitor can potentially augment targeted therapy.

That is [what was explored in] this trial with dabrafenib, trametinib, and navitoclax. It is interesting. It looks like the complete response rate is higher than you'd expect for targeted therapy alone, and it wasn't any more toxic [with the addition of navitoclax]. I believe it's a very interesting regimen. The field has shifted a lot, and in melanoma oncology, we're less reliant on BRAF inhibition. This certainly deserves further study and looks very promising from a molecular perspective.

Editor’s note: This interview was conducted prior to the conclusion of the 2023 ASCO Annual Meeting.

References

1. Luke JJ, Ascierto A, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study. J Clin Oncol. 2023;41(suppl; abstr LBA9505). doi:10.1200/JCO.2023.41.17_suppl.LBA9505
2. Khattack A, Weber JS, Meniawy T, et al. Distant metastasis-free survival results from the randomized, phase 2 mRNA-4157-P201/KEYNOTE-942 trial. J Clin Oncol. 2023;41(suppl 17):LBA9503. doi:10.1200/JCO.2023.41.17_suppl.LBA9503
3. Hamid O, Lewis KD, Weise AM, et al. Significant durable response with fianlimab (anti–LAG-3) and cemiplimab (anti–PD-1) in advanced melanoma: Post adjuvant PD-1 analysis. J Clin Oncol. 2023;41(suppl_16):9501. doi:10.1200/JCO.2023.41.16_suppl.9501
4. Tawbi HA, Hodi FS, Lipson EJ, et al. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047. J Clin Oncol. 2023;41(suppl 16):9502. doi:10.1200/JCO.2023.41.16_suppl.9502
5. Eroglu Z, Mehnert JM, Giobbie-Hurder A, et al. Randomized phase II trial of dabrafenib and trametinib with or without navitoclax in patients (pts) with BRAF-mutant (MT) metastatic melanoma (MM) (CTEP P9466). J Clin Oncol. 2023;41(suppl 16):9511. doi:10.1200/JCO.2023.41.16_suppl.9511