ASCO: Bristol Myers reveals I-O triplet data in melanoma as Iovance showcases 'paradigm-changing' combo result

In the evolving landscape of melanoma treatment, Bristol Myers Squibb (BMS) and Iovance Biotherapeutics are leading the charge with innovative immuno-oncology regimens. Both companies are presenting promising early clinical data for novel drug combinations in advanced melanoma, aiming to improve patient outcomes in this challenging field.

Bristol Myers Squibb's Triplet Therapy

BMS has introduced a triplet therapy that combines its PD-1/LAG-3 inhibitor Opdualag with the CTLA4 inhibitor Yervoy. This regimen has shown notable efficacy in phase 1/2 RELATIVITY-048 trial, shrinking tumors in 27 out of 46 patients with first-line melanoma. The observed overall response rate was 59%, with 17% achieving complete response. These results, based on a median follow-up of 49.4 months, will be detailed at the American Society of Clinical Oncology (ASCO) 2024 meeting.

The rationale behind BMS's triplet therapy is to surpass the outcomes achieved by its existing treatments for melanoma. Previously, Opdualag, a combination of Opdivo and the LAG-3 antibody relatlimab, showed a 43.7% response rate in first-line melanoma patients in the RELATIVITY-047 trial. The Opdivo-Yervoy combination exhibited a 58% response rate in the CheckMate-067 trial. Despite its efficacy, the Opdivo-Yervoy duo was less favored due to safety concerns.

A notable finding from the RELATIVITY-048 trial is the two-year survival rate: 72% for the triplet therapy, compared to 64% for Opdivo-Yervoy and 59% for Opdivo alone, as seen in CheckMate-067. While cross-trial comparisons should be approached cautiously, BMS highlights that differing patient populations and follow-up durations can influence outcomes. However, the triplet's safety profile is concerning, with two treatment-related deaths and 39% of patients experiencing severe side effects.

BMS acknowledges that the sample size and study design are not sufficient for regulatory approval. Further large-scale studies are essential to validate the efficacy and safety of this triplet regimen.

Iovance Biotherapeutics' Doublet Therapy

In contrast, Iovance Biotherapeutics is advancing its doublet therapy combining the newly FDA-approved cell therapy Amtagvi with Merck's Keytruda. This combination has demonstrated a robust 65.2% response rate in first-line advanced melanoma patients, with a notable 30.4% achieving complete responses. These findings come from the phase 2 IOV-COM-202 trial, based on a median follow-up of 21.7 months in a cohort of 23 patients.

Iovance's regimen clears the high efficacy bar set by analysts, who anticipated a greater than 65% response rate in a substantial patient group. Despite the small trial size, Chief Medical Officer Friedrich Graf Finckenstein, M.D., describes the response rates as "paradigm-changing" and "unprecedented," emphasizing the 30.4% complete response rate. Nearly all responses were ongoing at the data cutoff, with eight out of 15 responders in remission for at least 12 months.

In terms of safety, the doublet therapy presented high rates of severe adverse events, including thrombocytopenia, neutropenia, and anemia. However, these were consistent with the underlying disease and known profiles of Keytruda, lymphodepletion, and IL-2, as noted by the researchers.

Encouraged by these results, Iovance is advancing to the phase 3 TILVANCE-301 trial, which will compare the Amtagvi-Keytruda combination against Keytruda alone in untreated advanced melanoma. The goal is to achieve accelerated approval for the combination in the front-line setting, potentially transitioning Amtagvi monotherapy's post-PD-1 conditional approval into a full endorsement. The phase 3 trial will further seek full approval based on progression-free survival outcomes.

Conclusion

Both BMS and Iovance are at the forefront of melanoma immunotherapy, each bringing forward innovative combinations that show promise in improving patient outcomes. While BMS's triplet therapy requires further validation, Iovance's doublet therapy is moving rapidly through clinical trials with strong preliminary results. As these studies progress, they hold the potential to redefine the treatment landscape for advanced melanoma.

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