Oncology
Melanoma
Treating Immunotherapy-Refractory or -Resistant Melanoma
The number of effective treatment options for patients with melanoma that is refractory or resistant to immunotherapy is currently limited. Ongoing clinical trials are evaluating novel therapeutics in this setting, and findings from some of these trials were presented at the 2024 ASCO Annual Meeting.
Following these proceedings, featured expert Elizabeth I. Buchbinder, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Buchbinder’s clinical perspectives on these findings are presented here.
During our tumor board meetings, probably 90% of what we discuss with regard to our patients with melanoma is what to do next for those whose melanoma has failed frontline combination immunotherapy, be it nivolumab plus relatlimab or ipilimumab plus nivolumab. If their melanoma has a BRAF mutation, we consider using targeted therapy. If they received an anti–PD-1 agent alone, I often treat with ipilimumab plus nivolumab based on some data showing a 28% response rate to this combination. I also use ipilimumab plus nivolumab in patients who previously received nivolumab plus relatlimab, although we do not know the response rate in this setting other than what was reported in a small case series that was published in 2022.
Once we run out of standard ICI options, we are in a very tough spot. What we consider next for these patients depends a lot on how recurrence occurs. For example, if recurrence is a localized in-transit disease that is superficial or even subcutaneous, we may think more about using injection therapy.
At ASCO 2024, we saw data from the phase 1/2 IGNYTE study evaluating the combination of nivolumab and RP1, a herpes simplex virus type 1 (HSV-1)–based oncolytic immunotherapy, in patients with melanoma who failed anti–PD-1 therapy (abstract 9517). Many patients had good responses in injected lesions, and some good responses were also seen in noninjected lesions. So, in patients who have those localized recurrences, particularly those where surgery is unlikely to clear all disease, we sometimes consider an injection therapy. Talimogene laherparepvec (T-VEC) is a US Food and Drug Administration (FDA)–approved injection therapy that we use for patients with melanoma, and seeing data with other injection therapies is very interesting. I think that the problem going forward testing injection therapies is determining how to compare them. At this point, there is so little available to treat patients with melanoma in the second-line space that, when you see a nice response rate such as that reported in the RP1 data, you may say something like, “Well, maybe it’s worth it to move forward with that already, even without a real comparator.” At this time, options in the second-line space are limited to injection therapy, clinical trials, targeted therapy, or tumor-infiltrating lymphocytes (TILs) for the patients who are appropriate candidates for this.
There were a few new phase 1 studies presented at ASCO 2024 with some interesting results, although these results are very preliminary. One study evaluated SX-682, a CXCR1/2 inhibitor (abstract 9508). In addition, in the immunotherapy session, the bispecific antibody FS222 targeting PD-L1 and CD137 had a 60% objective response rate in post–PD-1–treated metastatic/advanced cutaneous melanoma (abstract 2505).
Another phase 1 trial with data presented at ASCO 2024 involved brenetafusp (also known as IMC-F106C), an ImmTAC bispecific protein (abstract 9507). This is the same class of therapy as tebentafusp, which is FDA approved for unresectable or metastatic uveal melanoma. Brenetafusp targets preferentially expressed antigen in melanoma (PRAME), which is on more than 80% of melanoma tumors, and also has a CD3 end that brings T cells in. There is a lot of talk about ImmTAC drugs in that the way they work may not lead to much tumor shrinkage, and the data in terms of response rates and progression-free survival are not so impressive. For example, the objective response rate for brenetafusp was low in abstract 9507, at only 13%. However, ImmTACs still may prolong survival, as tebentafusp demonstrated an overall survival benefit in uveal melanoma despite the low response rates. Because of the potential overall survival benefit, there has been a lot of excitement about these drugs, regardless of the responses not being very robust.
Another area where there is some excitement right now is with other targeted therapies. We are starting to see interesting activity beyond BRAF looking at pan-RAF inhibitors and some other drugs targeting the MAPK pathway in novel ways. Most of our patients have activation of the MAPK pathway, so we have a lot of patients with NRAS-mutated disease, and we are starting to see some interesting activity from pan-RAS inhibitors. I think that there has been some reinvigoration in the targeted therapy space, which will be interesting to watch in the future as well.
Garralda E, Oberoi A, de Velasco G, et al. First-in-human study (FIH) of FS222, a next-generation tetravalent PD-L1/CD137 bispecific antibody: safety, pharmacodynamics (PD), and antitumor activity in patients (pts) with advanced solid tumors including PD-1 refractory melanoma [abstract 2505]. Abstract presented at: 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.
Hamid O, Williams A, Lopez JS, et al. Phase 1 safety and efficacy of IMC-F106C, a PRAME x CD3 ImmTAC bispecific, in post-checkpoint cutaneous melanoma (CM) [abstract 9507]. Abstract presented at: 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.
Hassel JC, Piperno-Neumann S, Rutkowski P, et al. Three-year overall survival with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2023;389(24):2256-2266. doi:10.1056/NEJMoa2304753
Lezcano C, Jungbluth AA, Nehal KS, Hollmann TJ, Busam KJ. PRAME expression in melanocytic tumors. Am J Surg Pathol. 2018;42(11):1456-1465. doi:10.1097/PAS.0000000000001134
Menzies AM, Pires da Silva I, Trojaniello C, et al. CTLA-4 blockade resistance after relatlimab and nivolumab. N Engl J Med. 2022;386(17):1668-1669. doi:10.1056/NEJMc2119768
Patel SP, Dimou A, Victor AI, et al. Safety and efficacy of first-in-class CXCR1/2 inhibitor SX-682 in combination with pembrolizumab (pem) in patients (pts) with metastatic melanoma (mMEL) with disease progression on anti–PD-1 therapy [abstract 9508]. Abstract presented at: 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.
Vanderwalde AM, Moon J, Kendra K, et al. S1616: ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy [abstract CT013]. Abstract presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA.
Wong MKK, Sacco JJ, Robert C, et al. Efficacy and safety of RPI combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial [abstract 9517]. Abstract presented at: 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.
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