When Consensus Outpaces Capacity in Second-Line Melanoma

For patients with metastatic melanoma who have moved past frontline checkpoint inhibition and a BRAF/MEK inhibitor combination, the remaining options narrow quickly, and choosing among checkpoint rechallenge, a one-time cell therapy, or a clinical trial increasingly depends less on which option has the strongest response rate on paper and more on which one a given patient can actually access and tolerate.

During a virtual Case-Based Roundtable event for oncologists in the Dallas-Fort Worth area, Sapna Patel, MD, the Dr William Robinson Endowed Chair in Cancer Research and director of cutaneous oncology and cell therapy for solid tumors at the University of Colorado, reviewed second-line treatment data for metastatic melanoma. Patel emphasized that the logistics of referral, not just the clinical evidence, often determine whether a patient receives the treatment a room of oncologists agrees is correct.

CASE SUMMARY

• A 51-year-old woman was diagnosed 2 years ago with pT2aN1a BRAF V600E-mutated cutaneous melanoma of the left upper back for which she underwent wide excision and sentinel lymph node biopsy (SLNB); she declined adjuvant therapy.
• Five months after diagnosis, she developed pulmonary and hepatic metastases.
• Brain MRI negative for central nervous system (CNS) involvement
• First-line: nivolumab (Opdivo) plus ipilimumab (Yervoy)
• Patient achieved a partial response, lasting about 11 months.
• No adverse events of note
• Progression with new liver lesions
• Second-line: dabrafenib (Tafinlar) plus trametinib (Mekinist)
• Achieved disease control for 8 months
• Progression noted with new bone lesions and growth of existing liver lesions
• Toxicities included intermittent but severe fevers and fatigue
• Presents today with fatigue and moderate right-sided rib pain
• ECOG performance status (PS) of 1
• Brain MRI negative for CNS involvement

EVENT RECAP

Patel grounded the case in CheckMate 067 (NCT01844505), the trial establishing nivolumab (Opdivo) plus ipilimumab (Yervoy) as a frontline standard, now with nearly 12-year follow-up and confirmed objective response rates (ORRs) in the high 40% range.¹ For BRAF-mutant patients, she described how the field has largely moved toward starting with immunotherapy rather than targeted therapy, citing the DREAMseq trial (NCT02224781), which found that sequencing nivolumab/ipilimumab before dabrafenib plus trametinib produced better landmark overall survival than the reverse order.² Patel pointed to serial biopsy work showing that BRAF inhibition transiently increases T-cell infiltration into the tumor before T cells migrate out toward the lymph nodes, as part of the biological rationale for why timing checkpoint inhibition around BRAF/MEK exposure matters.³

Once this patient experienced progression on nivolumab/ipilimumab, she moved to dabrafenib plus trametinib, supported by long-term data showing a median overall survival of 25.1 months and an ORR of 68%.⁴ She achieved 8 months of disease control before progression with new bone lesions, alongside the fevers and fatigue Patel said are common with the combination and typically resolve once the drugs are held.

With both lines exhausted, Patel turned to lifileucel (Amtagvi), a tumor-infiltrating lymphocyte (TIL) therapy approved after checkpoint and, for BRAF-mutant disease, BRAF inhibitor exposure. In the C-144-01 trial (NCT02360579), patients with a median of 3 or more prior lines achieved an ORR of 31.4%, including a 5.9% complete response rate, with a median duration of response of 36.5 months; at 5-year follow-up, roughly one-fifth of this heavily pretreated population remained treatment free.⁵ Polling reflected that conclusion: 80% of attendees said they would recommend lifileucel for this patient.

However, the discussion that followed made clear that choosing lifileucel and obtaining it are different problems. Attendees noted patients are often reluctant to travel even across an urban area to a tertiary care center and asked what to use as a bridge while a patient awaits harvest. Patel acknowledged that referral-to-infusion timelines can stretch to 2 months or more once scheduling, financial clearance, and manufacturing are factored in, and that her program now often refers BRAF-mutant patients for harvest before they have completed BRAF/MEK inhibitor exposure, since insurance increasingly approves TILs before confirmed refractory disease to BRAF/MEK.

What makes the lifileucel data persuasive to Patel is less the response rate in isolation and more the long treatment-free intervals seen in responders. “If we go down the TIL therapy route, if you're a candidate for it, it is one-time treatment, and then you have these long treatment-free intervals, and if you're cured, you're really treatment free,” she said. “We know that [patients receiving ipilimumab/nivolumab] can get treatment-free intervals, but they get treatment free most often because of toxicity that causes them to stop.”

Patel also discussed an investigational option for checkpoint-exposed patients who are not TIL candidates: RP1 (vusolimogene oderparepvec), an intratumoral oncolytic herpes simplex virus related to talimogene laherparepvec (Imlygic; TVEC) but engineered to be more potent and to induce immunogenic cell death, generally paired with continued nivolumab. In the IGNYTE trial (NCT03767348), patients with melanoma who had progression on prior anti–PD-1 therapy achieved a response rate Patel placed in the 30% to 35% range, with roughly half of responders maintaining that response at 2 years and 44.8% at 3 years per data presented at the 2026 American Society of Clinical Oncology meeting.⁶

Patel noted the FDA had pushed back on interpreting that signal in isolation, since the single-arm design could not separate how much benefit came from the virus vs from nivolumab itself, prompting the ongoing randomized IGNYTE-3 trial (NCT06264180) comparing RP1 plus nivolumab against physician's choice in patients who have disease progression on both anti–PD-1 and anti–CTLA-4 therapy.

Patel was candid that RP1, like lifileucel, carries an access burden separate from its efficacy data. Injections require viral refrigeration and deep-cleaning protocols, run every 2 weeks for up to 8 doses, and demand sustained coordination with interventional radiology, a dependency she said can strain that relationship if a practice enrolls multiple patients without preparing its colleagues for the postinjection monitoring and fevers involved. She added that response rates climbed into the 40% range when both superficial and deep lesions were injected, reinforcing that patient selection, not just drug activity, will likely determine how RP1 performs in practice if it reaches approval.

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_{DISCLOSURES: Patel previously reported advisory board, steering committee, data safety monitoring board, consulting relationships with Bristol Myers Squibb, Cardinal Health, Castle Biosciences, Ideaya, Immatics, IO Biotech, MSD, Novartis, Obsidian, OncoSec, Pfizer, Replimune, Scancell, TriSalus Life Sciences, Veda Trials.}

REFERENCES

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2. Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186-197. doi:10.1200/JCO.22.01763

3. Liu C, Peng W, Xu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013;19(2):393-403. doi:10.1158/1078-0432.CCR-12-1626

4. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631-1639. doi:10.1093/annonc/mdx176

5. Medina T, Kim DW, Munhoz RR, et al. Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte cell therapy in patients with advanced melanoma: a 5-year analysis of the C-144-01 study. J Clin Oncol. 2025;43(33):3565-3572. doi:10.1200/JCO-25-00765

6. Wong MKK, Sacco JJ, In GK, et al. A 3-year landmark overall survival analysis of RP1 plus nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial. J Clin Oncol. 2026;44(suppl 16):9518. doi:10.1200/JCO.2026.44.16_suppl.9518