IGNYTE: RP1 + Nivolumab in PD-1–Failed Melanoma

Society of Cutaneous Oncology

2026-04-06

SoCO Journal Club · April 6, 2026

IGNYTE: when a compelling signal meets an inference problem

RP1 plus nivolumab produced durable responses in anti–PD-1–failed melanoma. The harder question was not whether the signal was interesting. It was what treatment effect the study had actually established — and whether that evidence was sufficient for regulatory or clinical adoption.

Meeting pulse

A heavily engaged melanoma group

Unique Teams connections

30

Reconnects reconciled

Median time together

99 min

Median attendance after reconnects were combined

Stayed at least an hour

83%

Present for at least 60 minutes

Participation

A few ways people participated

Camera on

63%

Had the camera on at least once

Unmuted

43%

Unmuted at least once during the meeting

Raised a hand

20%

Used the Teams hand-raise signal

The paper we discussed

Wong et al. — RP1 + nivolumab after anti–PD-1 failure

Primary article · Journal of Clinical Oncology

RP1 Combined With Nivolumab in Advanced Anti–PD-1–Failed Melanoma (IGNYTE)

Wong MK, et al. J Clin Oncol. 2025;43:3589–3599.
doi: 10.1200/JCO-25-01346

DOI

IGNYTE enrolled 140 patients with advanced melanoma and confirmed progression on prior anti–PD-1 therapy. RP1 was administered intratumorally with nivolumab. By RECIST 1.1 independent central review, the confirmed objective response rate was 32.9%, including 15.0% complete responses. Median duration of response was 33.7 months; 1- and 2-year overall survival were 75.3% and 63.3%, respectively. Responses were observed in both injected and noninjected lesions, including visceral sites.

The question beneath the paper: When an intratumoral agent is combined with continued PD-1 blockade in a single-arm trial, what exactly has been demonstrated — local activity, systemic activity, contribution of RP1, activity of the combination, or some mixture of all four?

Regulatory context mattered. The meeting took place during active uncertainty around RP1’s regulatory path. The preserved Journal Club presentation reviewed the July 22, 2025 FDA complete response letter, including concerns about whether IGNYTE constituted an adequate and well-controlled investigation, heterogeneity of the study population, and contribution of components. No safety concern was identified in the sponsor’s description of that letter.

Before the discussion

The survey revealed a group that liked the signal — but not the certainty

There is no preserved transcript from this session, so the most durable record of the group’s starting position is the pre-Journal Club survey. The responses were unusually useful because they separated biological plausibility from inferential and regulatory sufficiency.

75% Familiar with IGNYTE

Three quarters of respondents were already moderately or very familiar with the IGNYTE study before the session, and 94% reported prior clinical use of an intratumoral melanoma therapy.

56% Single-arm evidence can persuade

The most common view was that single-arm studies can be persuasive when results substantially exceed historical expectations. Only 12% said such evidence is often sufficient on its own for clinical decision-making.

56% ORR meaningful — but insufficient alone

Most respondents considered objective response rate moderately clinically meaningful in PD-1–refractory melanoma but not sufficient by itself. Another 25% considered it highly meaningful when responses are durable.

69% Biology looked plausible

Sixty-nine percent rated the proposed systemic immune mechanism as either highly plausible or plausible but still somewhat uncertain. The remaining 31% called it possible but not strongly supported.

65% Single-arm design was the leading limitation

The single-arm design was the most commonly selected limitation, followed by uncertainty about the contribution of RP1 versus nivolumab (41%) and interpretation of injected versus noninjected lesions (29%).

53% Preferred randomized add-on design

A majority selected randomization of RP1 plus nivolumab versus nivolumab alone as the most convincing confirmatory design. Another 27% preferred randomization against physician’s choice.

The inferential problem

Two questions were hiding inside one response rate

01 · Where?

Local effect or systemic effect?

Injected lesions are directly exposed to the intervention. Their shrinkage can demonstrate local antitumor activity, but it does not by itself establish a systemic treatment effect. Noninjected lesions therefore carry special interpretive weight when the intended claim is systemic benefit.

02 · What caused it?

RP1, nivolumab, or the combination?

Because RP1 was administered with nivolumab and there was no randomized component comparison, the observed response cannot cleanly identify the contribution of RP1. The survey recognized this: 41% selected unclear contribution of components as a primary limitation.

03 · Compared with what?

Historical expectations are useful — and fragile

The paper contextualized the observed ORR against low expected activity from continued anti–PD-1 therapy. The survey showed clinicians are open to that logic when the observed result substantially exceeds historical expectations, while also worrying about population heterogeneity and external validity.

04 · What endpoint?

ORR is informative, but its meaning depends on the question

The study’s 32.9% RECIST response rate was clinically interesting, particularly with a median DOR of 33.7 months. But the group entered the discussion largely unwilling to treat ORR alone as the whole evidentiary story.

05 · What estimand?

The clinical question should precede the estimator

The presentation used the ICH E9(R1) estimand framework to ask what treatment effect the trial was actually trying to learn. Notably, 69% of survey respondents reported no prior familiarity with the estimand framework — making the session partly a discussion of RP1 and partly a discussion of how trials define causal questions.

06 · What would settle it?

Randomization was the clearest path forward

When asked what confirmatory design would be most convincing, the strongest preference was an add-on comparison of nivolumab versus nivolumab + RP1. That design directly targets the contribution-of-components question that the single-arm study cannot resolve.

A response rate can be impressive and still leave the central causal question unresolved. For intratumoral combination therapy, where the response occurs and what comparison generated it are part of the treatment effect — not merely details of the analysis.

Where the discussion appears to have landed

Without a transcript, we should be careful not to recreate individual comments that were not preserved. But the survey and presentation materials point to a clear intellectual center of gravity.

The clinical signal was taken seriously. A 32.9% response rate, 15% complete-response rate, long duration of response, activity in noninjected and visceral lesions, and a comparatively favorable safety profile made RP1 + nivolumab difficult to dismiss as biologically uninteresting.

At the same time, interest in the therapy did not equal certainty about the inference. The single-arm design, patient heterogeneity, lesion-level interpretation, and inability to isolate the contribution of RP1 remained central problems. The survey’s open-text responses repeatedly returned to the same themes: attribution of systemic benefit, contribution of components, comparability with historical controls, and the limitations of the single-arm design.

The most defensible landing point was therefore not “the study worked” or “the study failed.” It was that IGNYTE generated a compelling therapeutic signal whose regulatory and causal interpretation depended on questions the study design could not fully answer.

Practice threshold

Regulatory sufficiency and clinical adoption were not the same question

38% Possibly approval-ready with postmarketing evidence

The largest group thought IGNYTE could possibly support FDA approval if accompanied by postmarketing requirements. Another 25% were uncertain, 19% viewed the evidence as sufficient for accelerated approval, and 12% thought randomized data were probably still needed.

40% FDA approval would be enough for routine use

When the question shifted from regulatory approval to personal practice, 40% said FDA approval would be sufficient, while only 13% said the current evidence was already enough for routine use.

About this recap: no meeting transcript was available for the April 6 session. This page therefore summarizes the published IGNYTE paper, the preserved SoCO presentation, the pre-meeting survey, and the Teams attendance record. It intentionally avoids attributing discussion positions to individual attendees unless they are preserved in those materials.

Our community

Who joined us?

The Teams report contains reconnects and one conference-room connection. Repeated display names are combined before the meeting-pulse metrics are calculated; the room connection is retained and flagged rather than treated as a named individual.

Name	Minutes in meeting	Camera on	Unmuted	Raised hand
Adam Whalley	99	Yes	Yes
Adam Yakovich	103	Yes	Yes
Adewunmi O. Adelaja	104	Yes	Yes
Alex Sorrentino	35
Ann W. Silk	103	Yes	Yes	Yes
Claire Verschraegen	88	Yes
David M. Miller	103	Yes	Yes
Don Lawrence	103	Yes	Yes	Yes
Elizabeth I. Buchbinder	103	Yes	Yes	Yes
Frances Collichio	80
Howard Kaufman	11
Isaac Brownell	105	Yes
Jacob Choi	64	Yes
Juliane Andrade Czapla	10
Kamaneh Montazeri	91		Yes
Karam Khaddour	43
Ken Tsai	99
Kevin S. Emerick	87	Yes
Manisha Thakuria	102	Yes
Maria Melendez-Gonzalez	57
Mariam El-Ashmawy	91
Michael Wong	101	Yes	Yes	Yes
Natasha Hill	97	Yes
Nikhil Khushalani	102	Yes	Yes
Replimune team	91	Yes
Ross D. Merkin	104	Yes	Yes	Yes
Ryan J. Sullivan	103	Yes	Yes	Yes
Suzanne Topalian	100
Vern Sondak	103	Yes	Yes
Vishal Patel	65

A useful disagreement about evidence

This Journal Club was less about deciding whether RP1 was interesting than about deciding what evidence is necessary to know why a treatment appears to work, how broadly the result applies, and when a promising signal becomes an actionable treatment effect.

Back to Journal Club Read the article