Replimune · RP1 · 2021 – 2026
When did injected lesions become an FDA concern?
The second letter traces it to a 2021 meeting. The first letter does not mention it. In 2026 the second letter's first numbered deficiency opens with it, and the approval's efficacy population is the patients with a non-injected lesion.
EphemerisX Research · Published · 5 source documents · 1 min read
Short answer
The FDA's second letter quotes a 2021 remark about judging responses in injected lesions; the first letter does not mention injected lesions; the second letter's first numbered deficiency opens with them; and the approval 8-K's efficacy population is the 91 patients with at least one non-injected lesion.
What the evidence shows
In 2021, according to the second letter, the FDA said: we consider the interpretation of responses in the setting of the intra-tumoral route of administration to be problematic in the lesions which have been injected
FDA · Apr 10, 2026 · p. 3.
Letter 1 does not mention injected lesions, RECIST, surgery, biopsies or duration of response. FDA · searched
The second letter: almost half (49%) of the patients with objective response had all their target lesions injected
FDA · Apr 10, 2026 · p. 4; counting two responders with no target lesions at baseline, over half (53%) of patients with objective response did not have noninjected target lesions
FDA · Apr 10, 2026 · p. 4. With those patients excluded, the response rate decreases markedly
FDA · Apr 10, 2026 · p. 4. It adds that pathology results may reflect local treatment effects at the injection site rather than systemic effects of the investigational therapy
FDA · Apr 10, 2026 · p. 5.
The company's resubmission included analyses of response in patients who had both injected and non-injected tumors
FDA · Apr 10, 2026 · p. 2; its 8-K says they showed no material difference in response rates between injected and non-injected lesions
8-K · Apr 13, 2026.
The advisory committee discussed whether the observed responses are indicative of systemic antitumor activity attributable to RP1
8-K · Jul 31, 2026. The approval 8-K reports 91 patients with at least one non-injected lesion included in the efficacy-evaluable population
8-K · Aug 7, 2026, with an objective response rate (ORR) of 24.2%
8-K · Aug 7, 2026.
Follow the thread
- What did the FDA tell Replimune before the BLA was filed?2021: responses in injected lesions “problematic”
- How did Replimune's 8-K describe the FDA's second letter?“No material difference” (8-K)
- What changed between the FDA's first and second letters?53% of responders: no non-injected target lesion
- Why do RP1's reported response rates range from 24.2% to 34%?24.2% in the 91 patients with a non-injected lesion
This investigation connects to
- How did two programs move forward after repeat FDA letters without running a new trial?Cross-investigation · Comparable evidence · with Outlook Therapeutics
- When is one trial enough? How the FDA weighed the evidence in three programsCross-investigation · Comparable evidence · with Aldeyra Therapeutics, Outlook Therapeutics
The documents, by date
The passages quoted
FDA Complete Response Letter, July 21, 2025
Letter 1 does not mention injected lesions, RECIST, surgery, biopsies or duration of response.
Open the document →FDA Complete Response Letter, April 10, 2026 · page 2
You also provided results from additional exploratory analyses of RPL-001-16, including analyses of patients who had a response to immediate prior anti-PD1 therapy and their subsequent response to the combination of vusolimogene oderparepvec and nivolumab, of progression-free survival, and of response in patients who had both injected and non-injected tumors.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 3
Finally, we noted that “we consider the interpretation of responses in the setting of the intra-tumoral route of administration to be problematic in the lesions which have been injected.”Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 4
FDA review identified that almost half (49%) of the patients with objective response had all their target lesions injected with vusolimogene oderparepvec. Furthermore, FDA review identified two additional patients deemed responders who did not have any target lesions per independent review at baseline.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 4
Thus, over half (53%) of patients with objective response did not have noninjected target lesions to assess systemic anti-tumor activity.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 4
When these patients are excluded from the analysis of the primary endpoint of ORR, the resulting response rate decreases markedly from your reported response rate in RPL-001-16.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 5
Histopathologic assessments were used to assess response, and in some cases, these results changed the radiologic response assessment of best overall response. In RPL-001-16, these histology specimens were not centrally reviewed, there is a potential for sampling bias with respect to biopsy specimens, and it is unclear whether a determination of tumor response based on pathology reflects local treatment effects at the injection site rather than systemic effects of the investigational therapy.Open at the source →
Replimune Form 8-K, filed April 13, 2026
In addition, the company provided detailed analyses showing no material difference in response rates between injected and non-injected lesions.Open at the source →
Replimune Form 8-K, filed July 31, 2026
The committee discussed two topics: (1) whether the single-arm IGNYTE study, as designed and conducted, allows for a reliable determination of the expected response rate and durability of response in the proposed population; and (2) the clinical meaningfulness of the response rate and duration of response reported in IGNYTE, and whether the observed responses are indicative of systemic antitumor activity attributable to RP1.Open at the source →
Replimune Form 8-K, filed August 7, 2026
The IGNYTE trial enrolled 140 patients with 91 patients with at least one non-injected lesion included in the efficacy-evaluable population. In this population, TUDRIQEV plus nivolumab achieved an objective response rate (ORR) of 24.2%, with a median duration of response of 14.1 months.Open at the source →