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FDA Accepts IND for RM-1995 Photoimmunotherapy in Advanced Cutaneous or Head and Neck SCC


The FDA has accepted an investigational new drug application for the photoimmunotherapy treatment, RM-1995, for patients with advanced cutaneous squamous cell carcinoma or head and neck squamous cell carcinoma.

The FDA has accepted an investigational new drug application for the photoimmunotherapy treatment, RM-1995, for patients with advanced cutaneous squamous cell carcinoma (CSCC) or head and neck squamous cell carcinoma (HNSCC), according to an announcement made by Rakuten Medical.1

RM-1995 is a conjugate of a photoactivatable dye (IRDye 700DX [IR700]) and a monoclonal antibody specific for cell-surface interleukin-2 receptor α-chain CD25. The device component of the treatment is the PIT690 Laser System, which is utilized to activate IR700 by illumination with 690nm nonthermal red light. The RM-1995 photoimmunotherapy was designed to specifically kill CD25-positive regulatory T cells within solid tumors, once illuminated with the 690nm nonthermal red light.2

CD25-positive regulatory T cells inhibit antitumor immune responses to promote tumor growth, and they can be specifically targeted with anti-CD25 antibodies. RM-1995 is viewed as a potential new treatment option that can directly reduce CD25-positive regulatory T cells within light-treated tumor lesions to elicit systemic anticancer immune responses.

"We are very excited to have achieved this regulatory milestone and delighted to be moving RM-1995 into the clinic," Mickey Mikitani, chief executive officer of Rakuten Medical, Inc., stated in a press release. "RM-1995 has the potential to attack the cancer in a novel way, targeting Tregs. Based on data from preclinical studies, RM-1995 photoimmunotherapy treatment is expected to result in acute killing of T regs within the tumor. We are developing drugs using various antibodies in our drug discovery program based on Rakuten Medical's IlluminoxTM platform, and RM-1995 is the second pipeline drug developed on this platform."

Preclinical data have suggested that RM-1995 photoimmunotherapy treatment can be utilized to specifically deplete intratumoral CD25-positive regulatory T cells to alleviate local restraint within the tumor microenvironment. This can improve the ratio of the CD8 T cells to CD25-positive regulatory T cells while reinvigorating effector CD8-positive T-cell responses.

In syngeneic mouse models, a cycle of anti-CD25 treatment produced anticancer responses that were comparable to those reported with anti–PD-1 therapy. Moreover, this therapeutic approach was also found to be highly synergistic when combined with anti–PD-1 agents.3

Other photoimmunotherapeutic agents beyond RM-1995 have been developed with the Illuminox platform, which is a technology that is comprised of a drug, device, and other associated components.

For example, the photoimmunotherapy RM-1929 (cetuximab sarotalocan), with is comprised of IR700 conjugated with cetuximab (Erbitux), is under investigation in heavily pretreated patients with HNSCC as part of a phase 1/2 trial (NCT02422979).4

The trial enrolled patients with histologically confirmed, recurrent HNSCC that could not satisfactorily be treated with surgery, radiotherapy, or platinum chemotherapy; these patients had to have no other standard-of-care options available to them. Moreover, patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, a life expectancy of longer than 4 months, and have previously received systemic platinum-based chemotherapy for recurrent disease, unless contraindicated or not recommended.

If patients had a history of significant cetuximab infusion reactions, a tumor invading a major blood vessel, or impaired hepatic or renal function, they were excluded.

Investigators administered a challenge dose of cetuximab at 100 mg to evaluate patient tolerability to the photoimmunotherapy. Intravenous dexamethasone and d-chlorpheniramine were used as pretreatment to reduce the risk of hypersensitivity.

Those who did not experience grade 3 or higher toxicity with the cetuximab challenge subsequently received a single treatment of RM-1929 at 640 mg/m2. Illumination of the tumor was done at 24 hours plus or minus 4 hours following infusion to allow the opportunity for drug distribution within the tumor.

A frontal diffuser was used to apply red light for surface light treatment of superficial tumors that were defined as being less than 1 cm thick, or a cylindrical light diffuser was used for interstitial placement of the diffuser into tumors that were 1 cm or deeper. Light was applied at an irradiation of 150 mW/cm2 for surface illumination and fluence rate of 400 mW/cm diffuser length for interstitial illumination.

The primary objective of the trial was to examine the safety of a single treatment cycle of the photoimmunotherapy in Japanese patients with recurrent HNSCC. Safety was examined by monitoring dose-limiting toxicities. Important secondary objectives included tumor response, pharmacokinetics, and immunogenicity.

All 3 patients enrolled to the trial were female and had a favorable ECOG performance status. Moreover, all patients did not respond to 3 or more prior lines of therapy, which included radiation, chemotherapy, cetuximab, and immunotherapy.

Results indicated that 2 patients achieved an objective response to treatment, both in the form of a partial response. The third patients experienced progressive disease following treatment with RM-1929.

Regarding safety, all patients experienced at least 1 treatment-emergent adverse effects (TEAE) although none were determined to be dose limiting. The most frequently experienced TEAE was application-site pain, and this was observed in all patients. However, this toxicity resolved within the 4-week study period. Localized edema was also a common toxicity; 1 patient experienced application-site edema, 1 experienced face edema, and 1 experienced localized edema. These events were noted to be mild in severity and to have resolved within 1 week of onset.

This was originally posted by our sister publication OncLive.


  1. Rakuten medical announces FDA acceptance of an investigational new drug (IND) application for RM-1995, a conjugate of IR700 and anti-CD25 antibody. News release. Rakuten Medical, Inc.; December 15, 2021. Accessed December 17, 2021. prn.to/3p7C3d3
  2. Vargas FA, Furness AJS, Solomon I, et al. Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity. 2017;46(4):577-586. doi:10.1016/j.immuni.2017.03.013
  3. Pioneering a new approach to treating cancer. News release. Rakuten Medical, Inc. Accessed December 17, 2021. go.nature.com/3GTEPbW
  4. Tahara M, Okano S, Enokida T, et al. A phase I, single-center, open-label study of RM-1929 photoimmunotherapy in Japanese patients with recurrent head and neck squamous cell carcinoma. Int J Clin Oncol. 2021;26(10):1812-1821. doi:10.1007/s10147-021-01960-6

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