PHIO: Roussy’s Robert Details Developments in Melanoma Medicine

By John Vandermosten, CFA


Phio Pharmaceuticals Unveils Clinical Plans for Neoadjuvant Intratumoral INTASYL in Melanoma

Phio Pharmaceuticals Corp. (NASDAQ:PHIO) hosted a key opinion leader (KOL) call on Friday, June 12, 2020 featuring Caroline Robert, M.D., Ph.D., the Head of Dermatology Unit at Gustave Roussy and co-director of the Melanoma research Unit at INSERM 981 Paris-Sud University. Dr. Robert presented the major clinical milestones shaping the melanoma landscape, best performing current treatments, their challenges, and the next innovative approaches planned, including Phio’s self-delivering RNAi (INTASYL) technology.

State of the Art: Melanoma Immunotherapy

Dr. Robert started the talk Friday with a brief overview of the current, most effective immunotherapy for melanoma, a combination immunotherapy of Anti PD-1/CLTA-4 which has a 50-55% overall survival at four years1. While far more effective than chemotherapy alone, which had a response rate of 10-15%, Dr. Robert voiced her frustration that treatment efficacy struggled to improve beyond the 50-55% response rate for the past several years2. New approaches are needed. Based on eighth edition cancer staging and 10-year survival rates, stage III (A-D) was identified as the opportune stage for intervention trials3. Resection is the primary therapy for stage III melanoma. While, at this stage, the tumor is not considered to be metastatic, metastasis is a continuum, and microscopic metastasis occurs creating the opportunity for relapse. After surgery, adjuvants are administered to counter the risk of recurrence, and adjuvant checkpoint inhibitors are known to prolong survival4. However, of particular interest now is administering neoadjuvants.

Neoadjuvant therapies

There are a number of advantages to neoadjuvant therapy, or administering the adjuvant before surgery instead of after. General neoadjuvant advantages include early determination of the efficacy of the adjuvant, ability to assess the necessity for additional adjuvant, and possible tumor reduction. Neoadjuvant immunotherapy has additional advantages via tumor infiltrating lymphocyte stimulation that can scavenge micro-metastases and thereby support long-term remission. Neoadjuvant immunotherapy has been attempted in mice, and the results demonstrate prolonged and complete survival as compared with equivalent adjuvant. Increased tumor-specific CD8+T cells were observed in blood and organs of neoadjuvant treated mice, supporting the immuno-effects of neoadjuvant immunotherapy5. Neoadjuvant immunotherapy has also been attempted in man. Patients with stage III melanoma were administered ipilimumab + nivolumab (Ipi/Nivo) either after surgery, or before and after surgery with results demonstrating a decreased tumor burden; however, considerable toxicity was observed6,7. Using a combination of monoclonal antibodies in therapy increases efficacy but also toxicity, and while Rozeman et al. optimized neoadjuvant Ipi/Nivo dosing to minimize toxicity, the minimum toxicity was still 20%; for patients who may not relapse, subjecting them to therapy toxicity may do more harm than good8. The systemic administration of neoadjuvants is a likely driver of toxicity.

Intratumoral immunotherapy

Local administration of immunotherapy improves T cell priming and avoids systemic toxicity. As intratumoral administration requires less drug, it can also save cost. Intratumoral injection can be guided using imaging methods like ultrasound or CT. Perhaps the most interesting benefit to intratumoral injection is the opportunity to affect tumor infiltrating lymphocytes which can provide distant immunity and scavenge micro-metastases. Intratumorally injected checkpoint-inhibiting antibodies have been attempted in man. While these will likely improve upon systemically administered neoadjuvant immunotherapy, once injected, mAb do not distribute readily through tissue; antibodies do not diffuse well, they only work on extra-cellular targets, can have unwanted off-target effects on proteins similar to the target, and compete with other antibodies in combination therapies. In comparison, self-delivering RNAi can specifically target a number of proteins simultaneously, intra or extra-cellularly, such as those commonly targeted in checkpoint inhibition. Of particular interest is neoadjuvant intratumoral self-delivering RNAi.

Neoadjuvant intratumoral Self-delivering RNAi (INTASYL)

Currently, preclinical work is in progress to prepare for investigational new drug (IND) submission. The investigation will take place in murine models (BP C57BL6/J, YUMM C57BL6/J, and B16 C56Bl6/J) and will target PD-1, PD-L1, CLTA-4, and TIGIT using Phio Pharmaceuticals’ INTASYL. Dosing amounts and interval will be optimized, safety and efficacy will be evaluated, and effects on distant targets will be of particular interest. Intratumoral INTASYL injection is already confirmed to distribute through tissue, especially when using multi-point injection; furthermore, INTASYL activity was also confirmed to differentiate between protein isoforms, something mAb can struggle with. Clinical trials in man are already being planned and are anticipated to commence in 1H:20. The dose escalating trial will evaluate safety and tolerability and will be conducted in patients with advanced resectable melanoma (stage IIIB/IIIC or IV-resectable). Dosing will be once a week for three weeks, and then tumors will be resected in week four.


The latest clinical work in combination checkpoint immunotherapy has been shown to be effective but toxic. Taking a neoadjuvant, intratumoral, and self-delivering RNAi approach can potentially circumvent the toxicity observed in the antibody trials, while potentially improving upon efficacy. IND-enabling studies for multiple INTASYL targets are underway, and PH-762 (PD-1) is expected to enter the clinic in 1H:20, and provide early readouts in 1H:22. This, of course, is subject to effects from the recent pandemic which may interfere with clinical trials, though delays are not anticipated. With such a promising technology and a $250 million potential market in melanoma, the hope is for INTASYL to establish a new standard in melanoma treatment.

Dr. Caroline Robert

Dr. Caroline Robert specializes in clinical and translational research in melanoma with a focus on immunotherapy, as well as adverse events in anticancer agents. She boasts hundreds of influential publications, chaired the Melanoma group of the European Organization for the Research and Treatment of Cancer (EORTC) from 2014 to 2017 and has been on the board of numerous Dermatological and Oncological organizations9.

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5. Liu et al. Clin Cancer Res 2016

6. Blank, et al. Nat Med 2018

7. Amaria et al Nat Med 2018

8. Boutros et al. Nat Clin Pract Oncol 2016