The Potential of Rigosertib in RDEB-Associated Cutaneous Squamous Cell Carcinoma

Part 2: Results from Trials Investigating Rigosertib

Andrew South, PhD, University of Wisconsin-Madison, discusses the results of 2 trials investigating the use of rigosertib among patients with recessive dystrophic epidermolysis bullosa (RDEB)-associated cutaneous squamous cell carcinoma (cSCC).

Dr South concluded that an option like rigosertib existing for this patient population would “give physicians and patients a treatment option in what is currently an untreatable and devastating complication of what is already a devastating disease.”

To revisit Part 1 of Dr South's interview, please click here.

Transcript:

Hi, I am Andy South. I am the Oros Family Professor in Rare Skin Disease in the Dermatology Department at the University of Wisconsin-Madison.

What were the methodologies of the 2 rigosertib trials?

Rigosertib, as a small molecule, can be administered either intravenously or orally, so we wrote the trial with those 2 options. The intravenous administration was based on the myelodysplastic syndrome protocol, and that was a 72-hour/3-day infusion, continuous infusion. That was a little challenging in these patients because A, it's a rare disease and they have to travel to the clinical site and in some cases that's long distances and then be hospitalized for at least 3 days while they receive that therapy. The other option was oral and rigosertib can be taken in pill form. The only other complication with that and recessive dystrophic epidermolysis bullosa is that patients often have esophageal strictures and these pills were quite large. So it's not an option for every patient to be able to swallow such large pills. And we're working on formulation, a liquid formulation for the drug, which will be much more applicable for those patients. The route of administration would've been a decision made by the patient and the physician. And for the oral administration, it's twice a day, a pill twice a day for 3 weeks, and then 1 week off. And then that's 1 cycle and continuing. For the IV administration, it was 72 hours every 2 weeks for the first 4 cycles, and then every 3 weeks, subsequently.

What were the results of the trials?

The trial took a long time to set up, complicated by the drug originating from a company in the US, the grant funding originating from an organization in the UK, and the first site to be opened was in Austria. It took a while to get that started. And then of course, the pandemic got in the way as well.

The first patient to be treated was in 2021, and that patient was an IV administration and showed a remarkable response after 3 months on trial, showed a complete response of multiple skin lesions on both the left and the right hand or arm. And that response was maintained for the 12 months of the trial. That's the first patient on-drug, a complete response after three months. That was super exciting results.

The second patient to be enrolled in the study was enrolled in Philadelphia, did not want to receive IV drug (the first patient received IV therapy). Patient had a number of complications because EB is a complicated disease and was on a lot of opioids for the pain of a very large tumor on the patient's back. Unfortunately, the patient didn't complete the first cycle as described — there was a 1 week holiday between 2 weeks, so the patient received oral drug for two weeks, had a week break another week, and then another week break, and then came in for the second cycle but didn't finish that second cycle and was having GI issues, constipation, which we attributed to the opioid use and so didn't finish, which is unfortunate.

The third patient to receive drug was also enrolled and treated at Thomas Jefferson University and also received the oral drug. And that patient showed stable disease after 3 months and then a complete response after 6 months. So again, the second patient to receive or complete more than 2 cycles showed a complete response and that complete response was sustained for the 12 months of the trial. So again, at that stage, super exciting results with this drug in this patient group.

Now, patients 4 and 5 were not as successful. Patient 4 came to the European site in Austria with very progressive disease with metastatic lesions and a very large tumor on the right leg that had previously been amputated to try and control the spread of the cancer, which unfortunately was not successful. Patient received drug and did show a quite astonishing response in a very large tumor on their leg. But unfortunately, the metastatic disease didn't respond in a similar way, and the patient progressed and came off trial.

The final patient, patient 5, received oral drug for the first 3 cycles, but we were monitoring PK, we were monitoring drug exposure in the blood of these patients, and that patient didn't have the level of exposure that the other patients on oral drug had shown. And wasn't showing such a good response as the other patient that had received more than 2 cycles of oral drug. So we switched that patient to IV drug and we saw a stable disease at 3 months, which was encouraging. But unfortunately the patient was traveling to Philadelphia, so it was at the US site, from out of state, and there were a lot of logistical reasons with that 3 day, 72 hour infusion and unfortunately couldn't meet the treatment schedule, and so came off trial. But that disease was promising and it's a shame that the patient wasn't able to sustain treatment. But as I said, this is a very complicated and devastating disease, multiple health issues in addition to obviously quite aggressive cancers.

Rigosertib has been used in a large number of patients prior, obviously the largest number being the phase 3 trial in myelodysplastic syndrome. But oral drug and IV drug have been used either as a monotherapy or in combination in a large number of patients, so the side effect profile is well described. The primary issue is urinary tract issues, so cystitis, hematuria, urgency. And those were the sort of side effects that we saw in the study with patients with recessive dystrophic EB and that cystitis, urinary urgency and complications, hematuria, resulted in dose reductions over the course of the trial. And that's detailed in the study. Those were the issues that really were the complications of the drug. And of course, in the 2 patients that had a sustained response, they were able to take drug for 12 months, albeit a reduced dosing.

What are the overall conclusions from these results?

To summarize, we treated 5 patients over 2 investigator-initiated trials: 2 of those patients showed a complete response, 1 at 3 months and 1 at 6 months; 2 other patients showed partial responses, either stable disease or a massive reduction of the primary tumor lesion; and 1patient didn't complete 2 cycles of drug. That’s 2 complete responses, 40%; 2 partial responses, 40%; and 1 failure. Super exciting data for this patient group.

A couple of reasons why that drug, which has been ineffective in other cancers seems to be, I have to be cautious about our excitement, seems to be efficacious in this particular patient group. The first one is that tumors that arise in this familial tumor prone disease seem to be very homogenous and driven down polo like kinase 1 dependent signaling route. And our idea in terms of the lack of response for the metastatic disease in one of the patients is that once a tumor has left the primary site, it's under additional selection pressures and then develops alternate signaling pathways that are not effective. But these homogenous tumors that arise in the skin at the primary site are dependent on polo like kinase 1 and are responsive to the drug. And that's one of the reasons.

The second reason is actually these patients have a failure to thrive because in addition to their skin lesions, they have issues with the GI tract. Generally, they don't thrive and grow as much as someone without the disease, and therefore patients, adult patients can be as little as 40 kg. And therefore, exposure of the drug and our PK analysis in this patient showed a much higher drug exposure systemically. Those are the 2 reasons why we believe that the drug has been efficacious in this patient group.

As for next steps, we're trying to develop a liquid formulation that will aid in patients being able to take the drug, especially those with GI issues. And GI issues can lead to a feeding tube, so again, pills are not very applicable to that route of administration. But there are some challenges at this point in time in terms of the drug, its patent, and the company that developed the drug and holds licenses. There are patents for treatment of this particular disease with this drug, and that at the moment we're just trying to sort out a company to take forward a more extensive clinical trial to develop this drug in this indication.

Can you explain the importance of investigating treatment options for this patient population?

Squamous cell carcinoma of the skin in patients with RDEB is the biggest cause of mortality. And for sure patients and families know this and know that that is a real risk and a real issue for patients. Any sort of treatment that can either extend the lifespan of a patient after being diagnosed with cancer or ultimately prevent the disease is going to be a huge benefit.

Right now in terms of standard of care for these patients, there were guidelines published in 2016, so they probably need to be updated — that was prior to approval of cempilumab, the PD-1 inhibitor, that's approved for treatment of cutaneous squamous cell carcinoma. The standard of care really was wide surgical excision and amputation of those extremities with progressive disease. Of course, that has had very little impact on that 5-year survival in this patient group. Cemiplimab has been used, a number of patients  are taking or have taken that drug. There are a few patients [with RDEB], anecdotal reports, of good response over, say, the first year or 2 years of receiving cemiplimab. But unfortunately, tumors pop up elsewhere. The primary tumor sometimes has a good response and then other tumors will arise elsewhere. It hasn't really been particularly effective, and certainly the numbers are much lower than the efficacy of cemiplimab in the cutaneous scrim cell carcinoma in the general population.

Having anything that's available to the physician to be able to treat these patients would be very beneficial. As we look into developing this molecule for treatment of patients with RDEB-associated squamous cell carcinoma of the skin we would hope that we can get a wider trial set up, get more patients treated, if we see a similar response rate we would hope that we could seek approval for this and then give physicians and patients a treatment option in what is currently an untreatable and devastating complication of what is already a devastating disease.

To revisit Part 1 of Dr South's interview, please click here.

Source:

Laimer M, South AP, Kitzmueller S, et al. Efficacy and safety of rigosertib in patients with recessive dystrophic epidermolysis bullosa associated advanced/metastatic cutaneous squamous cell carcinoma. Br J Detmatol. Published online: May 25, 2025. doi: 10.1093/bjd/ljaf205.