Need to know:

  • Pepaxto’s confirmatory trial shows it may have increased risk of death; oncologists will pause on uptake for now until the FDA digs into the data
  • Data analysis on subgroups, specifically on patients’ previous therapies or subsequent therapies may help find Pepaxto niches
  • Prophylactic antibiotics could alleviate infection risk among patients

Blood cancer oncologists are likely to hold back for now on using Oncopeptides’ Pepaxto in triple-class refractory multiple myeloma patients, experts said. Oncologists will be waiting on the FDA to provide further guidance on how to manage its increased death risk.

On 28 July, the FDA alerted oncologists that in the Phase III OCEAN trial, Pepaxto led to an increased risk of death. Subsequently, the FDA encouraged them to review their patients’ progress with Pepaxto. All ongoing Pepaxto trials have also been suspended. A public meeting will be staged to discuss additional OCEAN findings and explore continued marketing of the treatment.

Until the FDA decides on how it should address Pepaxto’s OCEAN data, most US oncologists will likely be more reluctant to use the treatment, said OCEAN investigator Dr Fredrik Schjesvold of the Oslo Myeloma Center. They will wait to hear from the FDA on any mitigation strategy to reduce risk before resuming use of Pepaxto, added University of California San Francisco Medical Center clinical professor of medicine Dr Thomas Martin.

Melphalan flufenamide, with the brand name Pepaxto, garnered FDA accelerated approval in February 2021. As a result, the treatment is not so established in US oncologists’ practice for there to be a comfort level to keep using Pepaxto, said another OCEAN investigator, Dr Ulf-Henrik Mellqvist of Sahlgrenska University Hospital in Sweden. Upon accelerated approval, the therapy’s overall efficacy data drew some pause for clinical benefit, which likely contributed to delayed uptake in the past five months, he added. Pepaxto’s April net sales totalled $3.3m, according to a 26 May media release.

Two alternatives to Pepaxto available

The FDA advised oncologists to discuss the risks of continued Pepaxto administration with patients in context of other treatments. In patients who are yet to take any therapies in the triple-class refractory setting, there are two notable options available: GlaxoSmithKline’s Blenrep and Karyopharm Therapeutics’ Xpovio, Martin said. However, both treatments have respective side-effect issues, he noted, adding it might come down to patient preference. Blenrep has a boxed warning on ocular toxicity; Xpovio has warnings on thrombocytopenia, neutropenia and gastrointestinal toxicity, among others.

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An Oncopeptides spokesperson said it does not have any concerns that the new FDA warning would dramatically impact uptake in the US. Pepaxto’s patient population has an unmet medical need with limited treatment options, the spokesperson added. Perhaps Pepaxto can still be used in patients who have early progression from Blenrep and Xpovio, Martin noted.

According to the FDA guidance, in the confirmatory OCEAN trial’s overall survival (OS) secondary endpoint, there were 117 deaths in the 246-patient Pepaxto arm (48%), compared with 108 deaths in 249 patients (43%) in the Bristol Myers Squibb Pomalyst (pomalidomide) active comparator arm. The median OS with Pepaxto is 19.7 months, versus 25 months with Pomalyst. The spokesperson said it will present OCEAN’s complete data at a scientific congress later this autumn.

Subgroup analysis valuable for Pepaxto uptake

The next step to understand Pepaxto’s clinical value is to find patient subgroups who are best suited for the therapy, experts said. OCEAN recruited all comers and finding subpopulations may be paramount due to the trial comparing two therapies with different mechanisms, Schjesvold noted. OCEAN investigated Pepaxto, a peptide-conjugated alkylating drug, versus immunomodulatory imide drug Pomalyst. All patients are given low-dose dexamethasone.

What treatment the patient has taken previously can help find Pepaxto’s ideal subgroup, Schjesvold said. Triple-class refractory patients are those resistant to all three classes of standard myeloma therapies: proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Perhaps patients who have previously progressed from an alkylating agent may not benefit from Pepaxto, Schjesvold noted. In OCEAN, there are patients who have previously received an alkylating agent and some have not, he added.

Subsequent treatments may have impact

Since the concerning discrepancy is related to Pepaxto’s OS data, results may have been affected by what therapies OCEAN patients have taken after progressing from Pepaxto or Pomalyst, Mellqvist said. For example, if a Pomalyst patient in OCEAN progressed earlier than another patient on Pepaxto, the Pomalyst patient would have received subsequent therapies sooner, he noted, adding this could bolster the Pomalyst patient’s OS result.

It is also possible that these subsequent therapies would be more effective if the patients have failed either Pomalyst or Pepaxto, further muddying OS data, Mellqvist added. Nevertheless, data collection of OCEAN patients’ subsequent therapies  represents an opportunity to find subgroups that experience the most OS benefit, he said. However, subsequent therapies can differ between countries, he noted.

The spokesperson said its analysis indicates there are patients that may benefit from Pepaxto, as well as patients who should have Pomalyst. How these hypothesis-generating data should be interpreted, and its clinical implications, are in an ongoing analysis, he added. Patients best suited for Pomalyst may be hard to pinpoint in OCEAN because all patients have progressed from an immunomodulatory imide drug, even if to various degrees, Schjesvold noted.

Prophylactic antibiotics could bolster survival

Another possible way to help increase Pepaxto’s OS data is to use prophylactic antibiotics, Martin said. Triple-class refractory multiple myeloma patients are already fragile, having gone through many prior lines of therapy on top of having low bone marrow reserves, he explained. And Pepaxto can further negatively impact these reserves, increasing risk of infection, he added. And so, preventive antibiotics might be able to help.

Apart from prophylactic antibiotics, another way is to increase these patients’ leukocyte count, especially neutrophils, to be able to combat infections, Mellqvist added. Pepaxto’s FDA label warns of thrombocytopenia, neutropenia, anemia and infections, among others. Patients who end up with neutropenia become highly sensitive to infections, and severe cases can be fatal, Martin explained.

But the spokesperson noted OCEAN did allow for antibiotics as prophylaxis and was recommended in both arms. While prophylactic antibiotics might be helpful, Schjesvold said that the number of infections in OCEAN between arms is not dramatically different. Pomalyst had slightly more infection events than Pepaxto in OCEAN, according to a 26 May company presentation.

Pepaxto helps with unmet need

While it was judicious for the FDA to pause ongoing Pepaxto trials on the back of new OS data, there is still potential for the treatment to be used in its present setting where there are currently limited options, experts said. In OCEAN’s primary endpoint, progression-free survival (PFS), final analysis shows Pepaxto was superior to Pomalyst (p=0.0311).

In OCEAN, while the OS data might favour Pomalyst, the confidence interval of the hazard ratio shows it may not be a definitive finding, Schjesvold added. The hazard ratio for OS of Pepaxto versus Pomalyst was 1.104, with a 95% confidence interval range of 0.846 and 1.441.

However, based on available data so far, it might be challenging for Pepaxto to demonstrate dramatic superiority over Pomalyst in the OS endpoint, Schjesvold said. Pomalyst is a high bar, in contrast to Pomalyst’s registrational trial which only compared it to steroids, Mellqvist noted. Pomalyst was FDA-approved in multiple myeloma in 2013.

Oncopeptides has a SEK 3.08bn ($358.1m) market cap.