Key takeaways:
- The FDA authorized expanded access to daraxonrasib for patients with pretreated metastatic pancreatic cancer.
- Its manufacturer can provide the drug to eligible patients for free while regulatory review continues.
Suneel Kamath, MD, knows too well the sense of helplessness that comes with living through what he calls “the doughnut hole.”
After compelling data from a late-stage trial are presented at a major medical meeting or published in a peer-reviewed journal, excitement about a potentially practice-changing treatment spreads like wildfire through the clinical community and the findings support a new drug application to the FDA.
Then, a monthslong wait begins.
“During this time, the trials are all closed, the drug is not on the market and nobody can get it,” Kamath, a gastrointestinal oncologist at Cleveland Clinic, told Healio. “You tell your patients, ‘The therapy should be available by this time next year. As soon as it is, I’m going to give it to you, but I can’t give it to you today.’ It’s a terrible feeling.”
The delay is most agonizing when the treatment under regulatory review is intended for people with a particularly lethal disease.
That explains the emotions Kamath felt — surprise, excitement and relief among them — when he learned the FDA would allow patients with pretreated metastatic pancreatic cancer to receive daraxonrasib (RMC-6236, Revolution Medicines) under an expanded access protocol (EAP).
Topline data from a randomized phase 3 trial showed the investigational oral medication doubled survival in this setting compared with standard second-line chemotherapy.
“With some diseases, lifespans are measured in years,” Kamath said. “Time certainly still matters, but most likely we have other viable treatment options. We can’t say that for pancreatic cancer. Many of the people we are treating today may not be alive when the next therapy is approved. If time is of the essence for any disease, it’s this one. When we know a drug really works, it is very difficult to educate our patients about why we can’t use it. To have the ability to offer the right treatment at the right time for our patients is amazing.”
‘This is not hyperbole’
Most pancreatic ductal adenocarcinoma (PDAC) cases are diagnosed at advanced stages due to absence of symptoms with early disease and lack of early detection strategies.
Only 13% of patients with PDAC — and 3% of those with distant disease — survive 5 years, according to American Cancer Society statistics.
Multiagent chemotherapy is standard, conferring median survival of less than a year in the first-line setting and about 6 months in the second line.
Daraxonrasib is an oral pan-RAS inhibitor in development for treatment of advanced solid tumors.
RAS mutations — particularly those in the KRAS gene — are found in more than 90% of pancreatic cancers. Although long known to be the key driver in disease development and progression, no therapy has successfully been able to target them.
The randomized phase 3 RASolute 302 trial included about 500 adults with previously treated PDAC. Some harbored RAS variants and others had no identified RAS mutations.
Investigators assigned trial participants to 300 mg daraxonrasib daily or investigator’s choice of standard IV cytotoxic chemotherapy (gemcitabine/nab-paclitaxel, FOLFOX or liposomal irinotecan plus 5-FU).
Results from a first interim analysis of the entire study population showed a near-doubling of OS in the daraxonrasib group (median, 13.2 months vs. 6.7 months; HR = 0.4; P < .0001). The trial met all other prespecified primary and secondary endpoints, including PFS, objective response and patient-reported quality of life. The most common toxicities observed in the trial included skin rashes, GI toxicities and mucositis.
“We use a lot of hyperbole in oncology,” Kamath said in an interview. “Terms like ‘breakthrough’ and ‘game changer’ are overused big time. This is not hyperbole. To have an incredibly effective drug that takes down a terrible target that is present in more than 90% of pancreatic cancers truly is a game-changing step forward.”
Last fall, the FDA included daraxonrasib in its Commissioner’s National Priority Voucher pilot program. The pathway accelerates review of products that align with one of five specified national health priorities, such as meeting a large unmet medical need. A decision on approval is expected at some point this year.
On May 1 — about 2 weeks after Revolution Medicines issued topline data from its interim analysis — the FDA issued a “safe to proceed” letter allowing the company to initiate an EAP for daraxonrasib. Under the protocol, Revolution Medicines can supply the drug at no cost to eligible patients with previously treated metastatic PDAC.
“Revolution Medicines commends the FDA’s expedited review and continued commitment to providing a pathway for patients with life-threatening diseases to access investigational therapies outside of a clinical trial when no comparable or satisfactory alternative treatment options are available,” a company press release stated. “This authorization represents a critical step in the process of opening an EAP. Revolution Medicines is moving as quickly as possible to ensure safe and equitable access to daraxonrasib for eligible patients in the United States.”
Licensed physicians must initiate all requests for expanded access to daraxonrasib on behalf of their patients.
‘A paradigm shift’
The enthusiasm surrounding daraxonrasib had been building long before Revolution Medicines issued its topline data announcement last month.
Kamath, who submitted his first request for expanded access 3 days after the FDA cleared the way, began hearing inquiries from patients about the drug last fall.
Andrew L. Coveler
“It has been on a lot of people’s radar for a long time,” Andrew L. Coveler, MD, director of the pancreatic cancer specialty clinic at Fred Hutch Cancer Center, told Healio. “This is the first of what hopefully will be many RAS inhibitors but, because this is the furthest along, many patients have been following it. If they hadn’t found out about it on their own, one of their family members had told them.
“You can imagine the stress they feel when they know this drug is coming — even before what amounted to unprecedented results from the phase 3 trial — but they can’t get it,” Coveler added. “That is incredibly difficult. To have a mechanism through which people don’t have to wait until FDA approval to receive this medication — potentially allowing a person who otherwise may be in the last few months of their life live more than a year — is a fantastic opportunity.”
Still, oncologists must ensure the enthusiasm surrounding this treatment is framed through the lens of realistic expectations.
“I had a conversation with a patient [recently] who asked, ‘Is this a cure?’ It is not,” Coveler said. “However, it is amazing to have a medication that we hope most patients will respond to and, even though there are side effects, it’s likely they will be significantly less than the toxicity with chemotherapy. So, it still will be a paradigm shift in treatment, and the ultimate goal is to help our patients buy more time until we identify something that is even more effective and even better tolerated.”
‘A new era’
The role of RAS genes in cancer, first documented in the early 1980s, has been the subject of intense research since the 1990s.
The commitment to overcome what has long been an undruggable driver mutation is paying off, Coveler said.
“This drug is not something people accidentally found could work,” Coveler said. “This is due to more than 30 years of solid dedication in the science community. I believe this is the beginning of an amazing time for targeted treatment.”
Complete data from RASolute 302 will be presented during the plenary session at ASCO Annual Meeting, scheduled for May 29-June 2 in Chicago. Anticipation already is building about how the capacity crowd in McCormick Place’s Hall B1 will respond.
In 2010, ASCO attendees gave a standing ovation following the presentation of data from a randomized phase 3 trial that showed first-line FOLFIRINOX extended survival by 3.5 months vs. gemcitabine for patients with metastatic pancreatic cancer.
“I can only imagine what it will be like after we hear these data, knowing we are seeing decades of research in this area come to fruition,” Coveler said.
Kamath has made sure he has no meetings scheduled “anywhere close” to the start time of ASCO’s plenary session. Like Coveler, he is optimistic that this is the first step in a broader transformation of pancreatic cancer treatment.
Multiple trials are underway to further evaluate daraxonrasib for pancreatic cancer, including one evaluating it as first-line treatment of metastatic disease.
Another agent in Revolution Medicines’ pipeline — zoldonrasib (RMC-6291), which targets KRAS G12D mutations — is being advanced into pivotal phase 3 trials for metastatic PDAC and non-small cell lung cancer.
Dozens of other RAS inhibitors are in various stages of clinical development.
“To me, this is more like the dawn of a new era and less about celebrating an individual drug,” Kamath said. “If you look at the way we treated pancreatic cancer in 2000, 2010, 2020 and now, you wouldn’t see a meaningful difference. To finally be at the point where we are able to change that narrative is incredibly powerful.”
For more information:
Andrew L. Coveler, MD, can be reached at acoveler@uw.edu.
Suneel Kamath, MD, can be reached at kamaths@ccf.org.
Sources/Disclosures
Source:
Healio Interviews
References:
Disclosures:
Coveler and Kamath report no relevant financial disclosures.
Ask a clinical question and tap into Healio AI’s knowledge base.
- PubMed, enrolling/recruiting trials, guidelines
- Clinical Guidance, Healio CME, FDA news
- Healio’s exclusive daily news coverage of clinical data
<
Leave a Reply