Timothy Yap, Ph.D., used to see patients nearing the end of their cancer journey in his phase 1 department at the University of Texas' MD Anderson Cancer Center. Either they fit into a phase 1 trial, or they were off to hospice for end-of-life care.
Things have changed, and the situation at his department is a little more hopeful nowadays.
“What's interesting is that patients are now getting referred at a much earlier line of treatment," Yap said in an interview. "In the past, 10-15 years ago, phase 1 is kind of like, you lost hope before you go to hospice. But that's no longer the case."
Why? Because cancer drugs are getting better. More specific. More tolerable. And it’s not just in the lab where patients are seeing these benefits. Yap points to advancements in treatments for KRAS G12D mutations that see patients getting referred earlier, simply because physicians now can test the exact genetic makeup of a patient’s cancer.
“That's how cool this is, because we're seeing progress being made in drug development that we are now delivering directly to patients,” Yap said, speaking about data presented that day at the European Society of Medical Oncology (ESMO). “These trials will give patients early access to drugs that they would otherwise not have access to.”
What’s behind this trend? Emerging data have pushed Big Pharma companies to move their major therapies up in the lines of treatment, trial by trial. The FDA’s Project FrontRunner encourages the same.
Traditionally, drug developers started testing a therapy in either the relapsed or refractory patient populations, where disease has returned after—or stopped responding to—treatment.
But the FDA’s guidance has encouraged sponsors and companies to test their products earlier sooner, rather than “work all the way backwards over time,” said Jeff Legos, Ph.D., head of global oncology and hematology at Novartis.
“This does provide an opportunity of accelerating innovation for patients by starting much earlier,” Legos said in an interview.
'A different mindset'
Israel Lowy, M.D., Ph.D., senior vice president of clinical sciences and head of translational science and oncology at Regeneron, says Project FrontRunner is helpful, but the FDA actions are really going where the industry was already heading.
“The FDA discussions are kind of in line with what everybody's realizing based on emerging clinical data. So I think we were keen to do this from the beginning,” Lowy said. “Certainly, it helps that the FDA is interested in this and supportive of it. I'd say that there hasn't been a clear instance yet where FDA position on this helps us figure something out.”
But Regeneron is, of course, “happy to talk to them and figure out ways forward.”
For his part, Lowy sees an even bigger challenges as the regulatory environment clears: “The hardest thing is actually getting investigators comfortable with the idea of doing this early, because many times these early clinical trials are in curative intent setting.”
“So the first thing you want to do is do no harm and make anything worse,” he said. “It’s a different mindset.”
Earlier does not always mean better, either, as Novartis recently found out. The Swiss pharma posted results at ESMO for Pluvicto showing that the radiopharmaceutical slashed the risk of disease worsening or death by 59% compared with a change of androgen receptor inhibitor in patients with PSMA-positive, metastatic castration-resistant prostate cancer who hadn’t received taxane-based chemotherapy. This in itself was a great result; however, there was also a preliminary sign of a 20% increased risk of death among patients who took Pluvicto in the study.
Novartis is also trying to push another radiopharmaceutical, Lutathera, earlier in the treatment line up for gastroenteropancreatic neuroendicrine tumors five years after originally gaining approval in the indication.
AstraZeneca is another major pharma with a goal of moving treatment into earlier lines. Imfinzi, already dominant in stage 3, unresectable non-small cell lung cancer when used following chemoradiotherapy, suffered a blow this week when an earlier test failed on the primary endpoint of progression-free survival.
Another hurdle for the field is developing new clinical endpoints as the treatment paradigm shifts. Regeneron and others are trying to figure out if the pathology at the time of surgery can be used to assess the efficacy of a treatment, potentially for a registrational endpoint.
“That's a long road to hoe, because we need a lot of data. There’s a lot of variability in how people report these pathologic outcomes,” Lowy said. What’s needed are correlative data that show the pathological responses lead to long-term outcomes in terms of event-free survival, he continued.
But the benefits are clear: Newer treatments, in some cases, have better safety profiles than legacy chemotherapies. If a patient could take, say, an immunotherapy sooner than a chemotherapy regimen, they might avoid some of the hallmark side effects of the latter option.
That’s the hope in lung cancer right now, Lowy said. Currently, the standard pre-surgical treatment for patients who have advanced but still resectable disease is immunotherapy plus chemotherapy.
“Ultimately, it would be great if we could identify additional regimens that could spare you the chemotherapy,” Lowy said. “In other settings like melanoma or non-melanoma skin cancer, those pre-surgical treatments currently do not involve chemo, so it's good to try to avoid that.”
Yap does not downplay the serious side effects associated with newer emerging treatments. For instance, KRAS inhibitors like Amgen’s Lumakras and Mirati Therapeutics' Krazati have been associated with liver enzyme elevations that can point to liver damage. And AstraZeneca and Daiichi Sankyo have found instances of interstitial lung disease for their joint antibody-drug conjugate Enhertu and its follow up datopotamab deruxtecan (Dato-DXd).
“We're seeing, I would say, compared with chemotherapy—which we know very well—a familiar enemy,” Yap said.
But many of the side effects are manageable and have been low grade, with some more serious outliers that are not to be dismissed, according to Yap. “In general overall, compared to say chemotherapy, it's night and day.”
Another piece to the front-line puzzle is the Inflation Reduction Act (IRA)—the drug pricing legislation that has become a rallying cry for the pharma industry. While Legos doesn’t agree with much of the legislation—particularly its insistence that small molecules should be treated with a different timeline than biologics for pricing negotiations—he does think it pushes pharmas to rethink where they start therapies in the line of treatment.
“If you think about only having nine years or 12 years to be able to demonstrate that innovation and be able to provide that product to patients, it does require us to think much more upfront and sooner as to what is our overall indication sequencing plan,” Legos said. “How can we start in the earliest line of therapy where we can potentially provide the biggest benefit to patients as soon as possible before that IRA clock runs out?”
Legos said Novartis is reviewing its portfolio right now to ensure its studies are set up to benefit the largest number of patients.
So do the IRA and Project FrontRunner compete with each other?
“They're complementary in some sense. I think they're coming at it from a different perspective. You have a mix of regulatory and a mix of policy and managing Medicare costs that are kind of working collectively towards one common goal: accelerating innovation to patients,” Legos said.