ODAC Member Disagrees With Outcome for Sintilimab/Chemotherapy in Nonsquamous NSCLC

Jorge Nieva, MD

During the FDA’s Oncologic Drug Advisory Committee (ODAC) meeting, held on February 10, 2022, 1 expert on the committee voted differently than the rest of the members. The vote of yes was 14 to 1 in favor of the FDA requiring more research to support a future approval of sintilimab (Tyvyt) injection in combination with pemetrexed and platinum chemotherapy for the first-line treatment of patients with nonsquamous non–small cell lung cancer (NSCLC).¹

Most of the voting members harbored concern that the phase 3 ORIENT-11 clinical trial–which supported the biologic license application for the sintilimab combination–was conducted in China only, with a 100% Asian patient population. Moreover, ODAC members and the FDA were not content with the study design, which focuses on the primary end point of progression-free survival (PFS).

Based on their feelings about the ORIENT-11 study and how it may relate to a United States nonsquamous NSCLC patient population, the FDA recommended that the sponsor conduct a noninferiority trial before another application for approval could be considered. Jorge Nieva, MD, disagreed with the requirement.

In an interview with Targeted Oncology™, Nieva, associate professor of Clinical Medicine at the Keck School of Medicine of University of Southern California and member of the ODAC committee, provided a recap of the recent committee meeting and explained his stance against further research for frontline sintilimab plus chemotherapy for patients with nonsquamous NSCLC.

Targeted Oncology: What stood out to you about the data from the phase 3 ORIENT-11 trial?

Nieva: I think the boringness of the trial is really what stood out. It was essentially a replicate of the other studies that have been done with pembrolizumab [Keytruda] and atezolizumab [Tecentriq] and showed very similar efficacy to the current FDA-approved drugs, which is not surprising considering the identical mechanism of action and identical biologic product. Although, obviously, there's going to be some molecular differences.

What did you take away from your peers of the ODAC panel during the meeting?

The thoughts were that because it was done in an entirely Chinese population, that the results were not necessarily applicable to a US population. And I think that's the takeaway that I think the FDA wanted us to have from the meeting.

The vote was 14 to 1. Can you explain your reason for voting the way you did?

Well, I think the biggest reason is, I'm concerned about the cost of drugs in the US. The FDA’s description of how they view ideal drug development with a multiregional trial model looks to me to be a very expensive way of doing trials. It requires global firms, and I think if we raise the bar too high on developing drugs, we're only going to be left with very expensive drugs. This particular drug was going to come to the market at a significant discount compared to current alternatives, perhaps 40% or 50% of the price of the current drugs. And I think the biggest barrier to care in the US, for lung cancer patients is access to these very expensive medications.

Now, of course, for the people who have insurance for the people who have Medicare, it's not too much of a problem unless, of course, their insurance is a managed care plan, or one that practices value-based care, or a plan that has limited resource and drug budgets, and chooses to engage in some kind of prioritization and how they spend their drug dollars. I see this very commonly in California. Patients who are enrolled in health insurance plans that are not straight fee for service. Well, more commonly experienced delays and have increasing restrictions on the use of these highly effective medications. Oftentimes, there will be very stringent criteria applied for the use of these medications, particularly in managed care settings. And I think that creates tremendous disparities in cancer care and cancer outcomes among populations that are affected by the cost of drugs.

It's not just financial toxicity on an individual level, it's on a health system level as well. And so, I voted no [to more research being needed], because I think we need to have cheaper pathways for drug development. I think we need to have the ability to bring these me-too drugs to market, because they are not very scientifically interesting, but economically have the potential to do a lot of good.

In the decision that was laid out, we didn't have an opportunity to discuss this or contemplate the impact that this decision was going to have on the health system overall.

During the meeting, the drug’s sponsor also mentioned that approved effective drugs like pembrolizumab were cost prohibitive. What were your thoughts when you heard that?

They were specifically referring to China. In that case, yes, because there was this concern, which I think was a very legitimate concern raised is that they didn't update their consent forms when pembrolizumab was approved by the local health authorities in China, to let people know that it was an option. And I think the company's response was almost good enough in saying that it really wasn't available, because patients had to have a lifetime of savings in order to afford the medication.

You mentioned during the meeting that it would be difficult to explain to a patient how the ORIENT-11 data apply to them. What do you think a global clinical trial of sintilimab should look like for it to be approved in the future?

We want drugs tested in ethnically diverse populations. I think it was less important for suntilimab than for some other drugs, because it was a me-too drug. And because it wasn't a novel molecular entity. I think I would have been completely onboard with the other groups, the rest of the group's decision making if this had been a novel, small molecule, or something with a novel mechanism of action, but this drug was neither of those things.

So, I think it's a real challenge now to ask how you would test the drug in lung cancer in the metastatic setting and do it in a global way, with a diverse population unless you go back into those countries that don't have access to PD-1 inhibitors and try to replicate the design.

I think the FDA was not happy with the design because it was an outdated design. It was a design based on the standard of care back in 2016 and not the standard of care in 2021. I don't think you really can design something with a 2021 standard of care with a survival or a PFS end point anymore. I just don't think it's possible unless you go to these underserved nations that don't have access to these medications. But I don't know if that was really the goal of the discussion.

Was there anything else that stood out to you during the meeting?

The other aspect that stood out from the meeting was that I think the message was loud and clear that the FDA needs to be engaged early, and that the other members of the committee and the FDA were not happy that the licensing application was proverbially dropped on their desk without a US investigation of the new drug application at the institution. So, I think that's going to be an important message for people who are developing drugs in the future, that the approach that was taken by the applicant in this case, is just not going to fly moving forward.

_Reference:

_{1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. Accessed February 10, 2022. https://bit.ly/3Bdwluu}