Why is pembrolizumab plus chemotherapy the right comparator for RELATIVITY-1093, and what would a practice-changing win look like?
The current standard for patients that don’t have actionable mutations, [including] those that have PD-L1 expression and even the PD-L1 negatives, is to use chemotherapy and immunotherapy, and the most commonly used immunotherapy in that combination has been pembrolizumab. The [RELATIVITY-1093] trial, which is trying to test this hypothesis of an augmented response with PD-1 and [LAG-3] blockade, needs to go against the standard of care, which is chemotherapy [plus pembrolizumab], but it needs to go further and try to find those patients that are more likely to respond. That’s why having a phase 2 trial [as a] baseline is important.
The decision was made that we are concentrating on those patients that have PD-L1 expression and nonsquamous histology. It’s important to look at the standard of care [because] we’re going to change what people are already doing in practice, and for people to feel comfortable that we are seeing a meaningful response that is worth changing what we’re doing.
Why is the RELATIVITY-1093 primary analysis focused on PD-L1 expression of 1% to 49%, and is that the greatest unmet need?
It was important to identify a group of patients who are currently not best served by our current strategy of chemotherapy and pembrolizumab. The high PD-L1 expressors, [at] more than 50%, already have several single-agent immunotherapy options that can work well. We’re not going to see a strong signal in that group, [which] already has a [high likelihood] of response to immunotherapy.
The [patients with PD-L1 expression of] 1% to 49% are the patients that we don’t know [about], because it’s a big range of patients. Some have low PD-L1, like 1% to 10%; some have [PD-L1] expression [of] 30% to 49%, and they’re on a continuum. We have seen that the amount of [PD-L1] doesn’t determine the response. It’s a big area of need to push forward in this group of patients that can respond, but we lose responses faster because they don’t have that high sensitivity to immunotherapy. The 1% to 49% [group] is definitely an area of need. The other area of need is [PD-L1–negative disease], but those are patients [for whom] other strategies are being researched.
With several established immunotherapy-based options in first-line nonsquamous NSCLC, what would a positive RELATIVITY-1093 result mean?
To beat the standard of chemoimmunotherapy and have a win, you don’t only need a statistically significant [HR], because that just means that it’s marginally better than the standard. We want to see a clinically meaningful improvement in [OS], and that’s why it’s important that this trial may take longer to [read out OS]. That is going to be what moves the needle for us to offer patients something better. That has to be supported by a good [PFS] improvement, a durable response, and, more importantly, good quality-of-life data that shows that adding another agent is not going to add more toxicity, because we want our patients to live longer but also live better.
The initial combinations of CTLA-4 [and] PD-1 [inhibitors] had high rates of colitis, [and] the benefit of that double checkpoint inhibitor [approach] was lost by the fact that many patients got sick, [which made it] hard to treat everyone that way. Now we’re selective about that combination. In this study, we want to find a combination that is well tolerated and that moves the needle in survival.
If nivolumab plus relatlimab and chemotherapy improves OS, how should that benefit be weighed against the toxicity of a second checkpoint inhibitor?
If this study is positive, [with] meaningful [PFS] improvement and meaningful durability of response, it’s going to take a while to see that 5-year mark move further, but we can see a signal in [PFS]. What is going to be critical for us is to then say we have the data. We did a randomized comparison head-to-head of these two groups, and that will make us feel comfortable changing the standard, but also understanding that we’re looking at a specific population of patients that are nonsquamous [and] have PD-L1 [expression of] 1% to 49%. We have to still do the testing [so] that we don’t include patients that have actionable mutations that will be best served by an actionable therapy, and that we have patients who have good performance status who can tolerate combination therapy.
What is also important about how this would change the algorithm is that sometimes patients don’t tolerate all of the [chemotherapy], and we’re relying on 1 immunotherapy to carry them over in the maintenance period. Having dual checkpoint inhibitors, [with] another mechanism to stimulate the immune system in that maintenance period, may make a big difference for patients living longer without chemotherapy.
The goals here are that it’s a positive trial compared [head-to-head with] the standard, so there are no doubts about what the addition will show, but also that we are going to be able to keep patients on a better, hopefully more effective, maintenance for long-term immune [sensitivity]. We’re engaging with T cells that are becoming exhausted over time, and that’s why sometimes PD-1 [blockade] is not enough, because you’re only having 1 mechanism of engaging the immune system. When you have 2 mechanisms, hopefully we’ll see a higher response, but also a more durable response over time.
What should community oncologists take away from RELATIVITY-1093 before results are available?
We have gotten used to this chemotherapy backbone regimen and expect that every patient will respond, because we have seen responses that were never seen 10, 15, [or] 20 years ago. The reality is that about 80% of patients that get started on our current standard of chemotherapy [plus] pembrolizumab, or a single PD-1 inhibitor, will progress within a year and a half. They’re not going to make it to the 5-year mark.
The other thing that we want community oncologists to know is that, like any new drug, we have to learn about the toxicity. We have data from the earlier trial [on] the addition of [relatlimab], and it’s been tested in melanoma. The amount of toxicity that you’re adding is reasonable. It’s not like we have to deal with new immune-related [adverse effects]. We are dealing with the same endocrinopathies and potential immune-related reactions that we have all learned to manage. That also is important, so that community oncologists will feel comfortable that this is a regimen they [could adopt] tomorrow, because it’s addressing the same types of [adverse effects] that they are used to addressing with [pembrolizumab], for example.
