Opinion
Video
Pros and Cons of Immunotherapy in Metastatic NSCLC
Specialists assess the pros and cons of using immunotherapy in managing metastatic non–small cell lung cancer and delve into dosage variations and considerations when choosing different immunotherapy types.
David Carbone, MD, PhD: Dr Dietrich, what advantages or limitations come with the use of immunotherapy in metastatic disease therapy?
Martin Dietrich, MD, PhD: One of the new options that we have in the proper biomarker setting is that immunotherapy can be given to a lot more patients than patients who are chemotherapy eligible, and [there are] a lot of patients who are more willing to receive them. In the metastatic setting, when we think about this as a palliative-intent treatment, those are relatively well-tolerated therapies that, even though they have their own set of adverse effects, are typically more agreeable for patients. In the metastatic setting, we don’t have to press the same level of intensity that we do in the curative-intent setting. Patients who may be older or sicker still have treatment options that may be suitable. There are concerns when we have a first-line selection. That’s very important. We have 1 shot in getting this right. I don’t want to offer, [and] I think that’s more often done than not, the label for first-line immunotherapy; [it’s] too broad for what is biologically useful. We should think about this as an option that should only be given to an appropriate patient. Sometimes we’re palliating ourselves by offering something that has a very low probability of helping. It’s a nice option to have a broad-spectrum impact here. We used a lot of combination immunotherapies in the platinum shortage with PD-L1–negative and PD-1–low [disease]. There is a little flexibility that will expand the amount of patients in the metastatic setting that can be tolerated. I would think of judicious use here as the best rule to proceed for patients. Just because we have options and we always say that it’s nice to have options, sometimes it’s terrible to have options that you need to turn down and say, “Although this is FDA [US Food and Drug Administration] approved, it is not an FDA endorsement for approval. It’s basically a regulatory hurdle but not necessarily a clinical judgment.” That might be a very important part. We’ll see that we use immunotherapy earlier and that patients may have progressed on or shortly after immunotherapy, and then the pool of options in the metastatic setting is quite limited.
David Carbone, MD, PhD: It’s amazing how in the NCCN [National Comprehensive Cancer Network] recommendations, there’s a whole list of approved options for different PD-L1 levels and new PD-1 inhibitors. But there are 2 camps. One is the PD-1 plus/minus chemotherapy camp, and then there’s the PD-1 CTLA-4 regimens. What factors do you use in picking between those 2 general approaches to therapy?
Martin Dietrich, MD, PhD: CTLA-4 in the lung cancer community is generally underutilized. We’ve seen subsets of patients where CTLA-4 is very reasonable, and in the PD-1–centric world that we’re living in, we have an inverse utilization of the biomarker for PD-L1 levels. The higher the better for PD-1 single-agent usage, and the lower for me starts at 50%, certainly for the PD-1–negative [disease], and even in the genotypic space for resistance mutations or mutations that may not be feasible, there may be a role for even including secondary markers [such as] TMB [tumor mutational burden] as an additional bonus of biological evaluation. There are many patients where long-term responses are not appropriately met with the single-agent PD-1 approach alone and oftentimes we add chemotherapy. But whether or not chemotherapy extends the longevity of a treatment response, and that’s an outcomes discussion for us to think about immunotherapy not as a median PFS [progression-free survival] shift by a few months but a landmark improvement in the 4- or 5-year phase, we’ve seen dramatic improvements there for the PD-1–negative [disease]. And across 3 prospective phase 3 trials, CTLA-4 [is] making an impact in the long-term survivor population. [We’ve seen it in] Checkmate 9LA [NCT03215706], we’ve seen this in [CheckMate] 227 [NCT02477826], and the PD-L1–negative [population] probably [has] the most impactful subset of data. But in [findings from] Poseidon [NCT03164616], PD-L1 levels were largely equalized in outcomes by the addition of an antibody to ipilimumab. The toxicity question has to be balanced with the expectation of outcomes. I don’t want to offer a patient an anti–PD-1 agent alone if I don’t think it’s biologically reasonable. The escalation to a combination immunotherapy is certainly reasonable. We’ve seen that positive prognostic impact across many prospective trials now. These autoimmune adverse effects are, in my practice, viewed as the surrogate activation points of the immune system that may confer a longer positive outcome.
David Carbone, MD, PhD: Even chemotherapy PD-1 therapies in PD-L1–negative [disease] seem not to do as well. [Let’s look at] the 5-year outcomes from KEYNOTE-407 [NCT03875092] [findings] in squamous [disease]. If you look at the PD-L1–negative subset, there was no difference. I fully agree with you; I am almost annoyed when I hear the survival of this regimen is 7 weeks longer than that regimen. What they’re talking about is a median survival, which, especially in immunotherapies, is not a good metric because it comes from a constant risk model where the curve goes down by a certain fraction every time and medians reflect the rest of the curve. But with immunotherapies, we generally find a 2-compartment model where a lot of people [experience progression] quickly but there’s a tail. In my mind, I’m viewing 3-, 4-, or 5-year landmark survivals as the gold standard to compare regimens. In the Keynote 407 5-year landmark survival in squamous PD-L1–negative [disease], there’s no difference between pembrolizumab and no pembrolizumab, whereas it’s 3 or 4 times better with the dual checkpoint inhibitor. Recent data from the [2023] ASCO [American Society of Clinical Oncology] [Annual] Meeting [in Chicago, Illinois,] showed that at 4 years, the 9LA regimen had continued benefit, especially in the subset [with] PD-L1–negative [disease]. The dual immunotherapy regimens have more toxicity, but we’re learning how to manage these. If you look, many patients have to stop 1 or both agents [because of] an immune toxicity. But one interesting thing that was reported at [the] ASCO [meeting] was that the survival of patients who had to have some component of their regimen stopped because of an immune-related toxicity was not worse than the survival of patients who were able to tolerate the full regimen. In fact, it was a little better, the landmark survival. If you use the combined immunotherapy regimen, you have to anticipate higher toxicities and manage them aggressively. Don’t be afraid of holding one of the agents. I usually have a very low threshold to stopping the ipilimumab or the anti–CTLA-4 and continuing the anti–PD-1. I’ve had many patients who do very well with that approach. That kind of approach is increasing in practice.
Transcript is AI-generated and reviewed by an AJMC editor.
