The availability of chemoimmunotherapy combinations and targeted agents for common and rare mutations alike in non–small cell lung cancer has fostered discussions that might have been unthinkable just a decade or so ago.
The availability of chemoimmunotherapy combinations and targeted agents for common and rare mutations alike in non–small cell lung cancer (NSCLC) has fostered discussions that might have been unthinkable just a decade or so ago, explained Edward B. Garon, MD, who added that such advances have created room for more nuanced discussions regarding the necessity of using PD-L1 expression to drive treatment decisions, prescribing adjuvant therapy without an overall survival benefit, and recommending radiation therapy for systemic disease.
“I started my faculty position about 15 years ago, and the meetings we would have had at that time were about things like the dosing of paclitaxel. Almost all the discussions and the points that we debate now are very far from the sorts of things we would have been debating [15 years ago], and in many respects is indicative of substantial success over the intervening 15 years. Although lung cancer remains a difficult disease, it is one for which people should be hopeful. Many patients have good outcomes,” said Garon, a professor of medicine in the Department of Medicine and Division of Hematology/Oncology at the Geffen School of Medicine at the University of California, Los Angeles (UCLA), in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, of which he was the chair.
“I have a second opinion clinic, and one of the things that I find is practitioners have a negativism about lung cancer and particularly advanced NSCLC. With only so many hours in the day, [practitioners] have tended to focus their efforts more on adjuvant breast patients, patients who they deem as situations where they can have a substantial impact, but I really would like for practitioners to take home that by being knowledgeable about the management of lung cancer, you really can lead to substantial improvements in both longevity for your patients, but also their quality of life.”
In the interview, Garon discussed the key takeaways from the virtual meeting, which covered frontline immunotherapy in advanced NSCLC, adjuvant approaches,targeted approaches in ALK-positive and EGFR-mutant NSCLC, and the roles of systemic therapy for local disease and local treatment for systemic disease.
Garon: In many respects, the frontline approach to immunotherapy has become more complicated over time. There is an appreciation that in patients who have high PD-L1 expression, which is generally defined as being greater than 50%, that immunotherapy alone is a reasonable option. There are multiple approaches that can be taken in that group. One is single-agent therapy; pembrolizumab [Keytruda] was the first agent that was approved in this setting, but the PD-L1 inhibitor atezolizumab [Atezolizumab] is now also approved in this setting as is the PD-1 inhibitor cemiplimab-rwlc [Libtayo].
The one unique indication is patients who have PD-L1 expression between 1% and 49%; that is a population for which there is approval for frontline pembrolizumab alone, although the data as to whether patients should receive that vs whether they should receive chemotherapy-based approaches [are not very compelling]. There was a recent meta-analysis from the FDA where it was at least suggestive that for most patients—certainly those who are not particularly elderly— that chemoimmunotherapy would be a better approach for patients in the 1% to 49% [group] and for those above 50%. There is now an approval for nivolumab [Opdivo] plus ipilimumab [(Yervoy) as well], and how to use that data is still evolving.
There was a recent study of pembrolizumab plus ipilimumab, which was stopped early for futility in those who have high PD-L1 expression. We can’t completely extrapolate that to nivolumab plus ipilimumab or the outcomes in patients with 1% to 49% expression. To complicate things further, the combination of nivolumab and ipilimumab was associated with what appeared to be favorable outcomes in patients who have no PD-L1 expression. However, that was not part of the intent-to-treat analysis and that is not part of the FDA approval for the combination, although it is a potential approach based on data from the CheckMate 227 trial [NCT02477826]. The National Comprehensive Cancer Network does list that [combination] as a possibility, but it is not FDA approved.
Chemoimmunotherapy combinations are widely approved. The main combinations that are approved are chemotherapy plus pembrolizumab, chemotherapy and atezolizumab, and there also is an approval for chemotherapy along with nivolumab and ipilimumab. Although not approved, we have now seen positive data for the combination of chemotherapy and durvalumab [Imfinzi] plus tremelimumab. Tremelimumab, at this point is not an available drug, but we have seen positive data there.
There remains a significant question as to what exactly the role of CTLA-4 inhibition is, in general, when it has been shown to lead to improvement in outcomes over chemotherapy. It is not clear whether that effect is driven by the CTLA-4 inhibitor or whether it is sort of dragged along with the effects of the chemotherapy and the PD-1 or PD-L1 inhibitor. Some data sets indicate that maybe in patients with low PD-L1 expression that you would have more favorable outcomes by adding a CTLA-4 inhibitor. Some data would indicate that maybe as one looks out over the longer term, that the benefits of CTLA-4 play themselves out more, but it’s a little hard to know based on the available data.
A significant encroachment would be one way of describing radiation with advanced disease. Radiation has always played a significant role in lung cancer, initially sort of as a potential substitute for surgery. It also has a clear role with chemotherapy in locally advanced disease, now generally followed by immunotherapy. But there’s a clear push to incorporate radiation more into advanced disease. How this plays out, we will see over time.
We sort of have a difficulty right now in that we have data that from a radiation oncologist’s perspective strongly support radiation in the metastatic setting. On the other hand, from a medical oncologist’s perspective, this data is generally not exactly what we’re used to seeing––randomized studies of 50 or so patients that got shut down by the data safety and monitoring board. It is an interesting situation because the radiation oncologists look at us medical oncologists and don’t understand how we can’t accept this data, and medical oncologists look to radiation oncologists and can’t understand how they can blindly accept these data. Our hope is that further studies will be able to elucidate this further. The problem is, because particularly in the radiation community, the opinions are so firmly entrenched, those studies may be difficult over time.
The adjuvant setting is becoming a major place for more novel therapies. Adjuvant therapy in lung cancer to date has really been plagued by problems associated with the toxicity and limited efficacy of chemotherapy. Chemotherapy in the adjuvant setting is associated with a real but small benefit, and the regimens that have shown to be of benefit have substantial toxicity. Two data sets stand to change that. One of them is already approved, and that is adjuvant osimertinib [Tagrisso] for EGFR mutation–positive patients. This is a somewhat controversial data set in some respects. The question really is whether 3 years of osimertinib is just delaying disease and leading to the same eventual outcome vs whether it is impacting the overall status of the disease.
Dr Goldman has been very supportive of the idea that osimertinib is likely to confer a survival benefit. I have been a little more cautious in that assessment, but despite that, I have found that patients are very eager to take what is clearly an effective therapy. There, of course, are data sets with other EGFR inhibitors where a disease-free survival [DFS] benefit did not translate into an overall survival benefit. However, based on how profound the data is from the ADAURA study [NCT02511106] looking at osimertinib in the adjuvant setting, there is significant encouragement that there will be more benefits seen from this approach.
The other phase 3 trial, IMpower010 [NCT02486718], is looking at adjuvant atezolizumab. The trial looked at patients who have PD-L1 expression of 1% or greater and who have stage II or IIIA NSCLC. Atezolizumab did confer a statistically significant DFS benefit. It did not reach nearly the magnitude of what was seen with osimertinib, but unlike osimertinib, which was looking at a small, targeted population, in this case, it was a much broader population. *This is not an approved indication [for this agent] right now, but it does have the chance to potentially move immunotherapy up into earlier disease settings. There remains some debate though; in patients who were lymph node negative, the benefit was not so clear. Esven frankly, in patients who had PD-L1 expression of 1% to 49%, the data was not so clear.
When facing the question of whether to use adjuvant osimertinib, it’s a discussion with the patient. Outside of a trial in patients who have stage IA disease that we don’t really have any data there, you do see some creep of the usage of osimertinib into those cases. A patient whose focus is strongly on quality of life and that is really their major focus and is a little bit skeptical of taking a medicine for 3 years, you can tell them that we don’t know yet that that is associated with benefit. That hasn’t necessarily been my approach in general.
The other group that I would be disinclined from doing it would be in older patients. You sort of have to view these as actuarial decisions. There are now people in their early 90s undergoing surgery. When you start looking at people in that age group, knowing that osimertinib can be an effective therapy at the time of metastatic disease, it becomes a little bit less clear that that is a group of patients that would benefit from adjuvant osimertinib.
Dr Lisberg highlighted a lot of the ongoing work with amivantamab, which is an antibody directed against MET and EGFR. It is now approved but is approved only for patients with the rare EGFR exon 20 insertion mutation. There is an approval, but it is for a sort of niche indication. Studies are looking at the combination of amivantamab and lazertinib, a third-generation EGFR inhibitor. Those data have looked promising in a salvage setting after patients have received osimertinib. There’s also some interest in looking at that [combination] even as an initial therapy. The data have looked promising. Amivantamab is a little bit different as an antibody and has been associated with infusion reactions. Also, of course, a rash that is more typical of the EGFR antibodies that oncologists are used to using, more in the spaces like colorectal cancer and head and neck cancer. Those are also toxicities seen with amivantamab, but we are going to be seeing ongoing evaluation of that agent.
I don’t think we can say that mobocertinib, which is a TKI directed against EGFR, or amivantamab is a preferred agent in patients with exon 20 insertions. We will see how it plays out in the marketplace. There are advantages to both. It is more convenient to take an oral pill. Though, there are toxicities associated with that. The diarrhea has been real.
On the other hand, the efficacy data in cross-trial comparisons, which we are always caution against, make you wonder whether perhaps amivantamab should be preferred. But the infusion reactions are real; they can cause significant problems. In general, not disastrous medical problems, but it can be miserable to the patient who may feel like they’re dying. Those are going to be issues that practitioners weigh when trying to decide between these agents. In reality, it is very possible that patients will receive both agents.
We are seeing that the newer generation of ALK inhibitors are superior to crizotinib [Xalkori], at least for progression-free survival, and a lot of this is driven by what Dr Cummings talked about was the huge difference in efficacy in the brain. We’ve known for a long time that crizotinib is not a particularly effective agent in the brain, almost uniquely poor in terms of its brain penetration amongst our targeted agents. Newer agents are much better.
In the up-front setting, alectinib [Alecensa] and brigatinib [Alunbrig] are approved. There are also data indicating that lorlatinib [Lorbrena] can be used after progression on those agents, but also it could be used in the up-front setting. That has become sort of the debate currently in the field. In cross-trial comparisons, lorlatinib looks really good. The concern is that the toxicity profile compared with some of these other agents is somewhat greater. That is a conundrum that practitioners are facing right now.
I have typically used alectinib as my initial treatment option. With any treatment decision, we become comfortable with our treatment choice. I have had some difficulty from a toxicity perspective when I have given lorlatinib. Now, I must be cognizant that when I have used lorlatinib, it is in a group of patients that is more advanced than the patients who I have given alectinib to if I’m using alectinib as the initial frontline therapy. It is always possible that some of the things that I am sort of attributing to toxicity are really associated with more advanced disease. For all of us, our thinking will evolve on this question, as we become more comfortable with using the agents and start seeing more patients who, for instance, are receiving lorlatinib as their initial therapy and get a sense of what the toxicity profile is in that setting.
*Editor’s Note: This interview took place prior to the FDA approval of atezolizumab for use as an adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on 1% or more of tumor cells, as determined by an FDA-approved test.