Cancer Topics – Beyond Adjuvant Chemotherapy: Precision Oncology in Early-stage NSCLC
ASCO Education · 31 minutes ·

Cancer Topics – Beyond Adjuvant Chemotherapy: Precision Oncology in Early-stage NSCLC

Adjuvant immunotherapy is a game-changer for early lung cancer, but it is not the best choice for every patient. Hosted by Dr. Rami Manochakian (Mayo Clinic), Drs. Karen Kelly (University of California Davis) and Howard West (City of Hope Cancer Center) explore considerations in shared decision making and personalizing therapy through patient cases. 

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Air Date: 12/15/21





SPEAKER 1: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

RAMI MANOCHAKIAN: Hello, and welcome to ASCO Education Podcast on new therapies for lung cancer. My name is Dr. Rami Manochakian. I'm a thoracic medical oncologist at Mayo Clinic Florida.

Today, I have the pleasure to speak with two very well known, nationally and internationally, thoracic medical oncologists specializing in the fields of lung cancer. I have Dr. Karen Kelly, who is a professor of medicine and associate director for clinical research at the University of California Davis Comprehensive Cancer Center. And I am also joined by Dr. Jack West, who's a medical oncologist as well as associate clinical professor in medical oncology at the City of Hope Comprehensive Cancer Center.

In October of this year, the FDA approved atezolizumab for adjuvant treatment of stage II to IIIA non-small cell lung cancer following a resection and platinum-based chemotherapy. This is the first adjuvant immunotherapy approved for lung cancer and has the potential to improve cure rates. In this podcast episode, we'll discuss how to implement this new therapy in the care of real-world patients.

We're going to start the conversation today with a patient case. We have a 64-year-old woman who is a 15-pack-year smoking history, quit several years ago in the 1980s, and was found on a screening CT to have lung adenocarcinoma. She underwent a full workup that included a negative EBUS and ultimately underwent a surgical resection with right upper lobectomy.

Surgical pathology showed a 3.2-centimeter invasive adenocarcinoma with some additional lepidic noninvasive AIS, and two out of eight N1 nodes were positive. The final staging was a pT2aN1 stage IIB disease. She had a molecular testing that included NGS that showed an EGFR activating mutation in exon-- 21-L858R substitution with no other driver mutation. And PD-L1 was checked, and it was 2%.

And we'll start with the first questions. And I'll start with Dr. Kelly, and then we'll ask Dr. West also to give his opinion. Given the currently available treatment and the new approvals, all the research evidence and guidelines that we have as of now, 2021, how would you manage this patient?

KAREN KELLY: Well, I think that that is a great question. And of course, for this patient, who does have that EGFR L858R mutation, that is a very important finding to have. And I applaud the ability to get the NGS sequencing, because that is important here, for patients today, based upon ADAURA results, which was the randomized trial after resection for patients with early-stage disease who got chemo or not, randomized to osimertinib versus placebo.

And so I think for this patient with that EGFR mutation, my driver in my treatment plan after adjuvant chemotherapy-- and I do want to make that important distinction here that, even though ADAURA did allow patients to not have chemotherapy, we are strong believers in evidence-based medicine that has shown that adjuvant chemotherapy has improved survivals and cure rates in this patient population. So after, I would begin with giving adjuvant chemotherapy for four cycles, cisplatinum-based. And then, based upon ADAURA, offer this patient osimertinib.

I do not believe that this is a patient that would benefit from a immunotherapy regimen. And I'm going to let Dr. West talk about that component of this case-- that immunotherapy, I believe, would be contraindicated.

RAMI MANOCHAKIAN: Excellent. Dr. West?

JACK WEST: I would say that some in the audience may know that I've had some issues with the design of ADAURA and had been critical of it at the time of its release. And I think it is always a little challenging when we have disease-free survival results, but not overall survival in a curative setting, because I believe our goal here should be to improve survival. And it's not clear, particularly with a treatment that is still ongoing, whether this is really just forestalling progression and going to translate to a survival benefit. So that comes up with ADAURA.

But that said, we are now in a situation where we have a remarkable improvement in disease-free survival with ADAURA that gave the adjuvant osimertinib for patients with a tumor harboring an EGFR mutation. And we don't yet have mature data for overall survival. I think we need to work with what we have, and that is giving the patient the benefit of the doubt and presume, until we see otherwise, that the remarkable improvement in disease-free survival will, we hope, translate to an improvement in overall survival.

So certainly, for patients with node-positive disease, I would definitely favor at least offering, if not clearly recommending, osimertinib. I would talk about the caveats that we don't yet have overall survival, but I would say that, based on what we know, with the limitations, I would be encouraged and would favor that.

And the important challenge, I would say, is what to do when you have potentially competing options, like adjuvant immunotherapy, specifically-- now in FDA approval for adjuvant-- atezolizumab, based on IMpower010 results that we first saw at ASCO in 2021 and have learned more about. And the results are also very impressive for at least a subset of patients, specifically those with stage II to IIIA disease and who have PD-L1-positive disease.

I would note that, when looking at subset analysis of IMpower010, the benefit is much more impressive in the subset of patients whose tumor has PD-L1 expression in the high range, 50% or higher, where the hazard ratio for disease-free survival is 0.43. And in contrast, for the patients with low PD-L1, that hazard ratio for DFS is 0.87. And of course, we don't yet have overall survival for this trial either.

So I would say that there is, arguably, a question of what you would do if someone has PD-L1-positive disease and an EGFR mutation. But I would note that we have seen in advanced disease that patients with a driver mutation-- say, particularly, EGFR-- are overwhelmingly more likely to benefit from targeted therapy against EGFR than immunotherapy. And if anything, it seems that PD-L1 expression for patients with an EGFR mutation or an ALK rearrangement doesn't necessarily mean the same thing as it would for someone with wild-type disease. It just is not nearly as strongly predictive of benefit, and the benefit with targeted therapy is far greater.

RAMI MANOCHAKIAN: Thank you to both of you. Really, I think you brought both a great point. I like what Dr. West said about we need to give the benefit of the doubt. We need to deal with what we have, because right now we don't have the OS benefit, talking about, obviously, the ADAURA, or even the IMpower.

And discuss with patients. Discuss what we're doing. Include them in the treatment decision and plan, and tell them this is why we're considering this and not. It appears that everyone feels that this patient, obviously, would not be the best candidate for adjuvant atezolizumab. Rather, very possibly get an adjuvant targeted-therapy osimertinib.

Speaking about adjuvant atezolizumab, I want to ask, who else you would not recommend, maybe, adjuvant atezolizumab to? And I'll start with Dr. Kelly again.

KAREN KELLY: So I think that we have learned a lot about other driver mutations based upon what we know about EGFR. And EGFR really has been the prototype for all the other mutations. And pretty much, they align with the findings with EGFR, particularly those of ALK, ROS1, and then we get into RET. And we can also talk about HER2.

And I think the difference here, between that category and that group of oncogenic drivers, is that they're characterized by being in patients who are never smokers. And so in my opinion, this group of patients that have those additional mutations-- either ALK, RET, ROS1. I would say, also, HER2-- those never-smoking, oncogenic-driven aberrations, really, would probably fall, in my opinion, into the same category that I don't think that they would be the best for atezolizumab.

I also base that on retrospective data from the IMMUNOTARGET data that came out in advanced disease, with monotherapy looking at a retrospective large series, multi-institutional, that showed that there really wasn't a benefit for mono-immunotherapy.

Now, I will say that, of course, we do have oncogenes that are smoking-related-- that being KRAS G12C, now, remembering that not all KRAS are smoking-related. But something like KRAS G12C. BRAF, typically, as well. Half of the MET oncogenes are in patients who are smokers. So I think if you're a smoker and you have an oncogene, then I think that it would be reasonable.

Again, based upon retrospective data-- I would say even based upon my own data from California-- we have found similar results. Even when you give immunotherapy with chemotherapy in patients with oncogenic drivers, they just don't have a benefit from immunotherapy. And I think we can logically make sense of that. They are more simplistic tumors. They don't have high tumor mutational burden. They don't have high PD-L1, for the most part. They're typically more characterized as being cold.

So I think it does make sense that this group of oncogenic-driven cancers, particularly those in never-smokers are really more cold tumors and don't respond. So I would add these others to the list that we do have data on, and that, of course, is EGFR.

RAMI MANOCHAKIAN: Dr. West, your thought? Especially, it looks like we're heading one way or the other to say that every patient with early-stage needs NGS testing.

JACK WEST: I think that we are in a challenging place where the principles are ahead of the actual data that we have. I think that we have been struggling with this for a few years now with things like the PACIFIC trial, where we've had very impressive data for not just disease-free survival, but now overall survival. But that was a pretty broad, inclusive population. It included patients with an EGFR mutation, ALK rearrangement, and didn't really specify otherwise.

And so the question is, do we broadly interpret that, well, if they were eligible for the trial and the trial is positive, they should be treated this way? Or do we make, I think, very logical inferences from stage IV disease that not only do these patients often not seem to benefit at all from immunotherapy, but that we could put ourselves in the challenging situation of giving immunotherapy and then having their cancer progress, and needing to give them a targeted therapy where there could be a harmful interaction between the osimertinib that we want to start and the immunotherapy that is still in their bloodstream?

And so that's a real challenge. So I think that we need to, now, do some extrapolation. And because of that, it does make sense to want to have this information to individualize the recommendations for the patient. And it's not a big leap, based on what we know about ALK, to presume that these patients are not going to be big beneficiaries or, likely, beneficiaries at all from immunotherapy.

I agree with Dr. Kelly about ROS1 and some of the other never-smoking-related driver mutations. I think it is important to say that we shouldn't paint all driver mutations with the same brush. We have seen from IMMUNOTARGET that KRAS and BRAF are not in the same category, and so we need to think of these individually. But I do believe that this information is going to be really helpful to make an informed, thoughtful decision for the individual patient in the exam room with us about whether they personally are likely to be beneficiaries of immunotherapy, targeted therapy, or whether they should withhold all of those.

KAREN KELLY: Can I make one additional statement? I just want to add to what Dr. West said, particularly raising awareness about the harm factor. I think, as physicians, we're very focused on wanting to help the patients in terms of, when we look at these biomarkers, let's look at them and give you what works for them. But we have to remember now, with the oncogenic drivers, that we can potentially harm them if we give them immunotherapy.

So I think we have to remember, now, the harm factor really comes to the forefront when we talk about immunotherapy and oncogenic drivers and the critical importance of knowing. Yes, we want to know if we can give osimertinib to those patients who are EGFR-positive. But in the same breath, we want to say, oh, immunotherapy would be harmful. So I think that's a little bit of a switch that we have to, as physicians, remember to have that really important conversation about why we don't want to give them immunotherapy.

I will say, many of my patients with EGFR or ALK or ROS-- they come in, and they want immunotherapy. And you really have to spend time explaining to them why they are not the best candidates for immunotherapy.

RAMI MANOCHAKIAN: Great point, great point.

And just one very quick question before I move two Case 2. Are you both testing for NGS for every early-stage cancer patient that comes to your clinic?

JACK WEST: I'll say that I would be most inclined to do that for a patient where it's likely to have an impact in the more immediate future. I would not say that I feel that this is a mandate for someone with a less-than-2-centimeter nodule, node-negative disease. You can argue that it would be nice to have this information at the time of relapse. But I think that, in general, you'd want to biopsy to confirm progression, relapse, disease, and the most important biology is what it is at the time of relapse and not what was resected two years earlier.

So to me, if it is potentially going to have ramifications for immediate management, so certainly for a node-positive cancer, I would say so. I think it's debatable about whether to do this in someone who has a significant smoking history and a squamous cancer, because the pre-test probability is not high. So I don't want to be too heavy-handed about that, but I would say it makes a lot of sense to think and act beyond the narrow indications that we have now just for looking at EGFR as well as PD-L1.

KAREN KELLY: Yes, I think to the point of harm. I think that we do need to be doing NGS testing in these patients that, I would say, meet the eligibility criteria from the 010 trial, in terms of adenocarcinoma.

I do agree with Jack that a small 2-centimeter tumor-- I wouldn't be checking that. But if you meet the eligibility requirements, and you're thinking along those lines for that patient, then I definitely would do the NGS, not only-- as I said, because you don't really want to harm a patient. If you don't know that they have RET or ROS, you could potentially harm them if you gave them immunotherapy. So I think that is my point. We've got to remember. Now we have to think about helping our patients, but also not harming the patients.

RAMI MANOCHAKIAN: Excellent. Thank you.

I'm going to move on to Case 2 briefly. This is more of a case of a patient that is a good representative of a patient who meet the eligibility for the IMpower trial that led to the approval of atezo. 71-year-old male who presented with chest pain. Workup showed a mass, a 4-centimeter left-lower-lung mass. A full workup, including PET and EBUS showed that lymph nodes were negative.

Also underwent left-lower lobectomy, and his staging was stage IIB, T2b, N1, with two hilar lymph node were positive. So again, very similar to the first case. A little just different size. NGS testing here did not reveal an actionable mutation, and PD-L1 was high, at a 60%.

So simple question, Dr. Kelly. Is this patient a candidate for adjuvant atezo? What benefit would you expect to see? I know we touched base on it a little bit in the first case. And then, how would you talk to your patient about potential side effects?

KAREN KELLY: So I think that this is the ideal patient for adjuvant atezolizumab, based, of course, on that very high PD-L1 of greater than 50%. That's where the data and the driver of the positive results really came from with that hazard ratio of 0.43. Remember that, in the subset analysis of the 1 to 49, the hazard ratio was 0.8 or higher. So it was really driven by the high PD-L1 status. So I think that this is a perfect patient to receive the adjuvant atezolizumab.

When I talk to patients about side effects, I begin always with saying that we now have enormous data points about the side effects of all of the immunotherapy drugs, based upon stage III disease and stage IV disease and other diseases. And these agents are, overall, well tolerated, but they do have some risk of serious side effects that are related to inflammatory signs and symptoms.

And so I do think that it's important to have a discussion about what I just group as "itises" that patients can really have. Any "itis" can occur. But the seriousness is, really, anywhere between 3% and 10% of that.

And the other thing that I'm very vigilant about with the patients is that-- I remind them that these side effects can occur at any point in time while you are on the drug, and then through several months after you've stopped the drug. So I think that that's really important to be very vigilant. It's a very different approach than chemotherapy, where we really have a great understanding of exactly when those nadirs are. So I spend time making sure-- and every time I see the patient, going over that whole list again to make sure-- that they are doing well.

So that's really how I approach a patient. And of course, make sure that they have a good understanding of those side effects.

RAMI MANOCHAKIAN: Thank you, Dr. Kelly.

Dr. West, do you agree that this patient is the ideal candidate for atezolizumab and you would offer that?

JACK WEST: I would. And I would say that it's a slightly different situation from why ADAURA is compelling to me. And I would say that ADAURA is most compelling despite the limitations in DFS being assessed in the middle of ongoing EGFR-inhibitor therapy. Here, we don't have a hazard ratio of 0.12 or 0.17 or something like we did in ADAURA.

But it is certainly impressive, certainly for the high-PD-L1 subgroup. And this is in patients who have completed their therapy in the past, and the benefit is sustained.

We also know from the mechanism of action over years of treating patients with advanced disease with targeted therapies and immunotherapy that immunotherapy can have remarkably sustained benefit, even after patients stop it. And so it's not hard to envision that patients will have a time-limited course of immunotherapy and still have very sustained, potentially permanent benefit from it. So I am impressed by the improvement in disease-free survival, even if it isn't of the same magnitude as what we saw with ADAURA, because it is being measured after patients have completed that therapy, and in particular for the patients with high PD-L1.

I do think that we need to be very thoughtful about whether patients in the 1% to 49% group are likely to benefit, in terms of overall survival, because we don't yet have overall survival data. The hazard ratio for disease-free survival is 0.87 here. And we've talked about the risks with immunotherapy are not generally catastrophic, but a lot of patients will have somewhat modest but sustained issues with thyroid problems, et cetera.

And this is the adjuvant setting. Patients may already be cured, and you're talking about an additional year of coming into the clinic for therapy. That is very costly and can have toxicities that I wouldn't want to minimize. So for me, personally, I would say it is quite compelling for those with high PD-L1. It's something to discuss for somebody with low PD-L1 in the 1% to 49% range, but not something that I would consider nearly as striking a benefit.

It does seem to me, from the subset analysis, that much more of the benefit of immunotherapy is limited to those with high PD-L1.


So in conclusion, if I ask each one of you, please, to give a word of advice for oncology providers regarding the implementation of adjuvant atezolizumab into routine care today-- and also, of course, we know this field is evolving in a very great and promising way. What are you envisioning in the near future will bring for patients with early-stage lung cancer and, of course, could change what we're talking about today?

Dr. Kelly?

KAREN KELLY: So first of all, I think adjuvant atezolizumab is a significant advance in the field of adjuvant therapy for lung cancer. Remember, we have not had an advance in many, many, many years. And in the subset of patients, particularly those with high PD-L1, I think the data is impressive.

To Dr. West's point about the 1 to 49, I do agree that we have to be careful, but we need more data. And I think that is where having the results of the other trials will be very, very helpful.

Now, we all know that PD-L1 is really a gradient. And so I do want to say that we can't just focus on one parameter from these trials. We do that, particularly, I think-- the PD-L1s greater than 50% with a hazard ratio of 0.43, a solid number there-- that works. But when you're at 45 or 40 or 30, you really need to take into consideration other patient characteristics and other factors in making those decisions. And of course, that's a shared decision with the patient as well.

So I think it's important to remember there are other factors that we all synthesize when we're talking to a patient and trying to make the best recommendation. So that's the art of medicine, is taking the science and putting it together to really help that patient that is sitting in front of you.

So nonetheless, this is an advance. And remember, this is how we started with stage IV disease. So I really do think, to Dr. West's point about the fact that these patients, after a year, are having this really impressive disease-free survival, we're very optimistic that that will translate into cures.

Now, I want to be clear here that overall survival doesn't mean cure. But again, if we look at cure fraction, I think we will see that with immunotherapy, because we are seeing that. And I know Dr. West and you also probably have cases where you're pretty confident that you've probably cured those patients with stage IV disease. We see that in a very silent way.


JACK WEST: I really agree. I have been commenting recently, reflecting that we have been pretty reluctant to say the C word, say "cure" for patients who have phenomenal unprecedented results with immunotherapy for stage IV disease, I think, based on our tenets that it's categorically not curable. But I think that immunotherapy has changed everything, and the rules are different.

I would say that the IMpowere010 trial is very important, does change practice, should change practice, and is just the beginning for introducing immunotherapy into the early-stage setting. There are many other trials coming, looking at immunotherapy.

In the adjuvant setting, we have seen very provocative data for neoadjuvant, which I think is also quite compelling and has the advantage of giving you more feedback about how your treatment actually worked. You're not treating blind. I think that in the next three to five years, we will have multiple different strategies, options to choose and that it's going to be a real quantum leap in how we translate some of the benefits that we have enjoyed in stage IV disease into earlier-stage disease to translate to better overall survival.

I think that we will begin to see that for some of these earlier trials, and so we will be able to talk not just about disease-free survival, but overall survival. We will be talking about this for immunotherapy and targeted therapies. And so just like it's been about 15 years since everything changed in the adjuvant setting with chemotherapy, this is the next iteration of that, where we are working on how best to refine our strategies in a more individualized way than chemo for everybody, but to personalize the optimal perioperative treatment strategy for the patient's individual cancer characteristics.

RAMI MANOCHAKIAN: Thank you. Thank you very much to both of you. I don't think we could have ended on a better note. It's definitely a hopeful era for patients with lung cancer. With all the recent advancements and research, I think our patients are living longer, living better. We still have a long way to go and, hopefully, more to happen in this field where we're able to offer our patients some personalized treatment depending on so many different factors.

This is all we have for today. I'd like to thank very deeply Drs. Kelly and West for a great conversation and for sharing their insight and expertise. Thank you to all our listeners. Thank you to our wonderful ASCO staff, and hopefully, for more ASCO Education Podcast to keep covering this topic of lung cancer.


Thank you all.

JACK WEST: Thanks for the opportunity.


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