Similarities and differences in the efficacy of neoadjuvant and adjuvant immunotherapies for localized non-small cell lung cancer (NSCLC) 

DR LOVE: Welcome to Oncology Today, optimal management of localized non-small cell lung cancer. This is medical oncologist Dr Neil Love. For this program, I met with Dr Heather Wakelee from Stanford University. In addition to this interview, there is also a corresponding presentation featuring Dr Wakelee’s slides. To begin, I asked her to discuss the two major adjuvant trials currently available, IMpower010 evaluating atezolizumab, and KEYNOTE-091 evaluating pembrolizumab.

DR WAKELEE: I think when we look at the overall results from both trials, when you look at the intention-to-treat patient populations, so that’s the Ib, Stage II, Stage IIIa, and both trials it was just over 10% Stage I, majority Stage II, maybe 40 — 30- to 40% Stage IIIa. That was true in both of those trials. When you look at all-comers, regardless of PD-L1 expression, the disease-free survival hazard ratios were really quite similar, .76 in KEYNOTE-091, .81 in the IMpower010, though, again, with that one, that final endpoint we couldn’t say statistically clearly one way or the other. But it’s going to be around that. So those numbers are pretty close to each other.

And so, I wouldn’t say that one is more or less positive than each other in that all-comer patient population when we were kind of boringly figuring out who do we think it’s going to help. The big difference is in the biomarker analyses. So in the IMpower010, we’re able to really clearly show that the PD-L1 level mattered a lot and the patients who really benefited were those with the highest PD-L1 expression on their tumors. And in that group, with the greater than 50%, there, that’s where we had this dramatic DFS and OS benefit. Again, you have to be careful to not “statistically” yet because of the way it was designed. So I don’t want to over-speak on that. But then with the KEYNOTE-091, at least what we’ve seen so far, we don’t have those clear biomarkers. There’s no way to select who are that 25% or so who are benefitting? Who is that quarter of patients who are benefiting versus everybody else? We can say that for one trial; not for the other. That’s the difference.

And that’s where it’s really confusing because in the metastatic setting the PD-L1 expression is really a critical biomarker for pembrolizumab. With atezolizumab, it's not been as important. And so we’re now in the opposite situation and I think that’s where everybody’s confused. We also need to be mindful that with the CheckMate study of neoadjuvant, there the PD-L1 matters. Pretty much all of our trials in the perioperative setting, PD-L1 has been important. But we haven’t seen all the results yet. So, as you said, it’s a confusing landscape. We like it when every trial has the same story and then we feel like we know the truth. Here the truth is still murky for PD-L1.

DR LOVE: And you see this issue throughout oncology now, lumping or splitting, in general, all kinds of subsets, but particularly the PD-1 studies. They’re so difficult to figure out. Sometimes I think about we’re so into biomarkers, I wonder what would happen if we hadn’t tested any of this stuff at all. It sounds like these two trials would probably have had similar results. They would have been moderately successful. The survival looks pretty encouraging. And maybe just everybody would get treated and we wouldn’t try to figure all this stuff out. I just worry that maybe — I know the assays the different. I know there’s the issue of treating people unnecessarily, but I mean these people have pretty bad recurrences and recurrence rates, to me. Like, you compare that to say breast cancer or something.

Anyhow, it’s confusing I guess for everybody in terms of who should not get treated, really.

DR WAKELEE: You’re bringing up really good points. When we look at Stage Ib though, compared to breast cancer, we’re not great but we are curing the majority of patients, right. When you look at Stage II it’s with chemotherapy, again the majority of patients is small, majority of patients who are cured just with chemo and surgery. When you look at Stage III, it’s the minority of patients and I think that’s the group that really needs that benefit.

I think many of us are, in that subgroup, now looking at neoadjuvant chemo and immune checkpoint inhibitors because the data from the CheckMate 816 with neoadjuvant approach looks in some ways better. We have more mature data we can clearly say overall survival. When you look at those hazard ratios they’re impressive. So in that group I think for Stage III, yeah, you’re going to treat them so why bother looking at those different PD-L1 levels. You can just give it to them ahead of time. But yet, there’s still some patients who aren’t helped. And when we look toxicity from checkpoint inhibitors, most of the time its measured, it’s tolerable, but there are very few patients I have in the metastatic setting where I would say they’ve really never had any toxicity from checkpoint inhibitor. There’s a lot of dermatological toxicities and those can be long-term issues. There’s a lot of hypothyroidism and other endocrinopathies which can be lifetime issues.

And so from a patient perspective, yeah, I’d really like to be cured of my cancer, if I end up getting cancer, but I’d prefer to be cured and not have to deal with some long-term chronic issue because of the treatment, which I maybe didn’t need. So I do think it’s important for us as a community to do that additional analyses, to try to figure out how do we know who’s really helped and who isn’t.

I mean look at the EGFR story. When that first broke, and we didn’t know about the EGFR mutations. You could argue well, just give it to everybody, and yet it’s really only that 10% who have an EGFR mutation who we’re helping at all and we’re not helping anybody else. And there’s probably biomarkers, and PD-L1 is the best we have, though it’s very flawed, would help us figure out who are we helping and who are we not helping. So I’m going to push back a little on your theory there.

DR LOVE: No, I mean it’s not really so much a theory, it’s just trying to grasp what’s really going on here, particularly from the point of view of a patient. Because, also, if you’re going to make somebody uncomfortable or have a rash or whatever in the 1 year maybe that they have to feel good before they relapse, that’s worth doing.

Available data on the treatment of patients whose disease relapses on or after adjuvant immunotherapy

DR LOVE: Let me ask you another question. What about treatment of patients who are getting adjuvant IOs and then relapse? Any trials out there? Anti-CTLA-4 plus PD-1 of any interest? For practical, retreatment with IO? I don’t know. How do you think the whole of that through?

DR WAKELEE: That’s a great question. So I’m going to step back from that. I think where we do have data is with adjuvant EGFR-TKIs. So, we don’t have that with osimertinib yet. But with some of the earlier trials that used erlotinib, we know that after it was stopped there were patients who recurred, but then when you rechallenge them, they responded. And so I think with EGFR… With TKIs in general, if you stop and then they recur, I think there’s good data you can restart.

With immune therapy, you have to wonder, okay, well, we don’t have a perfect biomarker. We don’t know if this is a patient who’s going to benefit or not. They’ve recurred. But I think, in general, I would use a checkpoint inhibitor in a patient where there wasn’t a contraindication to do so. And I would do it with chemotherapy because we know that the responses are higher with that combination. I still really think in the adjuvant setting we need to be looking at the combination chemo plus IO as opposed to the sequential approach that we did in the first trials. But at recurrence, I would definitely think about a checkpoint inhibitor plus immune therapy in a patient. I guess if they recur while they’re on it, and I’ve had a couple of patients in that setting I’ve done that. I’ve given them chemo plus IO, and I’ve done that partly because in the metastatic setting I have patients who they’ve been on chemo plus IO, they’re cancer starts to come back, you readd the chemo and they’ve responded again some of them. And so, I do think there’s something special about that combination. And so that’s what I’ve done in that setting.

Is there data yet? Is there a trial? I’m not familiar with one yet, but I think that’s the real practical question we’re all going to be facing.

DR LOVE: What about anti-CTLA-4?

DR WAKELEE: So anti-CTLA-4 in the metastatic setting, we’ve certainly seen — we had CheckMate 227 and others, where that is definitely a reasonable combination, CheckMate 9LA. I haven’t done it as much and part of that’s just my patient population. I have a lot of patients who have driver mutations where I don’t think that’s the best approach. But if a patient were to recur, who’d already had adjuvant single-agent checkpoint inhibitor, and I had to choose between chemo plus IO or IO/IO with CTLA-4, I think that would be reasonable, nivolumab/ipilimumab would certainly be a reasonable first-line choice. I don’t know that we’ve got any reason to think it’s a better choice than at any other time, but it’s a very reasonable option for them.

DR LOVE: Incidentally, I’m curious, there was a study out there looking at tremelimumab and durvalumab. Any interest in that? Do you think that’s going anywhere? Does that look to you like ipi/nivo or not as good as ipi/nivo? What are your thoughts about that?

DR WAKELEE: Yeah, that’s hard. There were some updates looking at specific subsets, looking at like KEAP1 and other mutations. And it wasn’t really clear to me that that was any better. I mean if you look at the trial overall, compared to the nivo/ipi studies, it hasn’t been as promising. Is that really because the drugs are that different, or is just not every trial is positive? I don’t know that we can really say that one way or the other. I don’t see a reason to necessarily pursue that. I mean when I’m thinking about combined CTLA-4 and PD-1, I’m using nivolumab/ipilimumab just because I’m used to it. But I think we’re still struggling in better figuring out who benefits from combined IO/IO and who doesn’t. The biomarkers were all over the place in all of those trials so far trying to be able to select who’s really helped.

Activity of immunotherapy in patients whose tumors are EGFR mutated

DR LOVE: So another issue that came out when you reviewed the data was the issue of patients with EGFR tumor mutations. You saw benefit in IMpower and they saw a benefit with KEYNOTE also, and yet it kind of seems you’re thinking that that’s maybe a statistical quirk? I guess you’re a deep believer that it just doesn’t help these people at any stage?

DR WAKELEE: I’m going to clarify then, because that’s not actually what I think. I think we just don’t know yet. It’s confusing. Again, we have to extrapolate. So in the metastatic setting, we know that if a patient has an EGFR mutation and has PD-L1 expression, there’s 10- to 15% of them who actually benefit a lot from an immune checkpoint inhibitor and I’ve had patients in my practice who’ve I given the single-agent checkpoint inhibitor in that setting who’ve done really, really well.

So it’s not that no patient with EGFR benefits from checkpoint inhibitor. That’s not the messaging. I think it’s some patients. It’s a smaller group. And why are they seeming to have more benefit when we’re giving these drugs in the adjuvant setting? I don’t know. But you’ve got 2 trials now, not just 1, so that makes you think it’s not just a fluke. It’ll be interesting to see as we get more trials out there. And we’re going to need to deep-dive as to, well, which of these patients are the ones benefitting? Is it just those who have high PD-L1 in the setting of EGFR? Is it something else? And if it turns out that that’s the truth, and that those patients actually get a survival benefit, and if in ADAURA with osimertinib we don’t see a survival benefit – we don’t know this yet, right — then maybe some patients with EGFR mutations are actually better off getting immune checkpoint inhibitors and not osimertinib. I think it’s too early to say that. My standard practice is still to give adjuvant osimertinib if there’s an EGFR mutation. But I think we really need to explore that question as to, again, what’s the best treatment for each patient? And maybe it is going to be a checkpoint inhibitor.

With ALK, it’s a totally different story. I never give checkpoint inhibitors to patients with ALK translocations or ROS. And I think it’s important for people to check and not do that because they will recur and then you’ve given a checkpoint inhibitor and you want to give a TKI, you can get into a lot of toxicity issues.

DR LOVE: Recently, I’ve been kind of saying a lot that I don’t know whether I have a bad memory and I’m just not remembering stuff, or whether I’m really hearing important things for the first time. But you just said something, and I’m pretty sure I haven’t heard, although maybe I have and forgot it, but I’m doing a webinar later today with Lecia Sequist, I’m going to ask her this exact question because I don’t remember anybody saying that. I just want to clarify. I think you said that you’ve had patients with high PD-1 levels and EGFR tumor mutations where you’ve given IO alone and seen really good responses. I understand it’s uncommon. But it’s happened.

DR WAKELEE: Yes, it has happened. And actually, we have data. So the ATLANTIC trial was the only — Marina Garassino did a presentation where they looked at the patients who had been on the trial, durvalumab, and they looked at those where the PD-L1 expression was high, it was 25% was their threshold, and in that group there was a 15% response rate, maybe 12, 12- to 15% response rate for single-agent IO in that setting of EGFR. And anyone who treats enough patients with EGFR mutation will see some of these folks and will have seen benefit.

It's a little bit more when it’s the L858R EGFR mutation as opposed to deletion 19. There was actually some data that came out of Taiwan where they’re slightly different, and definitely are patients who have that response. It’s not my first-line choice for them, but it’s something I will consider later down the road in that setting. And I definitely have patients who’ve done well.

DR LOVE: Well, I’m going to actually ask this as a question to the entire webinar audience and I predict less than 20% of the people will know that or believe that. So I think that’s really interesting.

Case: A woman in her mid 70s with EGFR-mutated NSCLC in her right lung

DR LOVE: Why don’t we talk a little bit about your cases.

So this first case, this 75-year-old woman, how long ago did you first see her? And maybe you can talk a little bit about what happened?

DR WAKELEE: Just saw her last week.

So this is a patient who came to our Tumor Board, actually. She had hip pain and was going to get a hip replacement. And so she got a chest x-ray and unfortunately, it showed a mass in her right lung. So she underwent rest of the work-up and it was really just this mass, which biopsy showed it was EGFR-mutated non-small cell lung cancer, exon 19 deletion. And we actually ended up giving her some — well, she went to surgery. We did give her a little bit of neoadjuvant osimertinib to just sort of shrink things a little bit first — I didn’t put that into the case. We will do that sometimes. I won’t ever do that in the setting where the surgeons have said “this is not operable” because even though cancers can shrink in the neoadjuvant setting, they never shrink in a way which makes the surgery easier. They’re always going to shrink into the mediastinum as opposed to away from it. So she looked operable, but we wanted to just get a little bit ahead. And then she went to surgery and did really, really well with that. We then put her on post-operative osimertinib.

She then actually had her hip replaced after she’d been osimertinib for a little while and had recovered adequately from her lung cancer surgery.

At this point, she’s doing really well. It’s been 2-1/2 years, so we’re approaching the 3-year mark. And we’re starting to talk about do we stop or not stop. She had Stage II disease to begin with. We’re approach the 3-year mark. She’s a little nervous about stopping. We ended up not giving her any chemotherapy just because of her age and it was Stage II — actually, sorry — she did have Stage IIIa because there was a little bit of microscopic focus in Level 7. She’s living a great life. She hasn’t really had much toxicity. She has a little bit of a mild rash. She hasn’t had any evidence of recurrence if we continue to scan her on a pretty regular basis. And so this is a tough question. She’s 75. Maybe she’s got another decade. Maybe she’s got a little bit longer. She feels great. She doesn’t have any cancer, evidence of recurrence. She was at high risk of recurrence to begin with. And so we’re facing this dilemma of when we do stop or not. But we still have 6 months and more ADAURA data coming out before we have to make a decision.

DR LOVE: And she’s totally, no symptoms, no side effects at all?

DR WAKELEE: Well, I mean she’s had occasionally a little of rash but not too much. And she thinks that with certain foods she gets a little bit of diarrhea at times, but it’s not bothersome to her. So, no. I mean she’s really living quite well.

DR LOVE: Actually, I was just flashing on a question that we have for this afternoon’s webinar with Lecia, which is, what do you about osimertinib in patients having surgery? Do you stop it before? Do you continue during? After? What do you do? And also, radiation?

DR WAKELEE: Great question. So for surgery, I usually have them stop it like the day before and don’t take it the day of. And then restart it just within a few days after. I think in patients with metastatic disease, you can get a flare; it’s rare, it’s less than 10% of patients. But there are some patients where when you stop the drug their cancer cells are just still so sensitive to that suppression that you can get flare, especially if it’s bone, so get bone pain and other problems. So I try to minimize time off drug in the post-operative setting. And really haven’t seen much issues. Same with cataract surgery. That’s what seems to come up the most commonly because just a lot of people need cataract surgery.

I think for radiation, if we’re dong radiation to the thorax, I will hold drug on the day, like the night before their getting it and the day of, because you can get some pneumonitis flare and you’ve got to be really careful with that.

For the brain, there is mixed literature on giving osimertinib in the setting of whole brain radiation. Some of the trials saying on problem; others say more toxicity. I try to avoid whole brain radiation; so this doesn’t come up too often. But I will usually hold it. Sometimes we’ll do this, if they’re getting radiation 5 days a week, I’ll give the drug like Friday night/Saturday night, but not Sunday night because they’re going to get radiation again on Monday. We don’t really know. So we all sort of do these different things, but there’s not great literature.

DR LOVE: So, before we go onto the next case, I’ll just note in the art of thoracic oncology here, even though when I read this case it looked like a great case but pretty straightforward. But then those other little two things you put there I thought were kind of interesting. I was already thinking why don’t you give her pre-op. There was a trial that was trying to do that and they couldn’t accrue people. And then I see now there’s a nother trial. I always thought that made sense to either shrink it down before surgery or shrink it down before chemo/radiation. And it was interesting that you kind of touched her up there a little bit. And then the other thing was you didn’t give her chemo. Huh?

DR WAKELEE: Right, in this case we talked about it. But she was really suffering a lot from her hip issue at the time and just really didn’t feel up to the chemo. So we didn’t do that. And I will add one of the, I think, advantages to giving neoadjuvant osimertinib in a patient like this where it’s — we thought it was going to be a Stage II, it ended up being Stage IIIa because there were just teeny, little focus in Level 7 — but some of these patients have occult bone metastases and when you start them on osimertinib they have a really good response, but they also started having a response in the bone and you can see it. And so, a lot of these patients really do have metastatic disease you just haven’t seen. And so that’s one of the benefits to sort of start, you make sure there’s really no other metastatic disease, and then you can think about going ahead to that surgery. But knowing that that’s not the definitive end of their care, it’s just sort of that step before they go to the definitive surgery.

DR LOVE: Yeah, that’s a really interesting idea. When you say “you see it” what, you have calcification in the bone or what?

DR WAKELEE: Yeah, sclerosis. Yeah.

DR LOVE: Wow! Interesting.

Oh, one other thing I was going to ask you about related to this no chemo issue. Am I correct in saying that there’s a trial looking osi versus nothing with no chemo in Stage Ib or Stage I?

DR WAKELEE: There might be. I am not involved in it.

DR LOVE: I don’t know if I’ve heard about it or dreamed about it or whatever. But do you think it’s a good idea? I think there’s a trial. But what about the idea, I mean you can’t really do it very well unless it would be I guess older patients who are not candidates for chemo or whatever. But the Ib’s seem like you could do osi versus nothing. And also, what about atezo versus nothing in Ib’s, or IO versus nothing in Ib’s?

DR WAKELEE: So I think we’re probably going to extrapolate from the data that we have. With ADAURA, there were patients with Stage Ib, not a big group, but enough to really look at, and less benefit there but not no. So it becomes an individual discussion and I think it would be hard to enroll.

I think with both KEYNOTE-091 and the IMpower010, just 10- to 15% of patients were Stage Ib. And at least for IMpower, we can’t really definitively look at that group yet because we haven’t had enough events, but we are going to do a deep-dive into well, what about those with different levels of PD-L1 expression? And is this the right approach? With KEYNOTE-091, at this point most of the data is kind of putting everybody together, but showing that the Stage I patients, if anything, were benefiting more than the Stage III, which, again, was another head scratching result from that trial. But I don’t think we’re going to do too many.

I think where there will be more, and we actually have a trial looking at this also, is utilizing the super sensitive ctDNA and maybe figuring out, well, if you do detect ctDNA with the super sensitive assays in the Stage Ib patient where you know that they’re more likely to recur, can you do things in that setting and other stages to prevent that from coming back? Can you make it go away I guess is really the question? And I think that’s where we’re heading more so than doing trials that are just exclusively to Stage I.

DR LOVE: Yeah, that’s a great though. You hear a lot about ctDNA.

Case: A woman in her early 60s with a smoking history and a 4-cm right lower lobe lesion

DR LOVE: How about this second case, the 60-year-old woman.

DR WAKELEE: So this is a 60-year-old woman with a smoking history. She smoked 40 pack-years. She had dyspnea. She was seen and had a chest x-ray which had a 4-cm right lower lobe lesion. She probably should have gotten in for cancer screening before that but she hadn’t. So a 4-cm mass in the right lower lobe. She had a PET scan. Showed uptake in this mass. Also, the right hilum and in s paratracheal lymph node.

Brain MRI was negative. Biopsy showed it was squamous cell histology and PD-L1 of 10%.

She got neoadjuvant platinum/gemcitabine. This was before we had the CheckMate 816, so she didn’t get nivolumab. This is someone I would have given nivolumab to in combination with chemo. She completed her 3 cycles. And mass was resected. It shrunk a little bit, but the paratracheal node was still positive.

And, again, this was before we had all of the adjuvant data, I think. This is someone where if she had come into my practice today we would talk about whether or not to give adjuvant atezolizumab. It would have been a hard one because it’s squamous and we know that that group didn’t benefit as much. PD-L1 level is 10%. So, is there benefit or not? I think we’re still in that maybe zone. So it would be a long conversation. It’s not a definite I would treat this patient, but it’s not a definite a wouldn’t either. So it’s a tough one. This is still a lot of patients where we don’t have clear data yet.

Anyway, in this particular one, she unfortunately did recur at 18 months with a pleural effusion. And so she’s gotten carboplatin/paclitaxel and pembrolizumab and actually had some response. She has some neuropathy, and, unfortunately, developed dermatomyositis. But is hanging in there right now. We ended up taking a little break from her immune therapy. She’d gotten through all of the chemotherapy and was just on the pembrolizumab maintenance when the dermatomyositis kind of flared. So we’re holding it for a little bit and watching her at this time.

DR LOVE: Not that it doesn’t make sense, but I’m not sure I’ve heard about a case of IO-related dermatomyositis. Have you seen other cases?

DR WAKELEE: Uh-uh. Yeah, I have. I have seen a couple.

DR LOVE: Hmm. And did it get better? What, you gave the patient steroids and held it?

DR WAKELEE: Yeah, and I work with the dermatologists as well when this is happening and our rheumatologists. So we have a pretty active group of folks interested in immune-related adverse events across a lot of the subspecialities of medicine. And I think it’s really important. Those connections are critical because I don’t remember how to treat dermatomyositis. I have to call them up and work with them to get the right mixture of medications. Because for me, I just start them on steroids. It helps, but you don’t want to leave people on long-term steroids.

DR LOVE: Sure. I mean is the patient getting better?

DR WAKELEE: Yeah, yeah. The dermatomyositis is better. And at this point, we’re just watching. She had a good response, but I don’t think she’s going to be one of that 20% where the disease never comes back. And I’ve had others. Had one last week where she actually decided to stop for a while. And a little bit concerning on her most recent CT. So then you always have that question of well, how much is it going to flare when you restart? But on this one, we’re still waiting and hoping she doesn’t recur.

Case: A man in his mid 50s with a smoking history and a left upper lobe mass with high PD-L1 expression

DR LOVE: All right. Let’s go to the next case, the last case you have there.

DR WAKELEE: So the third one, this is a 55-year-old man. He has a 45 pack-year smoking history. And he actually showed up for a CT screening, but unfortunately, had a left lower lobe — a left upper lobe mass. And uptake on the PET, only some hilar uptake. Nothing else anywhere else. And his brain MRI is negative. Adenocarcinoma. No driver mutation identified. And high PD-L1 of 50%.

So he went straight to surgery.

So he went to complete resection. And then he came to see me. And he actually went on the IMpower010 trial. So he received the adjuvant atezolizumab. And remember, that trial randomized patients to either get atezolizumab or to get best supportive care. So we knew which arm patients were on.

And he had a lot of fatigue when he was going through he treatment. He actually had to stop work during the time that he was on adjuvant atezolizumab. But once he completed, starting about 4 months later, he was able to get back to work and he’s feeling quite well at this time. And so far, doesn’t have any evidence of recurrence. So I’m hoping that he’s cured.

Now he was Stage II, so he maybe was going to be cured with surgery alone. He did get chemotherapy. I didn’t put that into here, but he did get through 4 cycles of adjuvant cisplatin and pemetrexed. And had usual, some nausea. A little bit of fatigue during that time. But didn’t really have any bad effects with the chemotherapy. But when he was on adjuvant atezolizumab, had a lot of fatigue.

DR LOVE: Was that placebo-controlled though? The trial?

DR WAKELEE: No, it wasn’t. It was best supportive care.

DR LOVE: Okay. So you knew. Okay, great. Yeah, obviously. Interesting.

What’s it like to see him now? and I’m just kind of curious like how you see this experience, how it affected him? He got involved in the clinical research study. What’s his state of mind nowadays?

DR WAKELEE: So coming in every 3 weeks for a whole year got a little rough on him and I think with the fatigue as well. And it is hard. I think when a patient has a cancer diagnosis, they want to be done. They want to get their surgery and be done. And when you think about other cancers, like breast cancer, it’s a different mentally, patients are expecting to have a lot of ongoing treatment. There’s a lot of support for that. In the lung cancer world, it’s just been tougher. It’s not the standard mentality. Now that we have adjuvant osimertinib when there’s an EGFR mutation, more patients are used to like, okay, I’m just going to take this pill. I’m going to take it every day for at least 3 years. And they get used to it.

With coming for an infusion therapy every 3 weeks, that gets a little old. People want to be able to get back to their lives. And when it’s on a trial and you don’t know if it’s helping you or not, it’s hard to keep going. And now we have patients who, okay, yeah. And we still need to stay in touch with you and make sure you’re doing okay because we need to know how people do to really understand what’s the DFS and overall survival endpoints.

And so that’s the hard thing for patients who have been part of a trial. It’s a hard part for anybody living with cancer, is that you’ve got to keep coming back. And every time you come back for visits, it’s like a reminder, oh my gosh I had cancer. And I think a lot of people want is live their life and have that be behind them. So that’s one of the struggles. And I think for him, it was hard. It was really bad fatigue for a while.

DR LOVE: It’s interesting when you talk about coming in for checkpoint inhibitor for a year. I was kind of thinking about the durvalumab locally-advanced situation, which I’ve talked with you about before. And, in a way, I mean to me, that was like the first evidence of IO — I’d call that kind of the adjuvant setting. I mean you can call it consolidation. And I’m curious, when you look at that trial, and then you look at IMpower010, do you sort of see IMpower010 following in that footstep in terms of long-term outcomes? Because now we’re seeing, I think it’s 6-year follow-up from the PACIFIC trial, that still, the curves are staying separate. Any thoughts about that?

DR WAKELEE: Well, I hope so. Again, I have to be careful not to be too biased. But based on what we know from the metastatic setting where we have patients where we stopped their treatment ears ago and they’re still not showing recurrence, small numbers, but real. When we got the data from PACIFIC where the patients where their cancer hasn’t come back, so far it still hasn’t come back and they’re living and doing fine. With the adjuvant trials it’s a little bit early, but I tend to look at those curves separating and I believe that’s real, and I believe they will continue to separate because if you’ve gotten an immune response, that should persist.

So I’m pretty hopeful that that’s a real outcome. And that we are improving lives and curing more patients with this approach.

Optimal treatment of localized NSCLC in patients who have alterations in RET, BRAF and ALK

DR LOVE: So I’ve got another case for you, which is your first patient, the one who got the osimertinib. Same exact patient, but she’s got a RET fusion.

DR WAKELEE: Yeah.

DR LOVE: All the others, and everything else, BRAF, ALK, you name it. And maybe they’re an oncologist and saying to you, how about some adjuvant targeted therapy. Any thoughts?

DR WAKELEE: Ah, good question. It’s hard not to extrapolate. I think at this point, when I talk about giving adjuvant targeted therapy to a patient, I tell them I don’t know if this is going to cure them, right, but it could delay recurrence. And the cost is going to be — well, the cost of the drug, right, but mostly it’s the risk of toxicity and trying to weigh it. And I think we have to keep in mind that not all TKIs are the same. When you’re dealing with osimertinib, your response rate is 80%. When you’re dealing with ALK-TKIs, your response rates are in that range of 80%. When we talk about some of the others, the response are lower. And when we talk about some of the others, the toxicity is different. So our RET inhibitors, maybe not quite as well tolerated as osimertinib. You’ve got some other things you’ve got to grapple with. And so you have to weigh. If you start someone on a TKI in the adjuvant, again, you’re treating blind. Some of these patients are already cured. And some of them are not going to respond. And every one of them is going to have toxicity.

I think that we will eventually be able to do the really great ctDNA tests. And remember, I work at Stanford with Max Diehn, and so a little biased towards the ctDNA and the newer assays, because we work with the newest, newest, right. Where we do think we’re getting to a point where we can be able to detect who really still has cancer and who doesn’t. And for those who don’t, to be able to stop and say, you’re done, you don’t need this treatment. And for those who do, to be able to say, you know what, your cancer is going to come back and if we give you this treatment it’s going to either prevent it from coming back, if they have like a great immune response, or it’s going to delay significantly when it comes back and then we’ve got to titrate the drug and the dosing so that’s it’s livable, right. And that’s where we’re heading. But for RET right now, I haven’t done that.

For ALK, I will confess that I have one patient where high relapsed risk because of Stage IIIa, actually, IIIa-plus. And a patient who was of an age where, and again, totally fine to take this medication. And so we talked about it and it’s off-label, but I’ve done it and I know I’m not the only one who has. I do think that it’s important that we have the long-term follow-up data from ADAURA that will be coming out.

I do continue to enroll patients onto the ALCHEMIST trial with crizotinib. We do have that open. The particular patient I’ve treated off-label was one where, that just, for a variety of reasons, they weren’t going to be able to go adjuvant alectinib data that we’ll be seeing at some point as well. So we’ll have more to inform us.

There is that ongoing study I mentioned, where there are multiple different drugs being looked at for specific mutations. And in RET, we do have — that’s one of the arms there. So I think it’s reasonable to keep enrolling. But it’s hard not to talk about it with these patients who are asking and then try to do that weighing in the sense of uncertainty as well.

Importance of primary care doctors screening their patients for lung cancer

DR LOVE: So one other question related to this topic of early-stage disease and that is whether or not, maybe as we look forward to the future, we’re going to be seeing more of these patients. And I’m curious what your thoughts are about the current approaches to screening for lung cancer? We don’t talk about it too much. I think maybe there’s some skepticism in general about its value. But also, what you see for the future, things like ctDNA and other ways to pick up the disease earlier? Any thoughts?

DR WAKELEE: Great question. So we really need to do better as a society with encouraging people to get screening for lung cancer. WE have clear guidelines. They’ve been modified. And there’s horrible uptake. And I think a lot of is just we need to educate our primary care doctors about why it’s important to find it. To get rid of some of the nihilism that still exists, that there is a lot we can do to help people if we do find it.

CT screening remains the best approach that we have. But as you mention, there are other things that we need to do. And I think ctDNA, other biomarkers. There’s some that are already on the market. I’m not convinced yet, but I think that we’re going to be moving in that direction where you will be able to do blood tests as part of your annual physical. It’s going to have to get followed up with imaging, because that can just tell your risk or not risk. And I think if we get to things that are overly sensitive, you cause a lot of panic for people who don’t actually have cancer. I think that’s a risk that we have right now with some of the tests. If it’s not sensitive enough, then you give people false assurances.

We’re still going to have cancers that grow so fast that you’re still going to miss them. But I think that’s where we’re heading is being able to do the really better blood assays of the future.

Where I struggle is a lot of my patients, the cases we talked about today, I had two patients with a smoking history, one without, but the majority of my patients where I practice have never smoked a cigarette. And there’s a lot happening, Asian-American population, and in Asia as well. And in other demographics where you get lung cancer as a non-smoker coming in the Latinx population as well. And we don’t know why. And so there’s a lot of effort being done there. And a lot of screening work, the TALENT trial that was in Taiwan in a group of patients at risk who didn’t have a smoking history, but family risk, showed that that was incredibly impactful to do that screening. There’s work being done in the US, but it’s small still. And yet, you can’t screen everybody, CT scans have their own risk. So we’re still sorting that out.

But to answer your question, I do think we’re going to be developing blood assays that we’ll be using instead of CT screening, probably within the next 5 to 10 years.

DR LOVE: This concludes our program. Special thanks to Dr Wakelee, and thank you for listening. This is Dr Neil Love for Oncology Today.