Current considerations that affect the choice of frontline therapy for patients with small cell lung cancer with the availability of novel systemic therapies.
Jared Weiss, MD: Thinking about the general systemic treatment approach, we have a patient, we have gotten their PET [positron emission tomography] scan, we have gotten their MRI of the brain and we are thinking about what to do for this patient. In my practice, the first thing I think about is the brain. The brain is much more like Manhattan in terms of real estate, than it is like Houston or even further Chapel Hill, North Carolina; it’s packed in. It doesn’t tolerate much pressure or extra space. I am thinking about the brain first and if there is anything other than the very least threatening brain disease, I am going to consult a radiation oncologist and talk about doing some kind of treatment for that. Assuming that there is either no brain disease or the most minimal asymptomatic disease, my next step is to think about systemic therapy with the goal, unfortunately is not of cure, but of extending the duration of life and preserving the quality of life. And that starts with triplet therapy or chemoimmunotherapy. We’ll go over the details in a little bit. Transitions to maintenance immunotherapy, in my practice, that’s always 4 cycles in the era of immunotherapy. I have pretty strong feelings about that. There is a little bit of heterogeneity in practice. Fortunately, response rates are high, and relapse is typically early and then at that point we are talking about next-line options and if that relapse is rapid which is defined a little differently in Europe or the U.S. but however you define rapid, you move onto the next line. If it is long, and again there is controversy over what’s long, a bit of Atlantic divide, then you could either rechallenge with the original regimen or move on to a subsequent 1.
Carl M. Gay, MD, PhD: I think there are a couple of interesting points here in the note section on this slide too, Jared. The role of radiation in patients that have extensive-stage disease I think remains quite controversial. It comes in 2 flavors, prophylactic cranial irradiation, which is a fairly widely accepted standard of care for patients that have limited-stage small cell lung cancer who have an excellent response to therapy and for many years was at least if not the standard of care, an acceptable form of care for patients that had excellent responses as sensitive stage setting. We are now 4 almost 5 years out from a relatively definitive Japanese study showing that patients not only failed to benefit in terms of overall survival here but, in fact, there was a trend towards worsening of overall survival. Nevertheless, I still haven’t seen it fall completely out of practice and occasionally we will have patients that I see as a second opinion who have received prophylactic cranial irradiation in the extensive stage setting. Maybe there is an occasional indication for that in an especially young patient or somebody that has a really dramatic response and is very motivated. But I’ve essentially eliminated that from my practice completely. Now that said with consolidated thoracic radiation therapy, that’s something I think there is a little bit more enthusiasm around. I agree with the note here that it’s still probably considered an investigational treatment albeit 1 with fairly strong data. I think what we don’t know about consolidated thoracic radiation is really how it integrates into the standard chemoimmunotherapy systemic therapy they are offering now. So this has not really been studied in the era of immunotherapy. There is an ongoing trial from NRG [NRG Oncology] that’s enrolling as we speak that is attempting to integrate consolidative thoracic radiation into IMpower133 atezolizumab [Tecentriq] plus chemotherapy backbone. Hopefully, we will get a somewhat definite answer there but at least in my practice even though there is not really evidence supporting it in patients who are on immunotherapy I have tried to integrate it in patients who only have residual thoracic disease. I don’t know, Jared, if you have done the same or if you’re waiting for further support.
Jared Weiss, MD: In that setting, I absolutely do the same thing, if the only residual disease is central thoracic. The other situation is if I consider the central chest response inadequate because when you don’t do it you end up doing it as an emergency later in probably more than half of the patients.Whether it’s a response or not if there is a lot of, I was about to say bulk, but the more honest answer fear factor, which is the integration of bulk and location of the bulk. If it’s either starting to compress airways still or threatening to do so. If I have that fear factor about the central chest, I am still doing it, but I have equipoise about it. Should I be pausing the radiotherapy? Should I be going right through it? I don’t have a clue. Do you have an opinion on that?
Carl M. Gay, MD, PhD: I approach it with almost magical thinking. I usually try to time it such that the consolidative thoracic radiation therapy happens between 2 regularly scheduled cycles of atezolizumab or durvalumab [Imfinzi], and then I convince myself I have not really given concurrent immunotherapy and radiation even though we know the half-lives of these drugs are very well. If I did pause it, I wouldn’t know for how long to pause it anyway because of that half-life issue, so I just try to keep the patients on schedule unless something really goes awry there. They are viable concerns whether or not this influences the risk for pneumonitis in these patients. I have not seen that anecdotally and I treat a fair number of small cell lung cancer patients, but I would be very interested to see not only the efficacy data from the NRG study and other smaller studies but also some of the adverse event data to see if that’s borne out.
Jared Weiss, MD: I am really amused by your response because if you’re wrong we are wrong together, that’s what I have done with the last few as well. Hopefully, that means that it at least makes sense and time will tell us if we are doing the right thing. I am very much with you in not being a fan of PCI [prophylactic cranial irradiation] for exactly the reasons you’ve listed but also for a very happy reason which is that some of our patients are living long enough to suffer the neurocognitive effects. Back in the day, we really didn’t worry about that and now there is a small but real portion of patients who are, so that quality of life consideration has happily come to the fore.
Carl M. Gay, MD, PhD: There is a little tale to particularly some of the immunotherapy containing regimen curves and I think we need to be mindful of that. There are also some trials evaluating whether or not either close MRI surveillance or even in the use of gamma knife in patients with small cell lung cancer, which have long been considered a faux pas for small cell lung cancer patients, might be able to spare them some of this neurotoxicity because it is certainly real. If you have given PCI to patients, it’s rare that they don’t suffer any consequence from that PCI I would say if they live long enough to see it. I think it’s something that really bears taking in mind and if you look back at the Japanese study that I reference the trend towards the overall survival was not because of the inefficacy of the prophylactic cranial irradiation those patients that got PCI in extensive-stage setting were at much lower risk of developing brain metastasis yet they still lived certainly not longer if not slightly shorter period of time. You have to imagine this is driven by adverse events and the inability to get future regimens of chemotherapy because of lingering toxicities from the PCI and so it’s not just about controlling brain metastasis it’s about controlling the overall health of the patient, I think. There is a sort of distant illusion to the new standards of care in small cell lung cancer that the use of chemoimmunotherapy, so I just want to make sure that we’re all on the same page as to which regimen we are talking about here. At least in the United States and now throughout most of the world we have several preferred regimens that are backed up by randomized phase 3 data and that’s the combinations of platinum etoposide with either atezolizumab or durvalumab. This was based on a brief snippet of the data in just a second, the IMpower133 and CASPIAN studies, respectively. For the most part, carboplatin is the law of the land for patients that have extensive-stage disease. The only time that I ever used cisplatin, and I am curious about your thoughts on this Jared because I think this is also borderline magical thinking on my part, but occasionally I will have a patient that has a myelophthisis and will have very-very weak counts coming in and I convince myself that cisplatin is slightly less myelosuppressive, so I am doing some benefit to the patient by giving them cis [cisplatin] instead of carbo [carboplatin]. These are patients that have platelet counts of 20,000 in the treatment naïve setting but I have not seen that go well and so I am not sure I am doing anybody any favors by taking that approach. Otherwise, I have a difficult time seeing any enthusiasm for cisplatin, which is generally a more difficult drug to give here, but maybe you feel differently, I don’t know.
Jared Weiss, MD: I have magical thinking just slightly different magical thinking. In the pre-trilaciclib [Cosela] era, I was sometimes using cisplatin for just that reason if the patient’s bone marrow was beaten up in the first round. For everyone else, in case this is not overwhelmingly obvious just to be clear cisplatin is rougher for everything other than myelosuppression. But in a modern era with our modern antiemetics and renal prophylactic regimens, cisplatin to me is a much less nasty drug than it used to be but that’s titrating degree of hatred, it’s still not a gentle drug. Frankly, neither is carbo [carboplatin] it’s just less so than cis [cisplatin], so I am with you. The other magical thinking I was referencing is sometimes in a very fit, very motivated patient when I am re-treating I will have the magical thinking that if I switch up their platinum and sometimes I will switch etoposide to irinotecan that maybe I will have a little more sensitivity and I mean this as a self-criticism in calling it magical thinking. I suspect if you did a randomized study it would not be different.
Carl M. Gay, MD, PhD: I think we have all dealt with the lack of progress in small cell lunch cancer for so long that we’ve all developed these coping mechanisms, as practitioners where you want to feel like you’re doing something or you’re not just repeating the same thing. I mean it’s hard to treat a disease where 1 of the standards of care is have you considered just trying the same thing that you did before over again? Right, there are very few. I mean, I treat a narrow range of diseases but I’m not that far out of fellowship. I can’t think of diseases where they say just go back to step 1 and try again when patients relapse. And so you know, I think we, in a self-deprecating way, we’re talking about these things but I think it’s universal you want to feel like you’re trying something different because if this patient only got 6 months of out of carboplatin and etoposide the first go around you know they’re going to get less out of it the second time through, why not try something different even if it’s just subtly different? I’m right there with you with switching between etoposide and irinotecan in those scenarios, and occasionally, switching between carbo [carboplatin] and cis [cisplatin] in those scenarios certainly without any data to back that up, but no reason to think we’re harming anyone by doing that. Some of those are listed here as well among the reasonable options for frontline systemic therapy as for the other recommended regimens, the ominously titled “Useful in Certain Circumstances,” I think that unless you have a patient that’s clearly not a candidate for immunotherapy, you know, an organ donor, solid organ transplant patient, or somebody that has a very, very brittle autoimmune disease, even there I would give yourself a lot of latitude in considering immunotherapy. I think the preferred regimens are the regimens for patients who have extensive-stage small cell lung cancer.
Jared Weiss, MD: I would say that before a patient is excluded from immunotherapy unless they have an organ transplant because PD-1 [programmed cell death protein 1] is the projection pathway that perhaps one of us ought to be consulted to address the question of whether they really aren’t a candidate before fully excluding anyone.
Carl M. Gay, MD, PhD:Yeah, I think that’s fair. Even though it’s a minority of patients that are benefiting from immunotherapy there is still, as I mentioned, a tail to that curve. These are the only long-term survivors that you’re going to get with small cell lung cancer, right? We were not getting any long-term survivors in the pre-immunotherapy era, and so yeah I think it’s a chance that you have to take for those patients even if they carry a rheumatoid arthritis diagnosis you’d rather just sort of manage the consequences of the toxicity than cheat them out of the chance at a long-term response. I think this goes back to the inability to predict who will benefit from immune check blockade in small cell lung cancer where PD-1 and a mutational burden has not worn out. There have been some hints here and there but when push came to shove those things were not predictive of benefit, so you have to treat everybody to get maybe 10% to 15% of patients that are going to benefit from it. That’s where we are now. Some of the specifics in these regimens and some of the attempts I guess to validate some of the other perhaps more familiar to our audience immune checkpoint blockade agents are listed here. I mentioned the IMpower133 and the CASPIAN studies. I think this is a fun question for discussion, Jared. Do you have any rationale for choosing between these 2? Once upon a time, durva [durvalumab] was offered every 4 weeks and so slightly more convenient, and then atezo [atezolizumab] nipped that in the bud. Is there anything that drives you toward 1 or the other here?
Jared Weiss, MD: The curves for these 2 trials are almost eerily superimposable, which to me just reflects that they were large well-conducted trials. They did their homework right and there was no luck intervening to make them different. To my mind, having 2 positive studies really just confirms the principle that PD-1 inhabitation adds to chemotherapy. If I had small cell lung cancer of extensive-stage and you were flipping a coin between the 2 agents, I wouldn’t be rooting for heads or tails. In practice, it’s not Schrödinger's cat, you have to choose 1 or the other.And to not totally cop-out, I do use atezolizumab and the reason is actually not related to a feeling about superior efficacy of atezolizumab, it’s because I really like trilaciclib, which we’ll get to, for preserving quality of life and it’s only approved in combination with atezo [atezolizumab]. It’s a very mundane reason but that’s what drives my practice.
Carl M. Gay, MD, PhD: I think that that’s the only reason that 1 could choose between them now. I agree with everything you say about the sort of 1 validating the other and vice versa. It’s also nice to sort of have 2 building blocks for clinical trial development. This keeps 2 companies very invested in the extensive-stage small cell lung cancer space and that’s a good thing for patients. If 1 company has something in their pipeline that might pair well with an immune checkpoint blocking agent then you don’t have to jump through the hoops that it takes to bring 2 companies together in a trial design. I tend to use atezolizumab. I will say, and I’m curious to hear your thoughts on trilaciclib later because I saw that on your slides and I’ve read a bit on your commentary before, our utilization of it at our institution has not been broad, to say the least, but that may not be fully justifiable at this point. I think it is worth mentioning here the other trials. Essentially, every immunotherapy has attempted this extensive-stage space and while atezolizumab and durvalumab I guess are the de facto winners there’s really not a lot to distinguish the outcomes from these trials. Pembro [pembrolizumab; Keytruda] fell a little short in the KEYNOTE-604 [clinical trial] but realistically the hazard ratio was not all that different than the others and could’ve just been a little bit of bad luck in trial design. Then, the nivo [nivolumab; Opdivo] was a phase 2 trial, but was just a little late to the punch, but had relatively similar outcomes. I’ll jump ahead to the first polling question that I’ll open up to the audience. I’ll read this and then Jared and I can talk about it a little while your answers come in. Of the following, which is the key factor you consider when selecting first-line therapy for patients? As options, we have patient fitness, progression-free survival data for the regimen, toxicity, or adverse events of the regimen.
Jared Weiss, MD: It’s interesting because most of these aren’t that different between the 2 choices we’re making. To my mind, philosophically, we treat extensive-stage or any incurable cancer for quality of life and duration of life, and I don’t know if either of those were directly up there. Quality of life is probably the most important for me but very challenging to measure. So for trial data, I’d say survival but that wasn’t up there.
Carl M. Gay, MD, PhD: I tend to agree with you. I included progression-free survival, which I think is an interesting thing to include there because progression-free survival is not really something where you can distinguish any of the small cell lung regimens. And frankly, on IMpower and CASPAIN you cannot distinguish the experimental from the control arms because the response rates are very similar through these patients. The progression is going to happen. It’s virtually inevitable in both arms. That overall survival tale is really the only thing I think that’s driving us towards adding immunotherapy to everybody. I guess if forced to choose the toxicity data is something you bear in mind, but as you said, for a very, very limited number of patients, it’s the only thing I can think to distinguish the frontline trials. As you said, taking into account the trilaciclib approval, sort of mitigating toxicity in 1 of the regimens vs the other might be a fair way to settle it. It looks like that audience was relatively split among several of these options. A lot of them thought about patient fitness, which I think is always, in small cell, is as relevant in any disease that thoracic medical oncologists [are] going to treat because these are often not fit patients who are getting progressively less fit by the day. Some others consider progression-free survival, which, I think, in general, is a good rule of thumb, but in small cell lung cancer it’s hard to choose something based on PFS [progression-free survival]. And then some consideration of toxicity there as choice C. Sort of like us, Jared, not a clear-cut winner, not a clear-cut driver of choice here.
Transcript edited for clarity.