: Maybe it’s changing an extensive-stage disease. We do see on all these immunotherapy curves there’s a better tail on the curve and who knows what’s going there. In limited-stage disease, this is on our list of potentially curable diseases with aggressive chemo/radiotherapy. This is a situation where I routinely use cisplatin/etoposide. There’s not much to say there from a medical oncology point of view. I’m a big fan of early intense radiotherapy, and I want Kristin to tell us what is early aggressive radiotherapy in this disease.

: Right now for radiation, we give 45 Gy bid [twice a day] with either the first or second cycle of platinum/etoposide. This was established as a standard of care by the Turrisi trial that was published in 1999, which confirmed what the CONVERT trial (that was published recently over the last 5 years) [showed]—the excellent contemporary radiation trial randomized patients to 45 bid or 66-Gy daily radiation with the hypothesis that the daily radiation to 66 Gy would be better. That did not end up being the case. There was no difference in overall survival between the 2 arms. Right now, people give either 45 Gy bid or 60 to 66 Gy daily. However, we did see an interesting trial presented at ASCO [American Society of Clinical Oncology], a small phase 2 Norwegian trial that was about 175 patients. They randomized patients to that standard 45 Gy bid compared with a dose-escalated bid radiation treatment course of 60 Gy twice daily. Their primary end point was 2-year overall survival and they did show significant survival difference: 73% versus 46%. This is a small phase 2 trial; we haven’t seen very much detail in regard to radiation technique. We don’t know much when it comes to local control, there wasn’t a difference in response rates between the arms. There’s also no difference in high-grade toxicity, which is puzzling. You would expect that with the dose-escalated radiation regimen you would get higher rates of esophagitis. I’m not sure what to make of that. I will say if you look at the control arm, it underperformed with median survival of just about 23 months. [In] the CONVERT trial, the 45-Gy bid median survival was about 30 months. I look forward to seeing this in publication so we can learn more details. I don’t think it’s practice-changing yet. It’s definitely interesting and I wouldn’t draw too many conclusions just until it’s tested in a larger phase 3 setting.

: It’s funny, I’ve always been a huge fan of the Turrisi trial, doing 45 Gy bid. It gets it done in 1 cycle and if you can start at day 1, by the time they get to cycle 2, they’re almost done with the radiation. They tend not to get their esophagitis until after the radiation is done so it all works out fairly well. How often is 45 Gy bid given?

: About 10% of patients get bid treatment. Logistically, it’s challenging. It’s difficult to schedule. Patients many times don’t like to come twice a day. In many radiation departments, it’s not in their routine to schedule somebody to come twice a day. For those reasons, for better or worse, it’s just not utilized as often as it probably should be. Even if it were positive in a large phase 3 trial, I still don’t know if it would replace 66 Gy given daily, which also gives great results.

: What are your views on PCI [prophylactic cranial irradiation] in a limited-stage setting?

: Right now, PCI is still standard of care in limited stage. It has shown to produce a survival benefit in meta-analyses; however, patients with limited-stage small-cell [lung cancer] are included in the SWOG MAVERICK trial, so we will be testing MRI surveillance in limited stage and I look forward to those results. It may be that perhaps we don’t need to do PCI if they’re getting q3 month MRIs. We don’t know that answer yet and I would hate to pull back on PCI in limited stage right now if the survival benefit in a patient population has the potential to be cured.

: We spent the majority of our first half of this thing talking about how immunotherapy has changed the standard of care in extensive-stage disease. Let’s get Steve and Roy’s opinion on limited-stage disease.

: I think that will be a big impact in the United States. There’s plenty of rationale to combine immunotherapy on the cusp of radiation. We learned in non–small cell from the PACIFIC study that there’s a potential synergy between them and that’s where we saw an improvement, not just in PFS [progression-free survival] but in overall survival, we now accept checkpoint inhibitors after thoracic radiation. Years ago early on, we had some concerns about the possible risk of pneumonitis. We didn’t know if it would be higher using immunotherapy after thoracic radiation but now, we’re very comfortable with that—the safety of that approach clearly established. Based on the rationale for potential synergy, once we start introducing checkpoint inhibitors in the limited-stage setting, hopefully we’ll see more cures. Our goal in limited-stage small cell with chemo and radiation is to cure patients, but we know that for the majority of patients, we don’t achieve that goal. Hopefully, use of checkpoint inhibitors will allow us to do that, and there are a couple of very important studies.

One of those studies is chaired by Dr Higgins and that’s using atezolizumab. Dr Steven Lin at MD Anderson did a small phase 2 [study] looking at concurrent thoracic radiation in non–small cell [lung cancer] with atezo [atezolizumab]—so radiation of the chest and atezo at the same time just to be sure there weren’t any worrisome signals in terms of pneumonitis. The rate of grade 3 pneumonitis was quite low, about 3%. Immunotherapy can [cause] modulation [in] the microenvironment and facilitate the efficacy or radiation and vice versa. This study is looking at atezolizumab with chemoradiation followed by atezolizumab maintenance afterward. Kristin, correct me, I think it’s NRG LU005.

: That’s currently enrolling, so we’re trying to send patients over to that study.

: Yes, we have just about 100 patients on so far.

: Roy, what about immuno combos in this setting? What do we know about the ADRIATIC trial?

: The ADRIATIC trial is looking at chemoradiation followed by durvalumab, and that’s certainly an approach. We’ve always been taught to use these drugs after and then to add tremelimumab. There's less enthusiasm for that right now given the results of that arm of the CASPIAN trial. These are curable patients; you want to watch out for the toxicity. The trial is ongoing, so it’s another setting. Perhaps in this setting, you can deliver the tremelimumab better, maybe it has a different effect after getting radiation but we’re not that optimistic given what we’ve already seen with CASPIAN trial.

: Yes, but certainly the concept building on the PACIFIC trial in non–small cell makes sense for the monotherapy arm.

: Yes, you can argue for that the effect of immunotherapy in a tumor that’s received chemotherapy and radiation therapy. You can almost imagine it would be nice to go study, but I think you’re warming up the whole microenvironment and making it ready for immunotherapy. As Stephen said, the toxicity of this is always a concern, but it looks like it’s quite manageable.

: Are there any parting thoughts to our audience in the general field of small cell? What’s the message you want? I’ll start with Kristin as our lone radiation oncologist.

: I’m excited that we have new therapies for patients with small-cell lung cancer. Immunotherapy has shown small but consistent survival benefits for our extensive-stage disease, and I’m excited about the prospects of moving that into limited-stage disease and curing more patients with small-cell [lung cancer].

: Although there are encouraging combinations looking at different immunomodulators, TIGIT for example, I think the only path forward to get those hazard ratios we’re used to in non–small cell [lung cancer] is with some type of reliable biomarker. We’ve done a lot of work looking at sequencing, looking at PD-L1, TMB [tumor mutational burden], there are just no obvious answers there. The greatest lead has to do with those transcriptional factor subsets looking at ASCL1, narrow D1, 

, maybe as a predictor for I-O [immune-oncology]. Without a biomarker, it’s only going to be incremental gains.

: We’re making progress. We’ve built on platinum, but I’d say we haven't made it all the way. I agree with the others that we need biomarkers, but as long as you’re having some activity, biomarkers become very viable because you can hopefully build on what we’re seeing. I think there’s so much more enthusiasm in the study of small cell than ever before. There are meetings on small cell alone. You recall Mark, the targeted therapies meeting we have every year, we always put small cell as the last session on Saturday. This year, we opened up with it. More investigators, more new ideas, and patients with this disease are benefitting from that. That’s a very positive thing.

: Thank you all. It’s been great. It’s been a great discussion. Hopefully, this will be helpful to our audience, and thanks for joining me today for this discussion on perspectives in small cell.

Videos

Review of Treatment for Limited-Stage Small-Cell Lung Cancer

: The same time that we had these data, we also had third-line indication for immuno-monotherapy in this disease setting, and I wanted to get the perspective. Dr Liu, clinically, how many patients get to second-line [therapy]? How many patients get to third-line? It’s a tough population, but what’s your experience there?

: There’s a lot of attrition with small-cell lung cancer, much more than with other cancers. We have published data in this setting. If you look at a group of patients who received first-line treatment, the data will tell us about half would get second-line and less than a quarter would eventually get third-line [treatment]. The approvals of nivo [nivolumab] monotherapy [and] pembro [

 monotherapy in the third-line are important approvals. But for a potentially transformative drug, they would have much less impact because patients wouldn’t survive long enough to receive third-line treatment. That’s why the front-line treatment with atezo/durva [

durvalumab] has the chance to make a much bigger impact.

: What is your standard second-line [treatment] following first-line chemo-immunotherapy?

: It’s a setting where I look for a trial if we can. Trials are my preference. If I’m taking a board exam, my answer is topotecan, but if I’m in practice, that’s a drug that I’m disappointed with. I find it very toxic; quality of life is not so great with topotecan. It’s a tough drug to receive and the responses are fairly limited. There are many other agents that are equally good or bad. Taxanes, irinotecan, temozolomide, if there’s CNS [central nervous system] efficacy. It’s an area where we have an unmet need for more potent agents.

:No. Topotecan—I hate using it. I have. We sometimes use taxanes here, but that’s where we send them over to phase 1. I still remember a patient I sent over to phase 1 years ago for an immunotherapy who is alive 7, 8 years later. Now, we’re in the post–I-O [immune-oncology] world. I think we look at I-O combinations if a patient is strong enough. Some of the ADCs [antibody drug conjugates], I think are worth exploring there, but it’s a tough area. At least, we’ve elevated from where we were in the past [by] having immunotherapy to begin with.

: We are seeing patients that get a fair durability to their responses on immuno-maintenance therapy. Is there a cut point in which you would think about going back or adding platinum/etoposide back in at some point?

: In the absence of data, it’s hard to say. If someone becomes resistant, add back some chemotherapy, and if chemotherapy is helping in the first place, probably knocking down some immune-resistant cells or regenerating some neoantigen [is a good idea]. It’s something to try and if someone is not having any issues with clinical progression, or if they’re just progressing radiographically, it’s worth a try.

: Any role for nivo/ipi [ipilimumab] in the refractory setting following first-line I-O? You mentioned I-O combinations earlier.

: We’ve done that and we’ve had trials. I’m a little disheartened in the fact that durvalumab/tremelimumab didn’t seem to have any effect up front because it’s a different situation. But nivo/ipi has phase 2 experiences, but you’re just giving the patient a lot of toxicity and the absence of any real data; I’ve not used it that much.

: I haven’t used it but the data look interesting. Lurbinectedin is a transcription inhibitor; it binds onto the DNA promotor region that prevents transcription. It also has an effect on tumor-associated macrophages, which may alter the microenvironment and help facilitate some immune responses. In a single- arm study of over 100 patients, it gave a response of about 35%. In [patients who were] platinum sensitive, that was up to 45%, and in [those who were] platinum resistant, 22%. It’s impressive for [patients who are] platinum resistant. We don’t have any drugs that are active in that setting. We’re waiting for the randomized data. We need a control arm there, and the ATLANTIC trial is looking at lurbinectedin with doxorubicin versus topotecan or CAV [cyclophosphamide, doxorubicin, and vincristine], and I think when we see those data, we’ll know more about just how active this drug is, but there is promise in that area.

: I would agree. When those data were presented at ASCO [American Society of Clinical Oncology], it was almost too good to be true; we were all very impressed and we’re waiting for the randomized trials. That could have a real mixture especially given our current paradigm using immunotherapy up front.

: Any appetite for PARP inhibition in this setting? There’s been some work, although I must say the data that I’ve seen have had a modest impact in this disease setting from my perspective. I don’t know if either of you have a different feeling.

: I find them exciting. When we think of PARP inhibitors throughout oncology, we often think of tumors that have defects and BRCA or a homologous repair, but these drugs also have some activity in small-cell [lung cancer]. Monotherapy didn’t really get us there. We remember the STOMP trial looking at maintenance PARP that didn’t really show much activity. I think there’s a lot more promise in combinations. It makes sense to combine a PARP inhibitor with a drug that will induce single-strand DNA breaks. Olaparib is a bit of a stronger PARP trapper than veliparib and in combinations with temozolomide for example, I think there’s some promising activity there. PARP inhibitors have more promise and maybe in combination with immunotherapy. We know from work that our colleagues have done that inhibition of PARP using PARP inhibitors, using CHK1 [checkpoint kinase 1] inhibitors will drive up PD-L1 expression and will induce T-cell infiltration. A CHK1 inhibitor will have an antitumor effect in small-cell lung cancer models, but if you deprive that model of CD8-positive T cells, it has no effect showing that its efficacy is medicated through the immune system.

Second- and Third-Line Treatment for ES-SCLC

: Kristin, I want to get your opinion. In the design of these trials we continue immunotherapy as maintenance. The 2 questions we used to address when we used to give 4 to 6 cycles of platinum/etoposide was A) is there a role for PCI [prophylactic cranial irradiation] in extensive stage disease, and B) is there any role for thoracic radiotherapy in this setting? I’m going to ask you that question first, and then if there are selected patients for which you would consider either, how do you integrate that when you’re giving maintenance immunotherapy?

: That’s a great question. Radiation oncologists now are wondering how PCI and consolidated thoracic radiation fit in with the results of the CASPIAN and IMpower133 trials. For PCI in the extensive stage setting, radiation oncologists have stopped recommending it due to the conflicting data. The trial led by [Ben] Slotman, [MD, PhD,] and the Japanese trial showed opposite results with improved survival with PCI given in patients who don’t get routine MRIs of the brain. The Japanese trial showed that there was not a survival benefit if we give surveillance to patients with extensive stage small cell lung cancer with q3 [every 3] month MRI. We’ve seen a shift in radiation oncology with not recommending PCI in patients with extensive stage small cell [lung cancer].

In IMpower133 only about 10% of patients received PCI, and in the CASPIAN trial PCI was allowed on the control arm, but not the experimental arm. We didn’t see any worrisome toxicity in the patients who did receive PCI in the Impower133 trial. But with PCI there is significant toxicity, and as a field, we’re trying to potentially move away from PCI. There are more trials now addressing MR [magnetic resonance] surveillance in both the limited stage and the extensive stage small cell population. The SWOG cooperative group is running the MAVERICK trial, for example, that will help answer this question. When patients do get PCI in extensive stage, there's also a trial run through NRG [Oncology], CC003, which is giving PCI with hippocampal sparing, which carves out the part of the brain that is responsible for creating memories to try to reduce cognitive changes. So as a field, we’re leaning away from PCI in this patient population and that’s where we stand now. I hope the SWOG trial gets completed. I think it’s a great trial, and I would encourage people to enroll patients to answer this question when it comes to PCI.

In terms of consolidated radiation, patients weren't allowed to get thoracic radiation on either of these trials. We do know now we have some safety data for the combination of thoracic radiation and immune checkpoint inhibitors, and there's not worrisome toxicity. The role of consolidation radiation to the chest and to metastatic sites is going to be evaluated in an NRG trial, NRG-LU007, which will activate probably late summer. I look forward to putting patients on that trial. Right now, I would say we’re giving thoracic radiation on a case-by-case basis in some patients who have had a great response and have a small amount of residual disease. We’re doing so cautiously, because again, there are a lot of unanswered questions. What dose do we go to? How do you integrate it from a timing standpoint? And this is a data-free zone. I think we’re best to put patients on NRG-LU007 to answer the question in a scientific way.

: There was a suggestion from a very old trial published in the late 1990s, an Eastern European trial, that suggested in those patients who have a great response, maybe you could get some mileage out of thoracic radiotherapy, and as well with the follow-up Slotman trial. Still controversial, we still think about it and talk about it, but I’m glad you’re doing NRG-LU007 to help bring some more clarity to it.

Role of PCI Versus Brain MRI Surveillance in ES-SCLC

: Roy and Stephen, what do you do in your own practice? Do you have a preferred agent?

: Atezolizumab was there first, and all else being equal, the drug there first usually gets more share. We’re using mostly atezolizumab now. I didn’t see anything in the data to switch. I will say the pembrolizumab data look very close. What it tells me is that we need a better biomarker here. The fact that all these trials are so close, it tells you that we have a population that’s heterogeneous, and some are probably benefitting more than others, and if you take a mixed population, you're going to see results like this. It’s great for patients, it’s clearly better than what we were using before, but we’re using atezolizumab at Yale [Cancer Center].

: It comes down to comfort. IMpower133 was presented in 2018, which was approved March 2019. Durvalumab was approved in March 2020. I think what might have changed it, if we had seen the third arm in CASPIAN, the tremelimumab arm, showing any benefit in survival, then that would have been a combination to pursue. But as you saw at ASCO [the American Society of Clinical Oncology annual meeting], the addition of tremelimumab did not improve survival over just chemotherapy alone. [Atezolizumab] and [durvalumab] both improve survival, And both are reasonable options. I didn’t see a compelling reason to change. CASPIAN, [durvalumab] is given every 4 weeks. We also have FDA approval for [atezolizumab] to give every 4 weeks. It comes down to comfort for me, and I’m still using atezolizumab.

: Roy, you mentioned we did see at ASCO the third arm of the CASPIAN trial, which was the durvalumab/tremelimumab arm. The interesting thing to me is that there didn’t seem to be any optimism about that combination, and I think the tremelimumab was stopped at a certain point. And the overall survival curve with continuing durvalumab alone eventually caught up with the arm that had only durvalumab in it. Roy, what are your thoughts, any hope for anti–CTLA-4 inhibition in this setting?

: I would say not. We already knew from trials with ipilimumab years ago, our colleague ran some of those trials way back when, that there was no real benefit with ipilimumab CTLA-4. And here, adding durvalumab clearly adds toxicity, but unfortunately, no benefit, as you mentioned. I think if there are going to be combinations in small cell lung cancer—and there have to be, because these data, while good, are clearly not a home run yet—we’re going to have to look at other aspects of the immune system and try to scientifically understand why there is some primary resistance to these agents. For now, I would stay away from the CTLA-4 inhibitors. That brings the grade ¾ toxicity up to the 40%-plus range, which is high in these very sick patients.

: Roy, you brought up before the issue of biomarkers. Obviously, in non–small cell [lung cancer], we routinely measure PD-L1. Any role for that in small cell?

: I think yes. The problem is with PD-L1 both in small and non–small, Mark, is measuring it accurately. It’s hard enough to measure in non–small cell where you get good pieces of tissue and there isn't crush artifact, and so forth. In small cell it’s hard to get good core biopsies and really measure it accurately. I think it’s a measurement issue, but I think PD-L1 probably has some role but we've not seen it so far. TMB [tumor mutational burden] could certainly be useful. There are a lot of data recently emerging with whole exome TMB, looking at 175 mutations per megabase in some of the data with pembrolizumab. I wonder if that could someday be used with small cell. All these need to be incorporated in the trials. Perhaps all of the groups that have done these trials could collaborate and pool their data sets to look at this.

Expert Approaches to Treating Extensive Stage SCLC

: With both of those being anti–PD-L1 antibodies, I’m going to ask Dr Liu, we are coming off the tail of our first virtual ASCO [the American Society of Clinical Oncology annual] meeting this year. And at that meeting we saw the presentation of 2 trials with PD-1 inhibitors, KEYNOTE-604 with pembrolizumab, and the ECOG-ACRIN 5161 trial, which was actually a phase 2 trial with nivolumab. Can you walk us through those and give us your impressions?

: Yes. These are 2 randomized studies and we saw results for the first time. The phase 3 trial you mentioned, KEYNOTE-604, was presented by Charles Rudin, [MD]. This was a very well-designed randomized, placebo-controlled large phase 3 trial. It included patients with previously untreated stage IV small cell lung cancer. All patients received platinum/etoposide, allowed either carboplatin or cisplatin, with a 1:1 randomization to concurrent pembrolizumab or placebo, followed by maintenance [pembrolizumab] or placebo. The study had 453 patients, of note, the vast majority, about 70%, received carboplatin. And it had dual primary end points of progression-free survival [PFS] and overall survival [OS]. What we saw at ASCO 2020 was the final analysis, and in that analysis KEYNOTE-604 was positive in that it hit its progression-free survival end point. The PFS favored pembrolizumab a median of 4.8 from 4.3 [months], the hazard ratio there was 0.73, the 1-year PFS rate from 5% with placebo to 15% with [pembrolizumab].

Unfortunately, overall survival did not cross the threshold for superiority. There was a numeric difference, median from 9.7 to 10.8 [months], hazard ratio of 0.80, but it did not cross that statistical threshold for a positive OS benefit. It’s interesting, if you take away 1 patient who inadvertently received the wrong treatment, it was a positive trial, just to show how close it was. We learned from KEYNOTE-604 there is activity there, comparable, in the same ballpark, as we saw with PD-L1 in IMpower133 for atezolizumab, and in CASPIAN for durvalumab. But unfortunately, this will not impact practice because it did not improve survival; while the trend was encouraging, it didn’t quite get there.

The ECOG-ACRIN 5161 was a randomized phase 2, through the cooperative group. It accrued remarkably fast, and this study looked at platinum/etoposide with or without nivolumab. No placebo, choice of platinum, this was a smaller study, a phase 2, 160 patients, and this study accrued in 7 months. Primary end point was progression-free survival, and that improved with nivolumab from 4.7 to 5.5 [months]. It’s a hazard ratio of 0.68. Even though a relatively modest size study, it was able to show a PFS benefit and was able to show a survival benefit. The OS hazard ratio there was 0.73. This was a smaller phase 2 positive for both PFS and OS. In a world where we have multiple randomized phase 3 trials showing an OS benefit with atezolizumab, durvalumab, unfortunately, no immediate impact in our clinic.

KEYNOTE-604 and ECOG-ACRIN 5161 Trials for ES-SCLC

: I’m Dr Mark Socinski from the AdventHealth Cancer Institute in Orlando, Florida. Joining me today in this virtual discussion are my colleagues, Dr Roy Herbst, a medical oncologist from the Yale Cancer Center in New Haven, Connecticut; Dr Stephen Liu, a medical oncologist from the Georgetown Lombardi Comprehensive Cancer Center of Georgetown [University] in Washington, DC; and Dr Kristin Higgins, a radiation oncologist at the Winship Cancer Institute of Emory University in Atlanta, Georgia. Today we’re discussing a number of topics pertaining to the use of systemic therapy in patients with small cell lung cancer. We’ll discuss the latest research in the field and the impact of recent clinical trials on making decisions for treatment selection in this population. Dr Herbst will summarize recent trials because in the past year, we’ve seen a change in the standard of care based on 2 trials, IMpower133 and the CASPIAN trial. Could you bring us up to date and give us your impression of those trials?

 Yes. Immunotherapy has changed the way we think of cancer care, certainly lung cancer care, and it’s moved to small cell lung cancer. It makes sense. Small cell lung cancer is a smoking-related disease, there are large numbers of mutations, high TMB [tumor mutation burden], and it’s an obvious place to look for a new indication. The first drug to move forward was atezolizumab. At the World Conference on Lung Cancer 2 years ago in Toronto, the results were presented of IMpower133, which took atezolizumab plus platinum and etoposide in extensive stage small cell lung cancer. In my career, I haven't seen any changes in the standard of care treatment for small cell lung cancer until now. This randomized phase 3 study had a hazard ratio in the 0.7 range in favor of the atezolizumab, and that was approved and has become a new standard of care. Just right on the heels behind that is a second drug, durvalumab, another PD-L1 inhibitor, in combination with platinum/etoposide. The CASPIAN trial, which we learned about late last year, also was positive and updated at ASCO [the American Society of Clinical Oncology annual meeting] this year, again, with a hazard ratio between 0.7 and 0.8.

We have activity here; it’s a survival benefit. Its modest, but clearly, it’s at the level where we consider that clinically significant, and it’s something to build upon. For patients with small cell lung cancer, it’s great that we have these 2 drugs available in the frontline setting for this disease.

IMpower133 and CASPIAN Trials for Extensive Stage SCLC

	Winship Cancer Institute of Emory University

Locally advanced non-small cell lung cancer (NSCLC) remains a challenging disease to treat, with a 5-year survival rate for patients with unresectable stage III disease of approximately 20%,

 even after definitive radiation therapy and concurrent chemotherapy. Yet the repertoire of tools for managing patients continues to grow, as researchers investigate novel strategies in radiation therapy as well as the introduction of molecularly targeted agents for this population.

The Radiation Therapy Oncology Group (RTOG) tackled important questions about dosing through RTOG 0617, a randomized phase III trial for patients with stage IIIA/B NSCLC that completed accrual in November 2011. This trial investigated standard chemoradiation to 60 Gy with concurrent carboplatin and paclitaxel, and consolidation chemotherapy, compared with high-dose radiation to 74 Gy with the same chemotherapy regimen. A second randomization was also performed after consolidation chemotherapy, with the trial arms consisting of cetuximab versus observation.

Preliminary results, presented in abstract form at the 2013 American Society of Clinical Oncology Annual Meeting, demonstrated inferior survival (median survival 19.5 months vs 28.7 months) and increased local regional failure at 18 months (25.1% vs 34.3%) in the high-dose, 74 Gy arm.

 Additionally, preliminary results have also demonstrated no improvement in overall survival with the addition of cetuximab after consolidation chemotherapy.

 On multivariate analysis, factors associated with reduced survival included 74 Gy, squamous histology, grade 3 or higher esophagitis, larger gross tumor volume, radiation dose to the heart (heart V50%), and heart contour not per protocol. There is no clear reason as to why patients in the high-dose radiation arm experienced poorer survival outcomes.

Possible reasons include the extension of overall treatment time in the high-dose arm, increased radiation dose to the heart, increased grade 5 events, and unreported toxicities.

It is now clear from RTOG 0617 that high-dose radiation to 74 Gy delivered at 2 Gy/day does not improve outcomes for unresectable stage III NSCLC. However, median overall survival for the 60 Gy arm was quite high at 29 months, the highest median survival for this population yet reported in a phase III trial. This study is also one of the first large studies in NSCLC to report nearly half of patients were treated with intensity- modulated radiation therapy (IMRT), an advanced technology that has not been utilized in prior phase III trials in NSCLC. It is likely that improvements in technology, including more accurate staging with FDG/PET and improvements in radiation delivery (

), are responsible for the excellent performance of the 60 Gy arm in RTOG 0617.

The RTOG is now investigating the use of in-treatment FDG PET/CT to determine if tumor dose can be escalated to improve the locoregional failure rate at 2 years. RTOG 1106 is a randomized phase II study that utilizes an FDG PET/CT obtained after 40 Gy to 46 Gy of external-beam radiation, and uses this PET/CT to reduce the volume of tissue that is incorporated in the radiation fields that receive high dose.

 This is the first randomized study to perform individualized, adaptive radiation planning based on metabolic changes that occur during radiation therapy. This study is currently actively enrolling patients.

Other strategies for improving outcomes for patients with unresectable stage III NSCLC include the use of molecularly targeted agents. Molecular testing on tumor specimens is now standard clinical practice for lung adenocarinomas. For patients with stage III adenocarcinomas with targetable genetic abnormalities, such as EGFR mutations or EML4-ALK translocations, it is unknown if the use of targeted therapy with agents such as erlotinib or crizotinib, respectively, confers a benefit beyond that of standard chemoradiation.

RTOG 1306 is a phase II randomized study comparing standard chemoradiation to 60 Gy versus 12 weeks of induction therapy with erlotonib or crizonitib in EGFR-mutated or ELM4-ALK translocated adenocarcinoma, respectively.

 This is the first clinical trial to examine molecularly targeted agents in a selected population for locally advanced adenocarinoma of the lung, and the results will be informative.

Lastly, stereotactic body radiation therapy (SBRT) has yielded great success in the early stage, medically inoperable NSCLC population. SBRT specifically refers to delivery of radiation using 3D localization of the target lesion, allowing very high doses per fraction (10-20 Gy) of radiation to be delivered with a high degree of precision and accuracy. The success of SBRT lies in the high dose per fraction and sharp dose gradients associated with this treatment technique that allow for normal tissue sparing from high-dose radiation regions. SBRT techniques have not been applied to the locally advanced patient population, but as radiation delivery technologies continue to improve, using SBRT techniques in patients with stage III disease is feasible.

At Winship Cancer Institute of Emory University, we recently opened a phase I study with a primary endpoint of defining the maximum tolerated dose of an SBRT boost after 44 Gy of concurrent chemoradiation.

 We hope to complete accrual by the end of 2015.

		IMRT-based planning is illustrated in the FDG PET/CT image, left, which allows for more precise delineation of radiation target volumes, as seen contoured in the inner red line on the radiation planning CT. At right, the heart is largely not included in the color wash, which represents the high-dose radiation isodose line.

			Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs concurrent chemoradiation for stage iii non-small cell lung cancer: randomized phase III trial RTOG 9410 [published online September 8, 2011]. 

			Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: results on radiation dose in RTOG 0617. 

			Bradley J, Masters GA, Chen H, et al. An Intergorup randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) chemoradiotherapy (CRT) +/- cetuximab (cetux) for stage III non-small cell lung cancer (NSCLC): results on cetux from RTOG 0617. 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01507428.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01822496.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01711697.

Articles

Locally advanced non-small cell lung cancer (NSCLC) remains a challenging disease to treat, with a 5-year survival rate for patients with unresectable stage III disease of approximately 20%, even after definitive radiation therapy and concurrent chemotherapy.

Kristin Higgins, MD