Teams of Phantoms and Accelerators clashed on a fall evening, leaving in their wake a storm of information and knowledge. On that fall night, at a CancerNetwork^®-hosted Face-Off, the expert-filled 2 teams—Team Phantoms and Team Accelerators—met to debate trial data and treatment combinations for patients with limited-stage small cell lung cancer (LS-SCLC) and non–small cell lung cancer (NSCLC). From trial data to hot topics to patient cases, these radiation oncologists debated the most prominent subjects in lung cancer care to date.

What is Face-Off? It is an educational program designed as a competition for teams to present to and against each other.

How does it work? There are 3 rounds: data presentations, topics, and patient cases. During each round, both teams can present and defend their ideas and challenge the other team. The judge determines the winner.

Round 1: Data Presentation

Team Phantoms Presents PACIFIC Trials and DUART Trial Data

Presented by Nitin Ohri, MD, MS

The first data shared during the Face-Off were from a collection of PACIFIC trials, as well as the DUART trial in patients with unresectable NSCLC. In the phase 3 PACIFIC trial (NCT02125461), where patients received concurrent chemoradiotherapy (cCRT) and then durvalumab (Imfinzi), the median overall survival (OS) was 47.5 months (HR, 0.72; 95% CI, 0.59-0.89); the 1-, 2-, 3-, and 5-year OS rates were 83.1%, 66.3%, 56.7%, and 42.9%, respectively.^1,2 The median progression-free survival (PFS) was 16.9 months (HR, 0.55; 95% CI, 0.45-0.68), with 1-, 2-, and 5-year PFS rates of 55.7%, 45.0%, and 33.1%. The objective response rate was 29.8% (95% CI, 25.6%-34.3%). Regarding safety, any-grade adverse events (AEs) occurred in 96.8% of patients, with grade 3 or 4 AEs occurring in 29.9%; AEs led to treatment discontinuation in 15.4%.

In the observational PACIFIC-R trial (NCT03798535), which evaluated patients who received cCRT and then durvalumab in real-world settings, the median OS was not reached, with 2- and 3-year OS rates of 72.3% and 63.2%, respectively.³ The median PFS was 25.1 months, with 2- and 5-year PFS rates of 50.1% and 42.2%. AEs of special interest occurred in 46.7% of patients, and AEs led to treatment discontinuation in 16.7%.

In the phase 3 PACIFIC-2 trial (NCT03519971), the median OS was 36.4 months (HR, 1.03; 95% CI, 0.78-1.39), and the median PFS was 1.8 months (HR, 0.85; 95% CI, 0.65-1.12).⁴ AEs of any grade and grades 3 or 4 occurred in 98.6% and 53.4%, respectively; AEs led to treatment discontinuation in 25.6%.

In the phase 2 PACIFIC-6 trial (NCT03693300), where patients received subsequent CRT and then durvalumab, the median OS was 39.0 months, with a 3-year OS rate of 56.5%.⁵ The median PFS was 13.1 months, with a 2-year PFS rate of 35.3%. AEs of any grade and grades 3 or 4 occurred in 76.9% and 6.0%, respectively; AEs led to treatment discontinuation in 27.4%.

In the phase 2 DUART trial (NCT04249362), where patients received definitive RT or palliative RT and then durvalumab, the median OS was 21.1 months, with a 1-year OS rate of 64.7%.⁶ The median PFS was 9.2 months, with a 1-year PFS rate of 39.6%. Regarding safety, AEs of any grade and grade 3 or
4 occurred in 97.1% and 40.2%, respectively, with AEs leading
to treatment discontinuation in 21.6%.

Team Accelerators on the Data

Finkelstein / The data for immunotherapy have been very compelling. For all of us, it’s been very compelling, but it was quite disappointing when we finally were able to do a trial that incorporated immunotherapy at the same time as concomitant radiation and chemotherapy without a tremendous benefit. So why is that? We’ve done conventional fraction radiation for so long. This has been the standard of care, and we’re coming back to a world where we’re realizing that [it] probably does have some [adverse] effects, potentially, on the immune system by creating lymphopenia.... We may now have the opportunity in that negative trial to be able to alter the way we do radiation therapy because, with the conventional ways we’ve approached it, unfortunately, there’s no benefit. Maybe we need to change when we deliver the radiation, the timing of it, and how it is given with the actual drugs to achieve the best outcomes.

Gomez / One other point that I’d like to make is that we all celebrated the PACIFIC trial, but we have to understand one of the key designed differences between that and the PACIFIC-2 study. The PACIFIC study essentially took the patients most likely to succeed with that regimen through randomization after concurrent chemoradiation. That certainly could have confounded the data and partially explained the difference between the 2 [trials].

Team Phantoms on the Data

Samson / The argument about lymphopenia is interesting because I completely agree with you, especially in locally advanced disease. We’re irradiating the complete blood pool every single day, especially when we have multistation N2 disease, the great vessels, and the heart. We know white blood cells are incredibly sensitive to very low doses of radiation. But if we pivot to the trials that have completed accrual for [stereotactic body radiation therapy (SBRT)] and concomitant immunotherapy—[the phase 3 KEYNOTE 867 trial (NCT03924869)] and [the phase 3 SWOG trial (NCT04214262)]—those are negative too. I wouldn’t expect lymphopenia with SBRT, in the same way that I would [expect it] with conventionally fractionated comprehensive thoracic radiation therapy to bulky N2 disease. These are nodes that are peripheral and nowhere near the blood pool and are delivered over just a few fractions. Lymphopenia is part of the story, but not the whole story, because we seem to be getting a similar signal with early-stage lung cancer with concomitant immunotherapy. With the [phase 3 PACIFIC-4 trial (NCT03833154)], we will have to see. That will be the tiebreaker because they did deliver immunotherapy a little bit differently in that trial.

Ohri / I like the idea of adjusting our practices to fit the immunotherapy era. If you go back, the most standard dose for locally advanced NSCLC is something that was developed in a trial from 50-plus years ago. It seems almost impossible that the correct radiation dose and schedule from 50 years ago is still the right schedule today. We just need to do a better job of innovating through prospective trials to identify how radiation can synergize with immunotherapy.

Team Accelerators Presents Data From the LAURA Trial

Presented by Aditya Juloori, MD

The phase 3 LAURA trial (NCT03521154) evaluated patients with locally advanced, unresectable stage III NSCLC who were randomly assigned to receive once-daily osimertinib (Tagrisso) at 80 mg (n = 143) compared with once-daily placebo (n = 73).⁷

The median PFS was 39.1 months (95% CI, 31.5-not calculable [NC]) with osimertinib vs 5.6 months (95% CI, 3.7-7.4) with placebo (HR, 0.16; 95% CI, 0.10-0.24; P = .001); the 12- and 24-month PFS rates were 74% and 65%, respectively, in the osimertinib arm vs 22% and 13% in the placebo arm.

The median OS was 58.8 months (95% CI, 54.1-NC) with osimertinib vs 54.0 months (95% CI, 42.1-NC) with placebo (HR, 0.67; 95% CI, 0.40-1.14; P = .140); the 36- and 48-month OS rates were 82% and 70%, respectively, in the osimertinib arm vs 73% and 52% in the placebo arm.

The median central nervous system (CNS) PFS was not reached (NR; 95% CI, NC-NC) with osimertinib vs 14.9 months (95% CI, 7.4-NC) with placebo (HR, 0.17; 95% CI, 0.06-0.32; P = .001); the 12- and 24-month CNS PFS rates were 87% and 83%, respectively, in the osimertinib arm vs 53% and 43% in the placebo arm.

Adverse events of any case occurred in 98% of the osimertinib arm vs 88% of the placebo arm, and grade 3 or higher AEs occurred in 35% vs 12%, respectively. Any-grade AEs were possibly causally related in 80% vs 41%, and for grade 3 or higher in 13% vs 3%. Notably, AEs led to death in 2% and 3%, respectively, to treatment discontinuation in 13% and 5%, and to dose reduction in 8% and 1%.

Discussing the Data

Moghanaki / What do you think about the control arm’s underperformance, with such high relapse rates?

Ohri / [The underperformance in the control arm] certainly gives us pause, and we generally think patients with EGFR-mutated lung cancer have an overall better prognosis than patients without those activating mutations. I wonder, do you know how carefully patients were staged? I know it was largely an international trial. Could many of those patients already have had metastatic or oligometastatic disease?

Juloori / All patients had an MRI of the brain at staging, but of course, we all know the importance of a PET scan as well. About half of the patients on LAURA were able to get PET staging, and about half were not, which is something that is somewhat inherent to a large global study being done in all kinds of practice settings. One thing I didn’t mention earlier that I think is very compelling is that when they look at the outcomes in patients who were PET staged up front vs those who were not, the HR was just about the exact same. It does not seem, based on those data, that the results we were seeing in the placebo arm were due to understaging.

Moghanaki / Do you think that the PFS benefit of osimertinib is because it cleans up disease in the field that the radiation was unable to eradicate, the systemic disease outside the field, or both?

Gomez / It’s probably a combination of both. In patients who are treated with osimertinib in the metastatic setting, we see substantial reductions in gross disease that’s visible. It’s obviously doing some killing there, but also in the metastatic space, there’s been a prevention of new sites of disease, as part of the prevention of progression. This dual effect is what makes it so effective.

Samson / Of the majority of patients I see in daily practice who have a targetable EGFR mutation, and by and large, the majority are diagnosed at stage IV because they’re presenting with symptoms. They weren’t eligible for lung cancer screening because they didn’t meet the criteria for it. I do wonder if, analogous to limited-stage small cell [lung cancer], we almost have to assume there’s a micrometastatic component to their disease that is different from a traditional NSCLC that’s smoking associated.

Round 2: Hot Topics

Topic 1: How to Increase Pulmonologist Awareness About Radiation Oncology

Team Accelerators

Finkelstein / There are 2 ways you can approach this. No. 1: The pulmonologist is going to see something, they’re going to work it up, and they’re probably going to be involved in creating the situation where the patient is biopsied. When that happens, more pulmonologists get interested in doing fiducial markers. It’s something interesting to us, and it’s interesting to them. We should have conversations with our pulmonology colleagues about placing markers to allow us to better visualize and treat patients. No. 2: When patients are under our treatment, sometimes they have [adverse] effects. We, as radiation oncologists, like to take care of our patients. We’d like to take care of our [adverse] effects, but I don’t think we have to do it all the time. Sometimes, if the patient has pneumonitis or esophagitis, you could call the pulmonologist and say, “Hey, this is your patient from the beginning. Would you like to be involved in the management of those [adverse] effects?” The pulmonologist may say, “I would love to,” or they may say, “It’s OK, you guys take care of [them].” But you’re having a conversation. When you have that conversation they go, “What do you actually do for a living?” Then, all of a sudden, you get into a conversation where you show them how cool our profession truly is—the ability to do 4-dimensional CT simulations, the ability to capture in real time where cancer is, and our ability to deliver plans that make sense, and are rational and reasonable. When we do that, they think we’re cool.

Juloori / I fully agree with you. One other thing to highlight is the importance of making sure [the patient] understands how important the role of the pulmonologist is in the role of stage I, stage II, stage III, even stage IV [disease] management by the importance of getting tissue for molecular testing, especially in the post-LAURA era in the metastatic space. We rely on them. They are a very important part of the team.

Team Phantoms

Thomas / We all have to understand more about what the other does. That’s where there’s sometimes a disconnect. When we’re in a tumor board and are talking about a PET scan being PET positive at an N2 node or an N3 node, and then the [endobronchial ultrasound] is potentially equivocal, what do we do? That discussion in terms of what the change in the field is going to look like as a radiation oncologist…doesn’t necessarily translate to what the patient then experiences for the rest of the team. For example, when you talk about pneumonitis, and somebody’s reading a scan and they’re saying that’s pneumonitis because you’re now treating more of a nodal station because you don’t have the information from your pulmonologist, that’s because there’s a potential disconnect in how you talk with the pulmonologist about why that is so important, and whether there’s a need to go back in and do that test.

Samson / One thing that can serve as a model is the [interventional VALOR trial (NCT02984761)], which is still ongoing. But you guys put pulmonologists front and center in that trial. They were the gatekeepers, and no one knows a patient’s lungs better than their pulmonologist. They know their lung function history. They know their smoking history. They know their other lung comorbidities, whether it’s [interstitial lung disease] or [idiopathic pulmonary fibrosis]. I could see a situation where the pulmonologist, if they were empowered to do so, would refer to both surgery and radiation oncology at the same time, if they know a patient’s lung function is borderline. That would help expedite care. It would help the patient feel more in control of their diagnosis and their choice to see both at the same time.

Topic 2: Concurrent vs Sequential Chemoradiotherapy for Stage III NSCLC

Team Phantoms

Thomas / Concurrent chemoradiation has gone through iterations in the past. We’ve tried to escalate to 75 Gy. We’ve tried to go down to [twice daily] for certain situations. But overall, what we’ve seen is that, in concurrent chemoradiation, what we consider the gold standard for now…is 60 Gy in 2 Gy per fraction. There’s something to be said about having a backbone of therapy that we know has been effective and trying to potentially build on that.

A lot of what was done in terms of concurrent chemoradiation for pancreatic cancer was ineffective because most of the radiation was not very well delineated in clinical trials. Now we’re at a stage where we have progressed 20 to 30 years down the line, where we have all these new tools and ways to do clinical trials. We need to take what we learn from the concurrent setting and try to build off it rather than shift gears completely into a sequential mode.

Ohri / I know our opponents are going to tell us that concurrent chemotherapy is a thing of the past and that it’s toxic and has limited efficacy. There were very sound randomized trials, dozens of trials, showing that adding chemotherapy to treatment sequentially—to radiation—improves outcomes. Six or so trials in a meta-analysis showed a survival benefit when making that chemotherapy concurrent. We have had many trials since then that have shown us that the chemotherapy that we give during radiation does not have to be toxic. It could be something fairly benign, like weekly low-dose carboplatin and paclitaxel. Anybody who could get sequential chemoradiation with full-dose chemotherapy most likely would be able to tolerate a lower dose of chemotherapy concurrently with the radiation. We no longer need to give adjuvant chemotherapy afterward with full doses; we can give immunotherapy. While yes, I believe that for selected subpopulations we will be departing from the backbone of concurrent chemoradiotherapy, for now, [concurrent chemoradiotherapy] still needs to be our default backbone for most patients.

Team Accelerators

Juloori / I appreciate our opponents’ efforts in this question, but I will mention that they’re citing trials and drugs that were developed when Bill Clinton was president [in the 1990s]. It’s time to move on…. We should be learning from our surgical colleagues. When we look at the current paradigms in the surgical trials, [the phase 3 CheckMate 816 (NCT02998528)] and [the phase 3 AEGEAN (NCT03800134)] trials, the excellent outcomes, in my view, are largely driven by intensification of systemic therapy up front. We talked earlier about the failures of PACIFIC-2, [the phase 3 CheckMate73L trial (NCT04026412)], and [the phase 2 NRG-LU002 trial (NCT03137771)] in doing immunotherapy concurrent with chemoradiation. So why don’t we move forward to the future of doing the exact same thing the surgeons are doing? Give 3 or 4 cycles of the best systemic therapy we have. Right now, that’s chemoimmunotherapy.

Gomez / The key point is that by doing the treatment sequentially rather than concurrently, it allows us to tailor our radiation more because we’re not limited by the bounds of the concurrent chemotherapy that they’re getting, which really restricts the doses that we can give. It allows us to individualize care more and allows for that systemic effect up front, which we’ve seen through multiple contemporary studies is so beneficial.

Topic 3: The Future of Brain Control for LS-SCLC and Extensive Stage SCLC

Team Accelerators

Gomez / Many of us can agree that [prophylactic cranial irradiation (PCI)] should go the way of CDs, rollerblading, and Starter jackets and be left in the 1990s. PCI is a very toxic treatment. It’s one of the most in-depth discussions that I have with the patients about the toxicity that they will have. They have significant fatigue, hair loss—which they find is a detriment to their quality of life—and true cognitive deficits. While in many patients those are subtle, in a significant proportion, those aren’t. Therefore, any treatment that we can forgo that has that type of toxicity is a win for all, including the patient No. 2 is that we saw earlier in the modern era with the [phase 3 ADRIATIC trial (NCT03703297)] that there is no clear role for immunotherapy for PCI. Both subgroups benefited from this approach. There wasn’t any clear interaction between the PCI and the durvalumab. We’re in a different era than when the PCI studies were published that demonstrated a benefit. No. 3, we have a very good option for patients who would typically have received whole-brain radiation therapy when they developed a brain metastasis. In the past, it was a matter of either getting a whole-brain [radiation therapy] now or getting a whole-brain [radiation therapy] later, and you getting a lower dose now or getting a larger dose later. However, with the advent of the [multicenter, cohort FIRE-SCLC study] and other reports showing that stereotactic radiosurgery is quite safe and quite feasible for patients who are monitored carefully with MRI, particularly when [brain metastasis is] caught early, patients tolerate [stereotactic radiosurgery] better. We can continue this approach over time of just monitoring closely and targeting lesions when they arise.

Team Phantoms

Samson / I understand all of your comments and agree. Surveillance MRI and the capability of MRI to do as many sequences as it can—1-mm slices—have revolutionized how we follow [patients with SCLC]. However, there still is not just an intracranial control benefit that was shown with historical studies, but also an OS benefit. Ultimately, it needs to be a shared decision-making discussion with the patient. Just like I wouldn’t withhold telling the patient, “Hey, coming up is your immunotherapy following your course of systemic therapy or chemoradiation therapy,” I don’t think a PCI discussion should be withheld by the medical oncologist when referring to radiation oncology. I give them the information.

Thomas / Part of our role is to help educate based on what we know today, and what we know today is that there is still a benefit [with PCI]. It depends on that patient’s perspective of how that disease is impacting them and what they consider the risks of the AEs are. Although we see this day-to-day in our clinics and we see what the AEs are, for that individual patient, taking on that burden of having to look at another MRI every 3 months might cause so much discomfort and anxiety that they might decide to do the PCI.

Round 3: Patient Cases

Patient Case

• A 63-year-old man who is a retired high school principal with a history of smoking, though he quit 8 years ago, diagnosed with adenocarcinoma, nonsquamous NSCLC with a PD-L1 expression of 40%. Currently has residual disease confined to the chest and an ECOG performance status of 1, stable labs, and a good quality of life.

• Initiated on pembrolizumab, pemetrexed, and carboplatin for 4 cycles, and lung mass decreased. Was referred to SBRT for liver lesion, and the lesion is no longer visible on PET after SBRT.

• What are your thoughts? Would you irradiate now? Would you wait and radiate later? Would you not irradiate the lung lesion?

When Would You Offer Local Consolidative Therapy?

Team Phantoms

Ohri / We have the [phase 2 NRG-LU002 trial (NCT03137771)], where patients in this setting who were randomly assigned to the experimental arm would’ve received SBRT to the liver lesion, as well as thoracic radiotherapy to sites of residual disease. Somebody who could not get SBRT to the thoracic disease would’ve gotten a dose of 45 Gy in 15 fractions. That study did not show a benefit in terms of PFS with regard to local consolidative therapy. But it’s important that we not throw the baby out with the bathwater. What we need to do is have discussions with the patient and with the other treating physicians. What’s missing is the imaging. We haven’t seen the scans. It’s a 2-cm tumor, with some small lymph nodes. Perhaps those could be treated very safely with conformal radiotherapy, in which case you might argue, what’s the downside? But if the nodes are bilateral, mediastinal, hilar, or covering a large span, maybe that’s something we should defer.

Samson / Yes, I would say the fact that the liver lesion was treated with SBRT and responded very well could be a key that this is a relatively radiosensitive disease and may prompt me to be more aggressive with radiation therapy. I would have a thorough discussion with the medical oncologist. I would want to see if they are going to transition to [pembrolizumab plus pemetrexed]. How are they handling therapy? Is the patient looking for a systemic break? Are they having some type of toxicity? This patient isn’t. But sometimes our medical oncologists do want to give a systemic therapy break. We can be the bridge between those treatments. In this patient, he’s got a good quality of life. His disease appears to be sensitive and responds well to radiation. I think we would be aggressive in this patient [and treat now].

Team Accelerators

Gomez / The current management is probably not the path that I would’ve taken, radiating the liver lesion in isolation after 4 cycles. In addition, the liver has been shown in some studies to be a poor prognostic site for metastatic disease. In that scenario where [the liver] may be an immune sanctuary, are you then ablating it to mitigate that risk? The general criteria at our institution for doing local consolidation off trial in a patient like this would be at least 6 months on treatment and having received the maximum response to systemic therapy. That’s not based on any single trial; it comes from our ongoing discussions—we present most of these cases in a dedicated component of our tumor board. All said, I think you’ve already gone down the path of doing local consolidation. You’re 4 cycles in. If the patient’s doing well and it looks like the radiation field will be manageable for the patient with acceptable dose constraints, then it’s reasonable to do.

Juloori / My view might differ from my colleagues because one important piece of information that’s missing here is what the PET scan is showing in the chest. In our practice in Chicago, the [method] we have adopted is that we’re getting a lot of PETs around the 6-month mark of systemic therapy, and we’re using PET to guide what to treat. If something is still active, we’re treating it. [If it’s cold, personally, I would not treat it.]

Finkelstein / There are only 2 reasons to offer radiation therapy, in general. One is the idea of cure, and that can be extrapolated to render somebody [no evidence of disease (NED)]. The second is for palliation…. When we talk about this, this comes back to whether we think we can render a patient NED. If we can, we’ve eliminated the ability of that site to send terrible things off to other places, but we also make that patient NED, where as far as humans can tell, there’s no cancer we can see in them…. Now, do we believe that that’s going to happen to this guy? Going back to the debate, this is where my colleagues on the Accelerator team said to engage a multidisciplinary approach. Get the buy-in of all your colleagues, talk to them, and communicate with them. If we’re all on the same team, pulling in the right direction, and you have shared decision-making with your patient, you pull the trigger. You’re going to do that, and the patient’s going to feel pretty good that you did the best that you could do for them, at that moment.

References

1. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol.2022;40(12):1301-1311. doi:10.1200/JCO.21.01308

2. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937

3. Peters S, Cristoph DC, Field JK, et al. Real-world outcomes with durvalumab after chemoradiotherapy in unresectable stage III EGFR-mutated NSCLC (PACIFIC-R). J Thorac Oncol. 2023;18(11):S83. doi:10.1016/j.jtho.2023.09.088

4. Bradley JD, Sugawara S, Lee KHH, et al. Durvalumab in combination with chemoradiotherapy for patients with unresectable stage III NSCLC: final results from PACIFIC-2. Presented at: 2024 European Lung Cancer Conference; March 20-23, 2024; Prague, Czech Republic. Abstract LBA1.

5. Garassino MC, Mazieres J, Reck M, et al. Durvalumab (durva) after sequential chemoradiotherapy (CRT) in patients (pts) with unresectable stage III NSCLC: final analysis from PACIFIC-6. Presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA61.

6. Filippi AR, García Campelo MR, Paoli JB, et al. Durvalumab after radiotherapy in patients with unresectable stage III non-small-cell lung cancer ineligible for chemotherapy: the DUART phase II nonrandomized controlled study. ESMO Open. 2025;10(9):105560. doi:10.1016/ j.esmoop.2025.105560

7. Lu S, Kato T, Dong X, et al; LAURA Trial Investigators. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi:10.1056/NEJMoa2402614