First-line Immunotherapy: IMPower133 Regimen



Naiyer A. Rizvi, MD: We’ve clearly moved forward with immunotherapy in the second- and third-line settings. But, again, from the first-line setting, nothing has been approved since etoposide and carboplatin for first-line treatment, so there are multiple approaches with maintenance chemotherapy, switched maintenance chemotherapy—different immunotherapies. Maintenance approaches have been negative over the past 20-plus years. I think it’s a landmark trial to have the combination etoposide-carboplatin and atezolizumab showing an improved survival in patients with extensive-stage small cell. Before Jamie tells us about the trial and her thoughts, would everyone agree that basically it’s universal that everyone, barring any contraindications, will be getting first-line I/O [immuno-oncology] plus chemotherapy now for extensive-stage disease?

Taofeek K. Owonikoko, MD, PhD: In the United States?

Naiyer A. Rizvi, MD: Yeah

Taofeek K. Owonikoko, MD, PhD: Yes. That should be expected of all of us at this point.

Naiyer A. Rizvi, MD: Yeah. So Jamie, tell us about the trial.

Jamie E. Chaft, MD: IMpower133 was a practice-changing trial of carboplatin-etoposide with atezolizumab or placebo. It was first-line small cell, no prior treatment. Treated brain metastases were allowed—untreated were not. And patients received just 4 cycles of therapy. And this is truly a practice-changing trial, to an improvement in overall survival of about 2 months that, while seemingly small, is relatively quite large for this disease. I don’t think we saw any anticipated safety signals. The drugs were otherwise as they would have been anticipated to be tolerated. And we now have our first new standard of care in some decades.

Naiyer A. Rizvi, MD: And so how many cycles of chemotherapy do you give?

Jamie E. Chaft, MD: The study was 4. I think my practice parallels to Taofeek’s in that most patients get 4. I think in the initially, about a year since the adoption of this new standard of care, there has been a bit more regulatory oversight from payers, and we’ve been limited at 4. Although would there be a place for synergy and pushing patients to 6 cycles, I think there could be. You could make a case.

Naiyer A. Rizvi, MD: And then the atezolizumab as a maintenance every 3 weeks, you give indefinitely?

Jamie E. Chaft, MD: Every 3 weeks until there’s a reason to stop, and that’s either toxicity or progression

Naiyer A. Rizvi, MD: Right. It’s interesting that the conversation we were having early was about us not really feeling so thrilled about chest radiation. But to Ticiana’s point, what we know about neoantigen release and some synergy with immunotherapy, maybe we should be trying to incorporate that into our paradigm. My experience with chest RT [radiotherapy] and I/O and other situations is that they don’t seem to cause more problems in terms of pneumonitis. Is that something you do? Would you give consolidation chest RT at the same time, and as part of the IMpower133 regimen?

Ticiana Leal, MD: That’s a great question. And I think we were a site, and we participated in IMpower133, so we had used chest consolidation prior to using immunotherapy. It fell off our radar in the sense that we were using immunotherapy and trying to understand what the pattern will be if we don’t use chest consolidation. Obviously, in the beginning, we were worried about toxicity and if there could be there more toxicity than benefit. I haven’t used a whole lot of chest consolidation in the era of incorporating immunotherapy in the maintenance setting. But I think that’s something our group has discussed, and we’ve used it in select cases. We’ll talk about the limited-stage study that is incorporating chemoradiation plus immunotherapy. That will also give us a lot of important safety and perhaps synergy data as well.

But that brings up a good question of how do you select patients for this regimen, right? Because one of the things I’ve seen clinically is patients get the IMpower133 regimen. They go on to the maintenance atezolizumab and progress locally in the chest, and it’s bulky disease, and it comes back pretty quickly. So I do wonder, and I think we really have to explore the chest consolidation for some of these patients for whom we worry about recurrence with SVC [superior vena cava] syndrome with bulky disease in the chest that comes very rapidly.

One other interesting thing that we did was we went back and looked at Flatiron Health data even before the approval of CARBO [carboplatin]—ETOP [etoposide]–atezolizumab. It was already in the NCCN [National Comprehensive Cancer Center] Guidelines. We went back and saw how clinicians were incorporating the atezolizumab-chemotherapy regimen even prior to FDA approval, and we saw that in about 20% of the cases, patients were receiving this combination regimen outside the eligibility criteria of clinical trials which, No. 1, tells a lot about our clinical trial, which doesn’t really apply to our real population. And then No. 2, the unmet need that people really wanted to use something and felt very strongly about trying this new regimen. There was a lot of enthusiasm. Patients with ECOG [Eastern Cooperative Oncology Group] PS [performance status] of 2, patients who perhaps got cisplatin instead of carboplatin, patients with organ dysfunction, which we commonly see, and so on. Selecting patients for this regimen beyond what we saw in the clinical trial is something that clinically we’ll have to see how that goes in real life.

Taofeek K. Owonikoko, MD, PhD: The use of thoracic radiation is something I struggle with. We all recognize that small—cell lung cancer is very challenging. We want to treat these patients, but we also have to perhaps learn the lesson that came from the approach of high-intensity multiagent chemotherapy compared with just going with doublet platinum chemotherapy that did not result in any survival advantage but more of toxicity for patient.

So we look at the CREST data. Granted, when you use the consolidation thoracic radiation, you delay progression in the chest. But 40% of those patients still progressed in the chest. Close to 70%, 80% of patients who did not have any thoracic radiation progressed, so you did reduce the rate at which patients were progressing in the chest. But the question comes, would you have been able to salvage those patients if you had waited, without rushing to give the thoracic radiation to everyone without knowing exactly who’s going to benefit?

And the other note of caution, there was the G0937 trial, which sort of adopted the same strategy, although that was not strictly thoracic radiation treatment. It was more radiation to all the areas of involvement, including the chest, as long as it’s 4 sites or less. Surprisingly, that study actually showed worse outcome for patients who got radiation treatment after completing frontline chemotherapy. So I think there could be a subset who would benefit. We don’t really know who those patients are, but let’s just say we have to give it to everyone because these are very sick patients who need treatment, we may be harming some of our patients who do not benefit from it.

Jamie E. Chaft, MD: Although we have a new standard of care with IMpower133, we have to admit that the outcomes are still underwhelming. The question of incorporation of radiotherapy, thoracic radiotherapy in particular, is absolutely worth studying.

Transcript Edited for Clarity

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