Small-Cell Lung Cancer - Episode 2

Standard of Care for ES-SCLC

March 25, 2021
Jared Weiss, MD, University of North Carolina at Chapel Hill

Stephen V. Liu, MD, Georgetown University

Experts in thoracic oncology review data from the IMpower133 and CASPIAN trials as well as the use of chemotherapy with PD-L1 inhibitors for treatment-naïve ES-SCLC in clinical practice.

Jared Weiss, MD: The addition of PD-L1 inhibitory therapy, or atezolizumab or durvalumab, is absolutely the standard of care for first-line treatment of extensive-stage small cell lung cancer [ES-SCLC]. This initially came about as a consequence of the IMpower133 study. This was a well-designed and simple study. It was a randomization where half of the patients got the then standard of care, carboplatin and etoposide, and the other half got the standard of care plus the PD-L1 inhibitor atezolizumab. Appropriately, patients received combination therapy for 4 cycles and then either got maintenance therapy with atezolizumab or placebo. Thinking about other elements of trial design that matter, PCI [prophylactic cranial irradiation] was allowed but not mandated. Of note, consolidative thoracic radiation was not allowed. Primary end points of this study were progression-free [PFS] and overall survival [OS]. Total alpha was 0.05 allocated between these. The impact of my practice is that this is the absolute standard of care that all fit patients get in the front line as a result of a PFS and OS advantage.

In my practice, every patient with extensive-stage small cell lung cancer who is sufficiently fit and whose values are appropriately oriented receive the combination of carboplatin, etoposide, and a PD-L1 inhibitor. I get imaging after 2 cycles and after 4 cycles, and in the event of tolerance and nonprogression, I treat with indefinite maintenance therapy with the PD-L1 inhibitor.

My practice results nicely mirror the trial results. The PFS and OS advantage is unfortunately small, but is real. The regimen is well tolerated in my practice, very consistent with the trial results from IMpower133. We do see the same adverse effects of chemotherapy, which are the dominant adverse effects. There’s nothing about the addition of atezolizumab that protects against myelosuppression and its downstream sequalae: nausea, fatigue, etc, that come with chemotherapy. And there’s nothing about chemotherapy that protects against the immune-related events that occur with atezolizumab.

One question I am frequently asked is whether given that small cell is a cancer that can have these paraneoplastic syndromes, do we see more paraneoplastic syndromes with the addition of the PD-L1 inhibitor? The answer in my experience is no, we don’t. The playbook for managing these toxicities is identical to what you would have done before. The management of myelosuppression-related events is dose reductions, dose delays, the use of supportive therapy. Very recently we had the approval of trilaciclib, which can be used to prevent them. For the management of immune-related adverse events, it depends on the event, but the mainstay is usually high-dose steroids.

The use of either cisplatin or carboplatin is considered acceptable in extensive-stage small cell lung cancer. I have strong opinions to prefer carboplatin for my patients. The survival advantage with cisplatin is trivial. It’s on the order of days, whereas the toxicity difference of these agents is dramatic. Carboplatin has far less nausea than cisplatin. It doesn’t have the nephrotoxicity problem. It doesn’t have the neurotoxicity problem. It doesn’t cause tinnitus and hearing loss. The one thing to be aware of that’s a little worse with carboplatin is blood cell count suppression, but with trilaciclib and Neulasta, these are easily managed. Both are reasonable, but I strongly favor carboplatin.

Stephen V. Liu, MD: The CASPIAN study was the second trial to show a survival benefit when immunotherapy was added to first-line chemotherapy. This was an open-label phase 3 trial for patients with extensive-stage small cell lung cancer and no prior therapy. This study did include patients with asymptomatic untreated brain metastases. Patients were randomized to 1 of 3 arms. The control arm was platinum plus etoposide, either cisplatin or carboplatin, for 4 to 6 cycles. There was an arm of platinum, etoposide with concurrent administration of the PD-L1 inhibitor durvalumab, followed by durvalumab maintenance. And the third arm was a combination of platinum, etoposide with durvalumab and the CTLA-4 inhibitor tremelimumab, followed by durvalumab maintenance alone. Prophylactic cranial irradiation was permitted only in the control arm, and no arms featured thoracic radiation.

This was a large study randomizing over 800 patients with small cell lung cancer. It showed that the addition of durvalumab to chemotherapy did improve overall survival. Median survival with chemotherapy alone was 10.5 months. With chemotherapy plus durvalumab, that improved to 12.9 months, with a hazard ratio for death of 0.75. The 18-month survival rate was 32% with durvalumab, 25% with chemotherapy alone. Based on this survival benefit, durvalumab was approved in combination with platinum/etoposide for the frontline treatment of extensive-stage small cell lung cancer.

Now, the third arm, the addition of durvalumab plus tremelimumab did not unfortunately improve outcomes. Median survival with durvalumab, tremelimumab plus chemotherapy was 10.4 months; compare that to 10.5 months with chemotherapy alone. Hazard ratio for death, 0.82. Dual checkpoint blockade, durvalumab/tremelimumab with chemotherapy, was also more toxic, with 1 in 5 patients, 21%, discontinuing therapy due to adverse events. Compare that to only 9% to 10% in the other 2 arms. The combination of durvalumab/tremelimumab and chemotherapy is not approved and not a part of our standard of care.

Both IMpower133 and CASPIAN were randomized phase 3 trials that demonstrated that the addition of a PD-L1 inhibitor to chemotherapy improved survival. While there are differences in study design, and these are 2 different drugs, the results are more similar than different. In fact, even with longer follow-up, those Kaplan-Meier curves for survival are almost overlapping. In my opinion, both agents are appropriate, both are approved, and I do not have a factor of one over the other. It comes down to comfort and perhaps nonclinical choices, such as cost or formulary restrictions. Both agents can be administered every 4 weeks as part of maintenance. The only salient difference between the trials that could come into play is the choice of platinum.

CASPIAN did permit either cisplatin or carboplatin, whereas IMpower133 only explored the use of carboplatin. I would be comfortable using cisplatin in combination with atezolizumab. I have no reason to expect they would perform differently, but the highest level of evidence with cisplatin is the durvalumab combination. I do not use cisplatin routinely. There are very few instances where I feel it’s appropriate to give cisplatin, a much more toxic drug in the setting of extensive-stage small cell lung cancer. But if, for example, someone had significant myelosuppression perhaps from marrow metastases and I was worried about the more myelosuppressive carboplatin, that may be an instance where I would use cisplatin. In that instance, the addition of durvalumab to cisplatin would be supported by more evidence and would be a reasonable choice. But overall, both agents improve survival, and are reasonable and appropriate.

Transcript Edited for Clarity