Durvalumab Combination Improves Outcomes in Patients With ES-SCLC

Luis Paz-Ares, MD, PhD

Luis Paz-Ares, MD, PhD

At the 2019 ESMO Congress, updated data from the phase III CASPIAN trial demonstrated delays in the development of new lesions and improvements in patient-reported outcomes (PROs) with the addition of durvalumab (Imfinzi), a PD-L1 inhibitor, to etoposide and platinum-based chemotherapy in the frontline for patients with extensive-stage small cell lung cancer (ES-SCLC).¹However, PD-L1 expression did not appear predictive of response.

Overall, 805 patients with previously untreated ES-SCLC were randomized 1:1 to receive either 4 cycles of etoposide and platinum-based chemotherapy plus durvalumab (1500 mg) every 3 weeks followed by maintenance durvalumab every 4 weeks, or up to 6 cycles of the etoposide plus platinum-based chemotherapy regimen alone every 3 weeks, plus prophylactic cranial irradiation (PCI) per the investigator’s discretion.

Prior results of the CASPIAN trial presented at the 2019 World Conference on Lung Cancer demonstrated that there was an increase in overall survival (OS) with the addition of durvalumab; median OS was 13.0 months versus 10.3 months in the durvalumab arm versus the control arm, translating to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.591-0.909;P= .0047) at a median follow-up of 14.2 months.²

The updated findings demonstrated that fewer patients in the durvalumab arm developed new lesions at first progression (41.4% vs 47.2%). The rates of total progression events were 84.3% versus 86.6% in the durvalumab versus control arms, while progression occurred in 71.6% and 72.1% of patients, respectively. Rates of nontarget lesion progression were 24.6% and 2.7%, while death in the absence of progression occurred in 12.7% and 14.5%, respectively.¹

In an interview withTargeted Oncology, Luis Paz-Ares, MD, PhD, medical oncologist and chair of Medical Oncology Department at Hospital Doce de Octubre in Madrid, Spain, discussed the findings for the CASPIAN trial that were presented at the 2019 ESMO Congress. He also addressed what next steps are necessary to further develop the durvalumab combination in this setting.

TARGETED ONCOLOGY: What was the rationale for the CASPIAN trial?

Paz-Ares:The CASPIAN trial actually looked at the effects of adding an anti—PD-L1 agent to the standard platinum-based chemotherapy combination in patients with advanced ES-SCLC. For a number of years, almost 3 decades, either carboplatin or cisplatin were the standard of care in this setting. Recently, we have seen that PD-1/PD-L1 inhibitors do have some interesting activity in lung cancer, specifically in SCLC as well. In fact, last year there was a study showing that adding atezolizumab (Tecentriq), another PD-L1 inhibitor, did improve survival in patients with this disease. This trial actually tried to evaluate the role of durvalumab, a PD-L1 inhibitor, as a combining treatment with chemotherapy in this setting.

TARGETED ONCOLOGY: What were efficacy data for the addition of durvalumab?

Paz-Ares:What we have seen in this trial at the interim analysis is the durvalumab arm of 4 courses of platinum-based chemotherapy plus etoposide plus durvalumab followed by durvalumab, demonstrated increasing survival as compared to the control arm, which was platinum plus etoposide for up to 6 courses followed, by the investigators criteria, with PCI, or not. The primary endpoint was met, increasing OS with a general increase in the hazard ratio of 0.73, which translates to an increase the median OS from 10.3 months in the control arm to 13 months in the experimental arm.

TARGETED ONCOLOGY: What were the significance of these data?

Paz-Ares:It is clear that anti—PD-L1 therapy is effective. The data from the CASPIAN trial are somehow [associated with] the IMpower133 trial with atezolizumab, so 1 trial confirms the other as a concept [that there is] improved survival, improved PFS, improved response rate, and the toxicity profile is manageable. There are no unexpected adverse effects.

The second thing that is relevant from that particular trial is all patients received cisplatin and carboplatin, per investigator’s choice. This is somewhat reflective of what is happening in real life. Secondly, we allow patients to receive treatment in the control arm after 6 courses of chemotherapy, which is something we do very frequently. Thirdly, and important as well, patients with asymptomatic brain metastases were below 20% without irradiation. Those are some added bits to this study that I think will have some impact.

How relevant is this for the patient? Overall, [the addition of durvalumab] decreased the risk of death by 27%. I think this is important. We increased survival by nearly 3 months. I would prefer it to be 3 years, but those data, I think, are relevant.

TARGETED ONCOLOGY: Could you speak to progression in patients with PD-L1 expression?

Paz-Ares:Mainly, those data say that in terms of PD-L1 expression, the expression of PD-L1 in our analysis in the tumor cells was really low and did not allow us to make any [conclusions]. I don’t think PD-L1 expression is going to be an effective biomarker to select patients in this setting.

Secondly, in terms of progression, I would say the anti—PD-L1 therapy of durvalumab added to chemotherapy decreased the progression rates of all places, including the central nervous system. Thirdly, in terms of PROs, the data are pretty significant, and I would say the treatment with durvalumab did not impair quality of life for those patients.

TARGETED ONCOLOGY: What would you say are the immediate next steps with this research?

Paz-Ares:There are many things to do. Concerning this particular trial, it is very important to get mature data. It’s going to be really important to see how much durvalumab is adding in terms of long-term survival. Second, what happened with the durvalumab plus chemotherapy arm, the third arm? The interim analyses were not reaching the threshold for significance, but we need to wait until the final analysis. That is an important point as well. Third, it would be nice to see further biomarker data to see if we are able to get some predictivity here.

Finally, in terms of the context of NSCLC, a number of other things have to be done. We’ve seen PD-1/PD-L1 inhibitors in earlier disease in the context of limited disease stage, particularly in combination with chemoradiotherapy. Secondly, some other alternatives of immunotherapy are going to be crucial here. Some of the attractive therapies would be, I think, from a rational point of view, bispecifics against the LL3 and anti-CD3. There is already 1 compound in clinical phase I trials. Of course, we have to learn a lot about the immune milieu of SCLC, such as which are the potential targets that we should target in this setting. Other agents have to be further investigated.

References:

1. Paz-Ares L, Goldman JW, Garassino MC, et al. PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN. Presented at 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA62.        
2. Paz-Ares L, Chen Y, Reinmuth N, et al. Overall survival with durvalumab plus etoposide-platinum in first-line extensive-stage SCLC: results from the CASPIAN study. Presented at: International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA002.