Updated findings from the phase 3 CASPIAN trial presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed maintained overall survival (OS) benefit of durvalumab treatment in combination with platinum etoposide chemotherapy vs chemotherapy alone, in newly diagnosed patients with extensive-stage small cell lung cancer (ES-SCLC) after more than 2 years of follow-up.

ASCO data showed that more than 10% of patients on durvalumab plus chemotherapy had not progressed and remained on treatment at two years vs 2.9% on chemotherapy alone.

However, the CASPIAN trial met the primary endpoint of OS in June 2019, reducing the risk of death by 27% (based on a hazard ratio [HR] of 0.73; 95% confidence interval [CI] 0.59-0.91; p=0.0047) which formed the basis of the US FDA approval in March 2020.

Adding an Anti-CTLA4 Antibody to the Mix

At the Virtual ASCO Annual Meeting held 29-31 May 2020, Prof. Luis Paz-Ares (Hospital 12 de Octubre, Madrid, Spain) presented the first report of the third study arm of CASPIAN, in which investigational CTLA-4 inhibitor tremelimumab was added to PD-L1 checkpoint inhibitor durvalumab on top of standard of care chemotherapy.

CASPIAN randomized 805 patients to 3 treatment arms: durvalumab + tremelimumab + etoposide cisplatin/carboplatin (EP) (n=268), EP alone (n=269), or durvalumab + EP (n=268). The primary endpoint of the study was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety and tolerability. Findings from CASPIAN reported previously in the Lancet that, after a median follow-up of 14.2 months, the addition of the durvalumab improved the median OS to 13.0 months versus 10.3 months with EP alone (HR 0.73; 95% CI 0.59-0.91; P=0.0047), with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months [2]. Consequently, in March 2020, the FDA approved durvalumab in combination with EP as first-line therapy for ES-SCLC.

In the current presentation, after a median follow-up of 25.1 months, the median OS was 12.9 months among patients who received durvalumab + EP compared with 10.5 months for those who received EP alone (HR 0.75; 95% CI 0.62-0.91; P=0.0032), fully supporting the initial report. Of note, the study design allowed the use of either backbone carboplatin or cisplatin; the OS data favored durvalumab regardless of whether carboplatin (HR 0.79; 95% CI 0.63-0.98) or cisplatin (HR 0.67; 95% CI 0.46-0.97) was the backbone chemotherapy agent used.

“Importantly, the separation among the curves seems to be observed over time and, indeed, survival at 2 years improves from 14% [of participants] in the control arm to 22% on the experimental arm. The magnitude of the benefit is very similar and very consistent across all the prespecified subgroups of patients analyzed, including those treated with cisplatin or those patients with liver or brain metastases,” said Prof. Paz-Ares.

However, the study’s third arm testing dual checkpoint blockade with tremelimumab + durvalumab + EP did not meet the prespecified threshold for statistical significance (P≤0.0418). The median OS for this combination was 10.4 months versus 10.5 months for EP alone (HR 0.82; 95% CI 0.68-1.00; P=0.0451). The OS survival rates at 18 months were 32.0% in the durvalumab + EP arm, 30.7% in the tremelimumab + durvalumab + EP group, and 24.8% in the EP cohort; at 24 months, those rates were 22.2%, 23.4%, and 14.4%, respectively.

The median PFS was 4.9 months for the tremelimumab + durvalumab + EP arm compared with 5.4 months for the EP arm (HR 0.84; 95% CI 0.70-1.01). The confirmed ORR and median duration of response were 58.4% and 5.2 months, respectively, in the tremelimumab + durvalumab + EP group compared with 58.0% and 5.1 months for the EP arm.

Safety events were consistent with the known adverse events (AEs) associated with the medicines. The rates of grade 3/4 and serious AEs were, respectively, 70.3% and 45.5% in the tremelimumab + durvalumab + EP arm, 62.3% and 32.1% in the durvalumab + EP arm, and 62.8% and 36.5% in the EP group. AEs leading to treatment discontinuation occurred in 21.4% of patients in the tremelimumab + durvalumab + EP arm, 10.2% in the durvalumab + EP group, and 9.4% in the EP cohort. Treatment-related deaths were 12 in the tremelimumab + durvalumab + EP arm, 6 in the durvalumab + EP arm, and 2 in the EP arm. In conclusion, the benefit-to-risk ratio favored treatment with durvalumab + EP, without tremelimumab, for treatment-naïve ES-SCLC.

Ongoing Survival Benefit With Durvalumab in ES-SCLC

While the third arm of the study missed the co-primary endpoint of the phase 3 CASPIAN study, the ongoing data constitute robust support for accumulating evidence that anti-PD-1L therapy boosts results when added to a platinum backbone.

Physician’s Weekly asked CASPIAN senior investigator Prof. Jonathan Goldman, MD, oncologist at the Ronald Reagan UCLA Medical Center, for his perspective:

‘’The idea was for this trial was to have a really clean control arm, a real-world comparator, with more than half the control arm patients receiving >6 cycles. The patients did really well for that regimen too, so I think we can be confident in the result and the meaningful additional element of durvalumab,” says Dr. Goldman.

“Unfortunately, adding tremilimumab to durvulumab did not have benefit, and I think now that that data will call into question CTLA-4’s role in small-cell lung cancer. There are other agents in other trials that have shown an improved response rate with adding to CTLA-4 to PD-1/ PD-L1 inhibitors and while there’s definitely an increase in toxicity at this point it is not clear that that is met with improved long-term outcomes.”

“The PD-L1 inhibitor, durvulumab, in chemotherapy has meaningfully improved survival in an area where there have been no changes for decades, and now to improve on that new standard, I think we have to become more creative,” Dr. Goldman says. It may be adding in other agents to the maintenance phase.”

Dr. Goldman says that they are looking at adding temozolomide and a PARP inhibitor to the maintenance phase of the PD-L1 inhibitor and notes that there are some potential benefits, including evidence of synergy between each of those different components, which was reported in Clinical Cancer Research as well as by us. “There’s been some excitement already about PARP inhibitors and immunotherapy drugs.”

 

“We really should also be focusing on the tail of the curve – the patients who received the most durable response in this study. On the durvalumab arm, there are 10-20% of patients who are still doing well, 18 and 24 months into treatment which is, without durvalumab, a rare event. I think our ability to select those patients up front right now is limited. PD-L1 expression does not appear to be a useful biomarker. Tumor mutational burden studies remain to be done; that analysis is underway. There is some thought that there are different histologic and genetically distinct subgroups of small cell lung cancer, and some of them do seem to be more inflamed and perhaps more susceptible to immunotherapy benefit, but at this point that is a hypothesis that requires prospective confirmation.”

 

  1. Paz-Ares LG,et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated Results from the phase III CASPIAN study. ASCO Virtual Meeting, 29-31 May 2020, Abstract 9002.
  2. Paz-Ares LG, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.  2019;394(10212):1929-1939.