Durvalumab Shifts Decades-Long SOC as First FDA-Approved Immunotherapy Regimen in LS-SCLC

The unprecedented improvement seen in overall survival (OS) with durvalumab (Imfinzi) vs placebo in patients with limited-stage small cell lung cancer (LS-SCLC) who did not experience disease progression following standard-of-care (SOC) concurrent platinum-based chemoradiotherapy represented a big advancement in a setting where the SOC has been stagnant, according to Suresh Senan, MRCP, FRCR, PhD.

“We presented the findings in the different chemoradiotherapy subgroups [including in those who received prior] prophylactic cranial irradiation [PCI], yes vs no; once vs twice daily thoracic radiotherapy; and cisplatin vs carboplatin as the chemotherapy backbone [with etoposide],” Senan said in an interview with OncLive®. “There was a consistent benefit with durvalumab [vs placebo] in all these subgroups, so the findings regarding the survival benefit for durvalumab are quite robust taking into account the variations in chemoradiotherapy practice that were permitted within the phase 3 ADRIATIC trial [NCT03703297].”

Data from ADRIATIC, which supported the December 4, 2024, FDA approval of durvalumab, revealed that the agent produced a statistically significant improvement in OS (HR, 0.73; 95% CI, 0.57-0.93; P = .0104) and progression-free survival (PFS; HR, 0.76; 95% CI, 0.61-0.95; P = .0161) vs placebo.1 The most common any-grade adverse effects (AEs) experienced by patients who received the immunotherapy (n = 262) were pneumonitis or radiation pneumonitis (38%), fatigue (21%), and rash (18%); grade 3 or 4 AEs included pneumonitis or radiation pneumonitis (3.1%), pneumonia (3.1%), diarrhea (1.9%), rash (0.4%), fatigue (0.4%), and dyspnea (0.4%).2 Following the publication of these encouraging data, investigators are awaiting data on the efficacy of durvalumab plus tremelimumab (Imjudo) from ADRIATIC.

In the interview, Senan detailed how the approval of durvalumab has changed care for patients with LS-SCLC. Senan is a professor of clinical experimental radiotherapy at the Amsterdam University Medical Centers in the Netherlands.

OncLive: What is the significance of durvalumab’s approval in LS-SCLC?

Senan: It is very significant because we’ve had little change in the treatment paradigm for the past 30 or so years—it has been concurrent chemoradiotherapy to the chest with platinum-[based chemotherapy plus] etoposide followed by PCI in fit patients, and that combination has not changed much. We’ve hit a bit of a plateau in survival; 5-year survival [rates] are approximately 30% and more than half of patients develop [disease] recurrence in the first 2 years of treatment. Therefore, the findings from ADRIATIC are very significant.

In the non–small cell lung cancer [NSCLC] locally advanced setting, durvalumab administered after completion of thoracic chemoradiotherapy improved OS and distant metastasis–free survival [vs placebo], and we believe that the prior chemoradiotherapy to the chest primed the tumor microenvironment, making it more susceptible to subsequent adjuvant immunotherapy. The same now seems to play a role in LS-NSCLC. It’s a bit surprising because in the trials of chemoimmunotherapy in extensive-stage SCLC, we saw [median] survival benefits with the addition of [durvalumab to] chemotherapy of approximately 2 to 2.5 months so this 22.5-month improvement in OS [in LS-SCLC] has been quite surprising. The only explanation we have is that the thoracic tumor microenvironment is being primed for immunotherapy in some fashion by the prior thoracic chemoradiotherapy.

What unmet needs does this approval seek to address?

An improvement in survival because for most patients we call [the SOC] a curative treatment, but it has not been curative. Cure is a primary objective, and we’ve now shown a very significant improvement in median OS of more than 22.5 months [with durvalumab vs placebo] which could be called the breakthrough for this disease—that’s the first step [as] the unmet need [is] improving cure [rates]. It also appears that the treatment is well tolerated despite being delivered for [up to] 2 years, and patient tolerability is a key issue. We have not seen any unexpected complications or difficulties in tolerating 2 years of durvalumab in this setting.

What was the design of ADRIATIC?

ADRIATIC is a phase 3, randomized, double-blind, placebo-controlled, international trial evaluating durvalumab with or without tremelimumab [vs placebo] as consolidation treatment in patients with LS-SCLC who had not progressed after concurrent chemoradiotherapy with or without PCI. The study included patients with stages I to III LS-SCLC and patients had to have a [World Health Organization] performance score of 0 or 1. They were randomly assigned to 3 study arms: Durvalumab alone every 4 weeks for up to 24 months, [matched]-placebo, or the third arm, which remains blinded, was durvalumab plus tremelimumab, with tremelimumab delivered for 4 doses before continuing with durvalumab alone. The dual primary end points were OS and PFS by blinded independent central review for durvalumab vs placebo.

What were key efficacy and safety findings from the ADRIATIC study?

Data from the first interim analysis revealed that durvalumab significantly improved OS and PFS vs placebo. The median OS improved to 55.9 months [with durvalumab] vs 33.4 months for placebo and the median PFS was 16.6 months vs 9.2 months, [respectively].

There were no new safety signals [observed]. The [rates of] maximum incidence of grade 3 to 4 AEs was similar in both arms at approximately 24%, but rates of AEs leading to treatment discontinuation were somewhat high in the durvalumab arm at 16.4% vs 10.6% [with placebo]. Of note, the any-grade pneumonitis rates—pneumonitis or radiation pneumonitis—were 38.2% in the durvalumab arm and 30.2% in the placebo arm.

Are there any ongoing trials within this space that are adjacent to this research?

There is [the phase 3] NRG-LU005 trial [NCT03811002] which investigated another immunotherapy agent, atezolizumab [Tecentriq], and the study design was somewhat different. There was the standard concurrent chemoradiotherapy arm, just like in ADRIATIC, but the experimental arm was atezolizumab delivered concurrently during the chemoradiotherapy followed by 1 year of maintenance. There are 2 aspects which are different [between the trials]. Firstly, immunotherapy was administered during concurrent chemoradiotherapy whereas in the ADRIATIC study it was after. Secondly, just 1 year of maintenance [was given in NRG-LU005 vs 2 years in ADRIATIC]. [However, data presented at the 2024 ASTRO Annual Meeting showed that the atezolizumab regimen did not improve survival vs standard chemoradiation in patients with LS-SCLC].

References

1. FDA approves durvalumab for limited-stage small cell lung cancer. FDA. December 4, 2024. Accessed January 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-limited-stage-small-cell-lung-cancer
2. Imfinzi. Prescribing information. AstraZeneca; 2024. Accessed January 14, 2024. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/9496217c-08b3-432b-ab4f-538d795820bd/9496217c-08b3-432b-ab4f-538d795820bd_viewable_rendition__v.pdf