Today, the Phase 3 results of DeLLphi-305 (@AmgenOncology @AstraZeneca) were presented by @sands_jacob at #ESMO26.

DeLLphi-305 delivered an unprecedented OS improvement (21.1 vs 12.7 mo, HR 0.42) for patients receiving tarlatamab + durvalumab, compared to durvalumab alone, in 1L maintenance after chemoIO induction for ES-SCLC. Studies like these provide renewed hope.

However, this data brings forth multiple concerns regarding international access to care, interpretation of contribution of parts, patient selection, and sequencing.

1️⃣ Equitable access to cross-over: at time of POD, only 12.2% of ITT population in the durvalumab arm (34/278) and 18.9% (34/179) of those who received subsequent anti-cancer therapies had access to tarlatamab.

This speaks to the global need to expand access to this life-saving therapy, as DeLLphi-301 demonstrated this impact with accessibility promptly available here in the USA as early as May 2024. Yet, @SclcSMASHERS all over the world still do not have this option even at relapse.

2️⃣ Line of therapy: while attrition to 2L may be significant in some practices & highlights the need to maximize proactive support & early palliative care, is there clear evidence of synergy with ICI+DLL3 TCE to transform outcomes, or is the effect additive? Preclinical data suggested synergy with this combination approach.

However, within subgroup analyses of those receiving tarlatamab in subsequent treatment, particularly in the USA, it appears there is signal of additivity, given the nullification of OS benefit with DLL3 TCE cross-over (in those receiving it as 2nd LOT).

Outside of risk of attrition, what variables favor using tarlatamab in 1LM vs 2L? Is the NE biology still preserved? Is the function of the immune system equivalently preserved following <4 weeks post chemoIO with myelosuppression?

3️⃣ Patient selection: Stratification with effective predictive biomarkers are key to know who can avoid any intensification, as they may be a durable ICI responder to monotherapy ICI.

Who can we avoid tarlatamab every 2 weeks indefinitely? Who should receive lurbi + atezo? Or durva + tarla?

More translational SCLC based biomarkers, beyond DLL3, are clearly of high unmet need to guide strategies.

4️⃣ Sequencing: if we use tarlatamab+durvalumab in the 1LM, what’s next? At POD, what approved option remains? Lurbi remains approved in the 1LM, but not at relapse. I-DXd BLA was voluntarily withdrawn. Trials are key, but enrollment for most global studies is brisk, particularly in the USA where enrollment is ~20% or less of the total cohort.

@SclcSMASHERS @LUNGevity @IASLC @ASCO @NCCN @LungCancerEu @lcrf_org @OncBrothers @OncoAlert @oncodaily @OncLive @lungoncdoc @RManochakian @LauraAlderMD @LaurenByersMD @Annechiangmd