Letter re: Global advances and future directions in lung cancer care: expert consensus and strategic priorities

I read with interest the expert consensus by Meyer et al.¹ regarding strategic priorities in lung cancer. While it provides a vital synthesis, the current roadmap faces significant methodological and clinical dilemmas that warrant discussion.

Firstly, we must address systemic research limitations. Accessing tissue in lung cancer involves high procedural risks. Automatically excluding patients with cytological diagnoses in phase III trials selects a ‘fitter’ population unrepresentative of real-world practice. We must also question if the translational output of tissue samples justifies biopsy risks and the cost of longer trial recruitment.

Furthermore, dose-finding standards in biological therapies still rely on the maximum tolerated dose model. This ‘chemotherapy-era’ approach targets wild-type receptors rather than identifying the optimal biological dose for the mutated target, leading to research programmes of promising agents being discontinued due to toxicity only seen at supratherapeutic levels, or drugs falling out of favour due to prohibitive real-world toxicity.

Secondly, we must identify low-cost improvements and de-escalation opportunities. Immunotherapy (IO) allows to exploit platinum sensitivity in lung cancer. Multiple retrospective studies describe platinum re-challenge.^2,3 However, with no commercial incentive to compare off-patent regimens, the benefit of platinum over the more toxic second-line docetaxel remains unexplored. If docetaxel is the sole second-line benchmark for drug approvals, novel regimens are compared against a potentially suboptimal standard. Furthermore, the immune effect of cytotoxic drugs and their potential synergy with IO also remain orphaned by pharma-led funding models.

We could also re-evaluate chemotherapy in early-stage EGFR-mutated non-small-cell lung cancer. In NeoADAURA, neoadjuvant osimertinib monotherapy and chemotherapy–osimertinib cohorts yielded 25% and 26% major pathological response, respectively, with substantial tolerability differences.⁴ Without prospective data demonstrating a survival benefit of adjuvant chemotherapy in this biologically distinct group, we must ensure that we are not over-treating based on historical paradigms.

Finally, evidence expectations must be adjusted to rare molecular subsets. ALK-positive patients face a rapid disease trajectory [often with central nervous system (CNS) progression] upon developing tyrosine kinase inhibitor (TKI) resistance, and trial recruitment has proven difficult in this setting. This was evident in IMpower150, which included the largest group of randomized ALK-positive patients, albeit only 29 patients globally, both before and after developing TKI resistance. A real-world study in 12 Australian centres describes only five ALK-positive patients treated with chemo-IO post-TKI in 4 years,⁵ reflecting both the rarity of the population and limited access to IO in this context. The benefit is substantial, but the evidence appears anecdotal. However, requirements must be adjusted for the limitations of the treatment setting. Confronted with the potential gains, does limited evidence justify denying chemo-IO treatment to this patient group?

It is striking that while we routinely offer IO to older, frailer, predominantly male populations with small-cell lung cancer for marginal gains, enthusiasm is more limited for younger, fitter, predominantly female ALK-positive patients to access approved CNS-active systemic therapy after developing TKI resistance.

While pharma-led research is positively transforming oncology, strategies to mitigate financial toxicity and maximize gains, while contextualizing treatment access criteria, are needed for a precise and equitable oncology practice.