Lung – NSCLC

For EGFRm patients: There is a potential new standard for consolidation therapy in Stage III EGFRm (Ex19del/L858R) NSCLC post CRT. Retrospective data already highlighted this strategy and the LAURA trial showed an ” overwhelming efficacy benefit “ for Osimertinib in this population. At ASCO 2024, preliminary results showed that Osimertinib reduced the risk of progression or death by 84% compared with placebo (HR, 0.16; 95% CI, 0.10-0.24; P < .001).

However, with no OS yet still available and the 81% crossover in the standard arm, many unanswered question still remain as to whether Osimertinib as maintenance improves survival compared to Osimertinib on progression.

Adding to the lack of efficacy for IO monotherapy in EGFR patients, the use of Osimertinib concomitantly with Durvalumab or within months post Durvalumab has been associated with increased risk of ILD and death.

For ALK positive patients: The use of Immunotherapy for ALK positive patient in the metastatic setting hasn’t been a success. Therefore, these patients have been excluded from all IO trials. Retrospective data started emerging, and were presented at ASCO 2024, and basically mirror what we see in LAURA for EGFRm.

For PD-L1 negative patients: Providing pre-CRT tumour tissue was optional in the PACIFIC trial (almost 36.7% of the randomized patients did not provide any tissue and were classified as PD-L1 unknown) and enrolment was not restricted based on PD-L1 expression. However, Durvalumab failed to show improvement in the PFS and OS in the (not pre-planned) post hoc analysis for this PD-L1 <1% subgroup. EMA therefore restricted the use of Durvalumab for this population. This decision was strongly criticized by the many experts including a panel of IASLC.

The new drug development strategy is already taking in consideration this issue since the ongoing PACIFIC 8 trial assessing the efficacy and safety of durvalumab (MEDI4736) and domvanalimab (AB154) compared with durvalumab plus placebo (standard PACIFIC regimen) includes only “documented tumour PD-L1 status ≥ 1% by central lab”  as well as “documented EGFR and ALK wild-type status (local or central)” in their inclusion criteria.

Not all EGFR mutations are similar. Fortunately our pathology reports mention the type of mutation and its sensitivity to which agents.

There are no comparative data for the best TKI to use upfront. Each has some particular characteristics, a different safety profile and intracranial activity.

For Alectinib and Brigatinib, there was some indirect comparisons and real world data in this setting that suggests that both TKIs are similar in efficacy but have obviously different safety profile. The Phase 3 ALTA-3 trial compared brigatinib to alectinib in ALK+ NSCLC patients who progressed on crizotinib and showed no difference in efficacy but a difference in safety profiles.

Lorlatinib has been scoring and on a different journey than the rest of the TKIs, mainly known for its incredible intracranial activity, the recent extended follow up data presented at ASCO 2024 have been astonishing, giving it a huge leap over all others and becoming the most potent TKI to use upfront. However, its safety profile has been very challenging for many physicians to incorporate it in the first line setting, “A pragmatic approach to managing AEs related to lorlatinib is required” and this was well adressed in this paper.

Unlike in the US, access to Lorlatinib in second line, at least in Quebec has been very difficult and uncertain for most prescribers. Anyway, I wonder if with the recent updates, is it true that “We should not celebrate false kings.” ?

One would advocate for the right TKI for the right patient and would recommend selecting the drug based on the tumor burden, comorbidities and intracranial disease at diagnosis.

Patients with exon-14 altered lung cancer have a bad prognosis and a very modest response to immunotherapy disregarding the expression of PD-L1. There are some random case reports and very small series highlighting few long term responders for whom we don’t have a good understanding of their disease. Many studies and combinations are currently in development, but for now treating these patients with IO single agent is discouraged, at least not in first or second line.

Patients with RET-fp NSCLC don’t do well on single agent IO, these come from old retrospective data and recent onesshowing the lack of benefit disregarding expression of PDL-1. There are obviously few success stories but should not be taken solely for decision making. Many emerging strategies are being in development and have been published since a while now, showing that they benefit the most from the use of TKIs and therefore should have these drugs incoporated in their treatment as early as possible.

ERBB2 encodes for HER2, a receptor tyrosine kinase overexpressed or altered in numerous cancers. ERBB2 alterations comprise a wide spectrum of genomic alterations with some of them considered activating. The main forms of HER2 alterations include: gene mutations, gene amplifications, and protein overexpression.

This area is still under study with some potential breakthrough and challenges.

The benefit of IO is very questionable, with poor responses to IO monotherapy. Until the image gets clearer, the approach for these patients would be CT alone or CT-IO in first line disregarding the PD-L1 status.