Stage as the Sole "Biomarker" for Adjuvant Pembrolizumab in Resected Stage IB to IIIA NSCLC without Considerations for PD-L1 Expression Level, ALK/EGFR Mutational Status, and Prior Adjuvant Chemotherapy per FDA Approval Indications of PEARLS/Keynote-091?

One of the most recent advancements in NSCLC was the approval of immunotherapy in the adjuvant setting. Both atezolizumab and pembrolizumab have been approved for the use in early stage NSCLC patients post resection. As it broadens the options for our patients, multiple approvals in the same setting are generally welcomed. However, there were important differences in the two studies that led to the approvals and the data could be confusing. Here we review IMpower010, the study that led to the first approval of atezolizumab in the adjuvant setting with comparison to the Keynote-091 study evaluating pembrolizumab in the adjuvant setting, gaining the most recent FDA approval for adjuvant use in early stage NSCLC.

ALESIA 5-Year Update: Alectinib at 600 mg Twice Daily Gives Lorlatinib a Run for Its Money in Asia.

Alectinib, a next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has demonstrated superior progression-free survival over crizotinib with both 300 mg twice daily (J-ALEX) or 600 mg twice daily (ALEX, ALESIA) dosing in three pivotal clinical trials. Given the similar median PFS achieved in the J-ALEX trial and the Asian subgroup of the ALEX trial, there remains debate about the optimal alectinib dose for Asians. The third pivotal alectinib trial, ALESIA, which was conducted exclusively in Asia to support the registration of alectinib in China, utilized 600 mg alectinib twice daily. The mature PFS was not reached at the initial publication of ALESIA. At ESMO Asia 2022, the 5-year update of ALESIA was presented with an impressive mature investigator-assessed PFS of 41.6 months (95% CI 33.1-58.9), which is numerically longer than the mature PFS of 34.1 months achieved by alectinib at 300 mg twice daily in the J-ALEX trial. Based on these results, as well as retrospective pharmacokinetic and responses and PFS data, Alectinib at 600 mg twice daily is the optimal dose for Asians. This has been based on the ALESIA trial and on the retrospective pharmacokinetic and responses and PFS data and has set the benchmark for ALK TKI as the first-line treatment for advanced ALK+ NSCLC in Asia. Importantly, lorlatinib, another next generation ALK TKI, also achieved an impressive hazard ratio with a still immature PFS in all patients, including Asian patients, in a recent subgroup analysis after a median follow-up time of 36.7 months. We await the final mature PFS of lorlatinib overall and for Asian patients in the CROWN trial to see if lorlatinib will set a new standard.

The Additional Exclusions of ROS1 Fusions (In Addition to EGFR Mutation and ALK Fusions) in the Cemiplimab NSCLC FDA Indication (EMPOWER-Lung 1 and -Lung 3). Catching Up with Current Scientific View of Immunotherapy in Never-Smoker Predominant Actionable Driver Mutation Positive NSCLC?

Cemiplimab is one of seven immune checkpoint inhibitors (ICIs) approved for the first-line (1L) treatment of advanced NSCLC in the US based on EMPOWER-Lung 1 and -Lung 3 trials. In addition to exclusion of NSCLC patients harboring EGFR mutations and ALK fusion from 1L treatment with ICIs, exclusion of ROS1 fusion is an additional unique exclusion the use of criterion for cemiplimab in the US FDA indication based on the design of the EMPOWER lung trials. We review the effectiveness of ICIs in never-smoker predominant NSCLC with driver mutations (EGFR, ALK, ROS1, RET, HER2) and question whether exclusion of ROS1 fusion would put cemiplimab at a competitive disadvantage given the requirement for insurance to prove ROS1 fusion negativity. We further discuss whether the US FDA as a regulatory authority has the right and responsibility to harmonize the use of ICIs in these actionable driver mutations to standardize community practice for the benefit of patients and to advance the development of next-generation treatment for these driver mutations.

From ASCEND-5 to ALUR to ALTA-3, an Anti-Climactic End to the Era of Randomized Phase 3 Trials of Next-Generation ALK TKIs in the Crizotinib-Refractory Setting.

The competing roles of various next-generation ALK TKIs in the first and second line treatment setting of advanced ALK+ NSCLC were based on many phase 3 clinical trials in both the first-line and crizotinib-refractory settings. The approval of all next-generation ALK TKIs was first in the crizotinib-refractory setting, based on a large-scale Phase 2 trial, and was then followed by at least one global randomized phase 3 trial comparing to platinum-based chemotherapy (ASCEND-4) or to crizotinib (ALEX, ALTA-1L, eXalt3, CROWN). In addition, three randomized phase 3 trials in the crizotinib-refractory setting were also conducted by next-generation ALK TKIs that were developed earlier before the superiority of next-generation ALK TKIs was demonstrated in order to secure the approval of these ALK TKIs in the crizotinib-refractory setting. These three crizotinib-refractory randomized trials were: ASCEND-5 (ceritinib), ALUR (alectinib), and ALTA-3 (brigatinib). The outcome of the ATLA-3 trial was recently presented closing out the chapter where next-generation ALK TKIs were investigated in the crizotinib-refractory setting as they have replaced crizotinib as the standard of care first-line treatment of advanced ALK+ NSCLC. This editorial summarizes the results of next-generation ALK TKIs in randomized crizotinib-refractory trials and provides a perspective on how natural history of ALK+ NSCLC may potentially be altered with sequential treatment. ALTA-3 compared brigatinib to alectinib, showing that both achieved near identical blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (19.2-19.3 months). Importantly, 4.8% of brigatinib-treated patients developed interstitial lung disease (ILD) while no alectinib-treated patients developed ILD. Dose reduction and discontinuation due to treatment-related adverse events were 21% and 5%, respectively, for brigatinib-treated patients compared to 11% and 2%, respectively, for alectinib-treated patients. Upon analysis of these findings, we speculate that brigatinib may have a diminishing role in the treatment of advanced ALK+ NSCLC.