Modern era systemic therapies: Expanding concepts of cure in early and locally advanced non-small cell lung cancer.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.

Impact of Adjuvant Atezolizumab on Recurrences Avoided and Treatment Cost Savings for Patients with Stage II-IIIA Non-Small Cell Lung Cancer in Canada.

This epidemiological model forecasted reductions in recurrences and recurrence treatment cost savings with adjuvant atezolizumab vs best supportive care among Canadians with stage II-IIIA non-small cell lung cancer (NSCLC) at national and provincial levels. The population had resected, programmed cell death 1 ligand 1 (PD-L1)-high (≥50%), EGFR-, ALK-, stage II-IIIA NSCLC eligible for adjuvant treatment. Patients with recurrence or death and the costs of treating recurrences were estimated for those receiving adjuvant atezolizumab or best supportive care each year (2024-2034). Proportions of patients expected to be event free up to 10 years after treatment initiation were extrapolated with parametric survival analyses. In the base case analysis, 240 fewer recurrences were estimated to occur over 10 years (2024-2034) with adjuvant atezolizumab vs best supportive care across Canada, with 136 (57%) and 104 (43%) fewer locoregional and metastatic recurrences, respectively. Projected costs of treated recurrences were CAD 33.2 million less over 10 years with adjuvant atezolizumab at a national level (adjuvant atezolizumab, CAD 135.8 million; best supportive care, CAD 169.0 million). This model predicts a considerable long-term reduction in recurrences and substantial treatment cost savings with adjuvant atezolizumab vs best supportive care for patients with PD-L1-high early-stage NSCLC in Canada.

Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.

BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.

Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

Canadian Consensus Recommendations for the Management of Operable Stage II/III Non-Small-Cell Lung Cancer: Results of a Modified Delphi Process.

The treatment paradigm for patients with stage II/III non-small-cell lung cancer (NSCLC) is rapidly evolving. We performed a modified Delphi process culminating at the Early-stage Lung cancer International eXpert Retreat (ELIXR23) meeting held in Montreal, Canada, in June 2023. Participants included medical and radiation oncologists, thoracic surgeons and pathologists from across Quebec. Statements relating to diagnosis and treatment paradigms in the preoperative, operative and postoperative time periods were generated and modified until all held a high level of consensus. These statements are aimed to help guide clinicians involved in the treatment of patients with stage II/III NSCLC.