Highlights on lung cancer 4

Dr Lizza Hendriks, a respiratory oncologist at the Maastricht University Medical Center (Netherlands), highlights four significant presentations on NSCLC from ASCO 2024 relevant to clinical practice.

A noteworthy presentation at ASCO involved the KRYSTAL-12 study, which examined the efficacy of adagrasib in patients with metastatic NSCLC)harbouring KRAS-G12C mutations. This follows the phase 3 trial of sotorasib, which showed improved median PFS in the same patient population compared to docetaxel. In the KRYSTAL-12 study, patients with KRAS-G12C-mutated NSCLC who had progressed on platinum-based chemotherapy and immunotherapy were randomised 2:1 to receive either adagrasib or docetaxel. The primary endpoint was PFS. The results were positive, with a median PFS of 5.5 months in the adagrasib arm compared to 3.8 months in the docetaxel arm, yielding a hazard ratio of 0.58. Additionally, the objective response rate was over 30% for adagrasib, significantly higher than the approximately 10% seen with docetaxel. The median duration of response was also longer for adagrasib. However, adagrasib comes with a distinct toxicity profile. Patients experienced mainly gastrointestinal side effects such as diarrhoea, vomiting, and nausea, whereas docetaxel is associated with standard haematological toxicities. OS data are not yet mature, so further follow-up is needed. In summary, the data for adagrasib in the KRYSTAL-12 study are promising and comparable to those of sotorasib. Both agents show an improvement in PFS, though the median PFS of 5.5 months suggests there is still room for improvement in treating KRAS-G12C-mutated NSCLC. The real challenge will be in improving these outcomes to establish a new standard of care, particularly in regions where reimbursement issues may affect treatment availability.

Another compelling trial in the oncogene-driven space focused on patients with EGFR mutations, particularly concerning brain and leptomeningeal metastasis. This investigator-initiated phase 2 trial included patients with common activating mutations (such as exon 21 L858R and exon 19 deletions), uncommon activating mutations, and EGFR exon 20 insertions. Given the high risk of brain metastasis in these patients and the limited effectiveness of drugs beyond osimertinib for intracranial activity, this study’s findings are particularly noteworthy. The trial had two cohorts: one for patients with progressive brain metastasis after progression on osimertinib and another for those with leptomeningeal metastasis. The treatment regimen involved lazertinib, a third-generation EGFR TKI, combined with amivantamab, an antibody targeting MET and EGFR. The data revealed a 40% intracranial response rate in the brain metastasis cohort, primarily following osimertinib treatment. In the leptomeningeal cohort, the response rate was approximately 30%, a significant finding given the challenging nature of leptomeningeal disease. Some patients experienced durable responses. Additionally, lumbar punctures were performed in the leptomeningeal cohort to analyse cerebrospinal fluid for circulating tumour cells, which showed a reduction in many patients. While this trial is not registrational, the results are promising, particularly in light of the Mariposa2 data. If lazertinib and amivantamab receive reimbursement for post-osimertinib progression, this combination could offer a valuable strategy for patients with active brain metastases or leptomeningeal metastasis.

The ADAURA trial update focused on minimal residual disease (MRD) in patients with stage 1b to 3a NSCLC harbouring classical activating EGFR mutations. Following complete resection and optional chemotherapy, patients were randomised to receive either osimertinib or placebo for three years. The trial had previously demonstrated positive outcomes in both DFS and OS. The key question remains whether all patients need osimertinib or if therapy can be personalised to target those at higher risk of disease recurrence. To address this, ADAURA included an analysis of MRD using a tumour-informed radar test, with baseline and follow-up samples from patients. Interpreting the MRD data posed challenges. Most patients were MRD-negative at baseline: only 4% in the osimertinib arm and 12% in the placebo arm. During follow-up, fewer patients in the osimertinib arm became MRD-positive compared to the placebo arm. Notably, those who became MRD-positive in the osimertinib arm did so mainly after discontinuing the treatment. Additionally, most MRD-positive patients in the osimertinib arm became MRD-negative during osimertinib treatment. These findings highlight the difficulty of using MRD to tailor treatment since the majority of patients were MRD-negative. More sensitive tests are needed to better predict which patients are at high risk of recurrence. Further research is essential to determine if MRD status can predict the benefit of osimertinib.

Staying in the early disease setting, the CheckMate 77T trial provided an important update on the use of neoadjuvant nivolumab combined with chemotherapy, followed by surgery and adjuvant nivolumab, compared with a placebo in place of nivolumab. This trial focused on patients with stage 1b to 3a NSCLC, with a significant portion having N2 disease. The trial was previously reported to be positive for event-free survival). An exploratory analysis based on N2 status was presented to address ongoing discussions about the benefit of adding neoadjuvant or perioperative immunotherapy for these patients. The analysis demonstrated that patients benefited from the addition of immunotherapy regardless of their N2 status. The addition of nivolumab did not complicate surgeries and provided an EFS benefit across the board. This finding supports the use of neoadjuvant or perioperative chemoimmunotherapy as the standard of care for resectable NSCLC without EGFR or ALK mutations. However, post-surgical treatment strategies need to be refined. Determining which patients require adjuvant immunotherapy and which can be spared remains crucial for future research. Academic clinical trials should focus on identifying patients who may benefit from de-escalating treatment (omitting adjuvant immunotherapy) and those who might need treatment escalation (adding further interventions on top of immunotherapy). This precision in treatment could optimise outcomes and minimise unnecessary therapy.