Benjamin J. Solomon

What is this summary about? The CodeBreaK 200 clinical study included patients with a type of lung cancer called non–small-cell lung cancer that has spread outside the lung (advanced) and had a particular change (mutation) in the KRAS gene. This mutation leads to the mutated protein called KRAS G12C and can lead to lung cancer. The CodeBreaK 200 clinical study looked at whether treatment with sotorasib works better and has fewer side effects than docetaxel. Sotorasib has accelerated approval or full approval for use in over 50 countries for patients with previouslytreated advanced KRAS G12C–mutated non–small-cell lung cancer. What did investigators find? There were 171 adults in the sotorasib group and 174 in the docetaxel group. The median time that patients in the sotorasib group whose disease was no worse or who did not die was 5.6 months. For patients in the docetaxel group, this was 4.5 months. After 1 year, 25% of patients in the sotorasib group had disease that was no worse or did not die. This happened in 100% of patients in the docetaxel group. In total, 48 out of 171 patients (28%) in the sotorasib group had a positive effect to treatment, and their tumors shrunk in size by at least 30% or disappeared. This happened in 23 out of 174 patients (13%) in the docetaxel group. Additionally, 141 out of 171 patients (82%) in the sotorasib group had tumors that either remained stable or shrunk in size. This happened in 105 out of 174 patients (60%) in the docetaxel group. Patients in both the sotorasib and docetaxel groups had a similar median survival (10.6 months in the sotorasib group compared with 11.3 months in the docetaxel group). Almost all patients treated with sotorasib or docetaxel had side effects. They were severe in 56 out of 169 patients (33%) receiving sotorasib and 61 out of 151 patients (40%) receiving docetaxel. What is the key takeaway? Sotorasib is an effective treatment for previously–treated patients with advanced KRAS G12C–mutated non–small-cell lung cancer.

Lorlatinib is an oral treatment for patients with advanced ALK-positive non-small cell lung cancer (NSCLC). Its efficacy was demonstrated in the CROWN clinical study, in which data from 5 years of follow-up demonstrated effective long-term disease control in patients with advanced ALK-positive NSCLC. While lorlatinib has a distinct side effect profile, its side effects are generally manageable. Managing side effects successfully is critical to preserving patient quality of life and promoting adherence to treatment-both of which are key to maximizing the long-term benefits of lorlatinib. The CROWN study showed that lorlatinib-associated side effects can be managed with dose adjustments, such as lowering the daily dose, without sacrificing treatment effectiveness. This guide, developed collaboratively by patients living with advanced ALK-positive NSCLC and healthcare professionals experienced with managing lorlatinib treatment, aims to help patients understand what to expect from treatment and how to take an informed, active role in their care.

LIBRETTO-001 (ClinicalTrials.gov identifier: NCT03157128) is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. With 19 months of additional follow-up, we report the final efficacy and safety results of selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy (N = 247) or were treatment-naïve (N = 69). The objective response rate (ORR) was 62% for pretreated patients and 83% for treatment-naïve patients. Duration of response (DoR) was 31.6 months for pretreated and 20.3 months for treatment-naïve patients (median follow-up approximately 38 months). Median progression-free survival (PFS) was 26.2 months for pretreated and 22.0 months for treatment-naïve patients (median follow-up approximately 40 months). Median overall survival was 47.6 months in pretreated patients and was not reached in the treatment-naïve group (median follow-up approximately 43 months). At the 3-year landmark estimate, 57% of pretreated and 66% of treatment-naïve patients were alive. Among 26 patients with measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-DoR of 9.4 months and CNS-PFS of 11.0 months. The safety profile of selpercatinib was consistent with previous reports. With substantial additional follow-up, selpercatinib continued to show durable responses and intracranial activity, with a manageable safety profile in patients with RET fusion-positive NSCLC.

Molecular testing plays a critical role in guiding optimal treatment decisions for lung cancer patients across a variety of clinical settings. While guidelines for biomarker testing exist in other jurisdictions, to date no best practice guidelines have been developed for the Australian setting. To address this need, the Royal College of Pathologists of Australasia collaborated with the Thoracic Oncology Group of Australasia to identify state-based pathologists, oncologists and consumer representatives to develop consensus best practice recommendations. Sixteen recommendations were established encompassing appropriate biomarkers, lung cancer subtype, tumour stage, specimen types, assay selection and quality assurance protocols that can inform and standardise best practice in molecular testing of lung cancer. These multidisciplinary evidence-based recommendations are designed to standardise and enhance molecular testing practices for lung cancers and should help ensure laboratories provide high-quality molecular testing of lung cancer for all Australians, including those from regional or remote communities.

This is a summary of the results of an ongoing study called CROWN. In the CROWN study, researchers looked at the effects of two medicines called lorlatinib (Lorbrena) and crizotinib (Xalkori) for people with advanced non-small cell lung cancer (NSCLC) who had not been treated yet. Everyone in the study had changes in a gene called anaplastic lymphoma kinase, or ALK, in their cancer cells. The changes in the ALK gene can make cancer grow. This analysis looked at how well lorlatinib and crizotinib worked and their side effects in people with advanced ALK-positive NSCLC after 5 years. After observing people for an average of 5 years, researchers found that more people who took lorlatinib were still alive without their cancer getting worse than the people who took crizotinib. At 5 years, the probability of being alive without their cancer getting worse was 60% in people who took lorlatinib compared with 8% in people who took crizotinib. Fewer people who took lorlatinib had their cancer spread within or to the brain than the people who took crizotinib. In more than half of the people who took lorlatinib, tumors that had spread to the brain did not get worse, and no new tumors spread to the brain after 5 years. In contrast, in about half of the people who took crizotinib, tumors that had spread to the brain got worse or new tumors spread to the brain after 16.4 months. More people who took lorlatinib (115 out of 149, or 77%) had severe or life-threatening side effects than people who took crizotinib (81 out of 142, or 57%). These side effects were like the ones reported in the earlier 3-year analysis. The 5-year results from the CROWN study showed that more people who took lorlatinib continued to benefit from their treatment than those who took crizotinib. The 5-year benefit of lorlatinib in people with ALK-positive NSCLC has never been seen before.Clinical Trial Registration: NCT03052608 (Phase 3 CROWN study) (ClinicalTrials.gov).