Plasma pre-treatment T790M relative allelic frequency in patients with advanced EGFR-mutated non-small cell lung cancer predicts treatment response to subsequent-line osimertinib.

BACKGROUND: Approximately half of all patients with advanced EGFR-mutant NSCLC will develop acquired resistance to first or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) with a T790M mutation. In the AURA3 trial, patients with a T790M mutation had a response rate of 71% to osimertinib, a third-generation EGFR-TKI. The response to osimertinib may vary according to plasma T790M mutation frequency. Our aim was to determine the effect of plasma T790M mutation load on treatment response to osimertinib in an Australian multi-institutional cohort. METHODS: We performed a retrospective study on patients treated with osimertinib in the second-line setting and beyond between 2016-2018 from ten centres in Australia, who had T790M mutations detected in tumour or plasma. The primary objective was to investigate if there was a difference in disease control rate (DCR) between patients with high vs. low T790M relative allelic frequency (RAF) as detected in plasma, using a 0.3 RAF cut-off, as determined by ddPCR or BEAMing PCR. Secondary objective was to determine the survival outcomes according to high versus low plasma T790M RAF. Additional analyses were performed to investigate the survival outcome for patients with plasma versus tissue T790M positivity. RESULTS: A total of 139 patients were included in this study. Patients with higher RAF demonstrated higher DCR (74% vs. 36%, P=0.02), however there was no statistically significant difference in survival outcomes in the two groups. Exploratory analysis showed that patients with tissue T790M+ had improved DCR compared with those with plasma T790M+ (89% vs. 68%, P=0.01) and longer progression free survival (median 15.4 vs. 9.7 months; HR 0.51, 95% CI: 0.34 to 0.77, P=0.003) and overall survival (median not reached, HR 0.51, 95% CI: 0.30 to 0.86, P=0.02). Patients who were tissue T790M+ demonstrated superior survival compared to plasma T790M+ after correcting for confounding variables in a multivariate model. CONCLUSIONS: DCR was superior in patients with higher plasma T790M mutation load versus lower plasma T790M mutational load, without significant survival benefit. Plasma T790M RAF is a potential predictive biomarker which should be investigated and validated in larger prospective studies.

ALK-Rearranged Non-Small Cell Lung Cancer in 2020: Real-World Triumphs in an Era of Multigeneration ALK-Inhibitor Sequencing Informed by Drug Resistance Profiling.

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.

Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population.

INTRODUCTION: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. METHOD: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. RESULTS: A total of 98 patients were included with a median age of 70 years (range, 46-91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6-6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6-13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. CONCLUSIONS: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.