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Advances in Targeted Therapies for NSCLC at the 2017 Oncology Annual Meeting

Alectinib, the optimal first-line therapy for ALK-positive NSCLC. In the global, randomized phase III ALEX study (Abstract LBA9008) involving 303 previously untreated patients with advanced ALK-positive non-small cell lung cancer (NSCLC), the anaplastic lymphoma kinase (ALK) inhibitor alectinib (600 mg twice daily) compared with crizotinib (250 mg twice daily) reduced the risk of progression or death by 53% (HR 0.47, P<.0001). Based on independent review, treatment with alectinib more than doubled the median progression-free survival (PFS; 25.7 months with alectinib vs 10.4 months with crizotinib; HR 0.50, P<.0001). Importantly, alectinib provided superior PFS regardless of baseline central nervous system (CNS) metastases (CNS-positive HR 0.40; CNS-negative HR 0.51) with impressive CNS objective response rate (81% vs 50%) and median duration of response (17.3 months vs 5.5 months). In addition, 12-month incidence of CNS progression was more than four times lower in patients receiving alectinib (9.4% vs 41.4%; HR 0.16, P<.0001). There was no difference in median overall survival (OS), but data are not yet mature. Alectinib was associated also with a more favorable adverse event (AE) profile, with fewer grade 3-5 AEs (41% vs 50%). Alice Shaw, MD, PhD (Massachusetts General Hospital, Boston, Massachusetts, United States), concluded her presentation by saying that these data, along with similar data from other studies of alectinib in Japanese patients, establish alectinib as the new standard of care for patients with previously untreated ALK-positive NSCLC. These results were simultaneously published in New England Journal of Medicine. Discussant Sanjay Popat, MD, PhD (Royal Marsden Hospital, London, United Kingdom), agreed that, based on these results, alectinib is the preferred first-line ALK inhibitor for patients with and without CNS metastases. He also discussed alectinib mechanisms of acquired resistance, including the most common G1202R mutation which is sensitive to the third generation ALK/ROS1 inhibitor, lorlatinib (Abstract 9006).  He highlighted that, moving forward, global genotype-directed trials are needed to identify the best sequence of therapies.

Front-line dacomitinib outperforms gefitinib in EGFR-mutant NSCLC. According to results from the phase III, randomized, open-label ARCHER 1050 trial (Abstract LBA9007) that included 452 treatment-naïve advanced NSCLC patients with EGFR-activating mutations, the second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) dacomitinib at 45 mg daily prolonged median PFS by 5 months compared to standard first-generation gefitinib at 250 mg daily (14.7 months vs 9.2 months; HR 0.59, P<.0001). The overall response rate (ORR) was similar between the two treatment arms (74.9% vs 71.6%), but duration of response was significantly longer in patients receiving dacomitinib (14.8 months vs 8.3 months; P<.0001). Overall survival data are not yet mature. However, the higher potency of dacomitinib was associated with increased toxicity and 66% of patients required dose reduction compared with 8% of those receiving gefitinib. Incidence of grade 3 diarrhea, skin rash, paronychia, and mucositis were higher with dacomitinib while hepatic toxicity was higher with gefitinib. Overall, improvements in patient-reported measures of key-diseases associated symptoms were similar in patients treated with dacomitinib and gefitinib. Tony Mok, MD (Chinese University of Hong Kong, Hong Kong, China), who presented these data, concluded that this is the first phase III randomized study to directly compare a second-generation EGFR TKI with a first-generation TKI for first-line treatment of patients with advanced EGFR-mutant NSCLC, and that these results suggest that dacomitinib should be considered as a new treatment option for first-line management of patients with EGFR-positive NSCLC. Dr Popat, who also discussed these data, agreed that dacomitinib represents an additional new standard of care, though its use may be limited by the pending FLAURA data (osimertinib first-line) that are expected later this year.

Osimertinib highly effective against CNS metastases. In a subgroup analysis of T790M-positive patients from the phase III AURA3 trial whose disease progressed in the brain on initial EGFR TKI (Abstract 9005), the EGFR TKI osimertinib (80 mg daily) resulted in a 70% CNS response rate, compared to 31% with chemotherapy. Osimertinib treatment also resulted in a 6.1 month improvement in PFS over chemotherapy in patients with CNS metastases (11.7 months vs 5.6 months; HR 0.32, P = .004). Four of 7 patients with leptomeningeal metastases at baseline also responded to treatment with osimertinib. Of note, CNS responses were observed regardless of prior brain radiotherapy. In his discussion, Dr Popat commented that these data indicate high activity of osimertinib in the brain and call into question the role of CNS radiotherapy in treating brain metastases. He suggested that patients with T790M-positive NSCLC who disease progresses on first-line therapy should be switched to osimertinib early in order to reduce the risk of brain metastases.

For new data covering immunotherapy in lung cancer presented at the the 2017 ASCO Annual Meeting in Chicago, please see prIME Oncology’s Virtual Poster Session in Lung Cancer and prIME Downloadable Slides in Lung Cancer.

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