Lorlatinib Versus Pemetrexed-Based Chemotherapy in Patients With ALK-rearranged NSCLC Previously Treated With Alectinib

Among 90 patients who experienced disease progression during alectinib treatment, 38 of them received either PEM (n = 22) or LOR (n = 16) as subsequent treatment. The objective response rate and the median progression-free survival were similar in the PEM and LOR groups (objective response rate: 45% versus 44%, p = 0.92; median progression-free survival: 6.9 mo versus 6.2 mo, p = 0.83, respectively). Disease progression during treatment occurred in 22 patients with PEM and 14 patients with LOR. The central nervous system (CNS) was the most common site of progression in both groups. In patients without CNS metastasis at baseline, the cumulative incidence rate of CNS progression was lower over time in the LOR group compared with the PEM group (p = 0.045), whereas in patients with CNS metastasis at baseline, there were no significant differences in cumulative incidence rate of CNS progression between both groups (p = 0.43). READ ARTICLE

Journal of Thoracic Oncology DOI:https://doi.org/10.1016/j.jtocrr.2022.100311

Authors: Yuki Takeyasu, MD, Tatsuya Yoshida, MD, Ken Masuda, MD, Yuji Matsumoto, MD, Yuki Shinno, MD, Yusuke Okuma, MD, Yasushi Goto, MD, Hidehito Horinouchi, MD, Noboru Yamamoto, MD, Yuichiro Ohe, MD

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superi..... READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2021.07.035

Authors: D. Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James C.H. Yang, Ji-Youn Han, Maximilian J. Hochmair, Ki Hyeong Lee, Angelo Delmonte, Maria Rosario, Garcia Campelo, Dong-Wan Kim, Frank Griesinger, Enriqueta Felip, Raffaele Califano, Alexander I. Spira, Scott N. Gettinger, Marcello Tiseo, Huamao M. Lin, Yuyin Liu, Florin Vranceanu, Huifeng Niu, Pingkuan Zhang and Sanjay Popat

The Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non–small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted condit..... READ ARTICLE

Clinical Pharmacology in Drug Development
DOI:10.1002/cpdd.641

Authors: Meera Tugnait,Neeraj Gupta,Michael J. Hanley,Karthik Venkatakrishnan,Daryl Sonnichsen,David Kerstein,David J. Dorer,Narayana Narasimhan

Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation

Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases. A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial pr..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.08.009

Authors: Nicholas J.Thomas, Nathaniel J. Myall, Fangdi Sun, Tejas Patil, Rao Mushtaq, Chandler Yu, Sumi Sinha, Erqi L. Pollom, Seema Nagpal. Ross Camidge, Chad G. Rusthoven, Steve E. Braunstein, Heather A. Wakelee and Caroline E. McCoach

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Introduction: Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy. Conclusions: Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.10.156

Authors: Weihua Li, Lei Guo, Yutao Liu, Lin Dong, Lin Yang, Li Chen, Kaihua Liu, Yang Shao, Jianming Ying

Advances in Treatment of Locally Advanced or Metastatic Non–Small Cell Lung Cancer: Targeted Therapy

KEY POINTS:
Most epidermal growth factor receptor (EGFR)-mutated NSCLC (exon 19 del and L858R) should be
initially treated with osimertinib.
Anaplastic lymphoma kinase (ALK) fusion-positive NSCLC should be initially treated with alectinib,
brigatinib, or ceritinib; however, tolerability issues limit the use of ceritinib.
ROS1 fusion-positive NSCLC should be initially treated with entrectinib over crizotinib given central
nervous system activity.
BRAF V600E-mutated NSCLC should be initially treated with dabrafenib plus trametinib.
Neurotrophic tropomyosin receptor kinase fusion-positive NSCLC should be initially treated with
entrectinib or larotrectinib.
Patients with HER2 or EGFR exon 20 insertions, RET fusions, NRG1 fusions, MET amplification and
exon 14 skipping mutations, and KRAS G12C mutations should be initially treated with standard-ofcare chemoimmunotherapy; however, there are targeted therapies under investigation showing
promise. READ ARTICLE

Clinics in Chest Medicine DOI:10.1016/j.ccm.2020.02.003

Authors: Nicholas P. Giustini, Ah-Reum Jeong, James Buturla, Lyudmila Bazhenova

$Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial$

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial

Introduction: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase–positive NSCLC. Conclusions: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.004

Authors: Rudolf M. Huber, MD, Karin H. Hansen, Luis Paz-Ares Rodríguez, Howard L. West, Karen L. Reckamp, Natasha B. Leighl, Marcello Tiseo, Egbert F. Smit, Dong-Wan Kim, Scott N. Gettinger, Maximilian J. Hochmair, Sang-We Kim, Corey J. Langer, Myung-Ju Ahn, Edward S. Kim, David Kerstein, Harry J.M. Groen, D. Ross Camidge

Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearrange Non–Small Cell Lung Cancer

Clinical variables describing the natural history and longitudinal therapy outcomes of stage IV anaplastic lymphoma kinase gene rearrangement positive (ALK-positive) NSCLC and their relationship with long-term overall survival (OS) have not previously been described in detail.
Patients with stage IV NSCLC treated with an ALK inhibitor at the University of Colorado Cancer Center from 2009 through November 2017 were identified retrospectively. OS curves were constructed by using Kaplan-Meier methods. Multivariate Cox proportional hazard analysis was used to determine the relationship of variables with OS.
We concluded that patients with stage IV ALK-positive NSCLC can have prolonged OS. Brain metastases at diagnosis of stage IV disease does not influence OS. Having more organs involved with tumor at stage IV presentation is associated with worse outcomes. Prolonged benefit from pemetrexed is associated with better outcomes. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.014

Authors: Jose M. Pacheco, Dexiang Gao, Derek Smith, Thomas Purcell, Mark Hancock, Paul Bunn, Tyler Robin, Arthur Liu, Sana Karam, Laurie Gaspar, Brian Kavanagh, Chad Rusthoven, Dara Aisner, Robert Doebele, D. Ross Camidge