Publications by authors named "Alice T Shaw"

182 Publications

Continuation of Lorlatinib in ALK-positive NSCLC Beyond Progressive Disease.

J Thorac Oncol 2022 Jan 10. Epub 2022 Jan 10.

Medical Oncology, National Institute for Cancer Research CRO-IRCCS, Aviano, Italy.

Introduction: Lorlatinib, a potent, selective third-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK TKI), showed overall and intracranial anti-tumor activity in patients with ALK-positive non-small cell lung cancer (NSCLC).

Methods: Retrospective analyses in the ongoing phase II trial (NCT01970865) investigated clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with prior crizotinib as the only ALK TKI were Group A (n = 28); those with ≥1 prior second-generation ALK TKIs were Group B (n = 74). LBPD was defined as >3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with a best overall response of complete or partial response or stable disease were included.

Results: There were no major differences in baseline characteristics between groups. Median duration of treatment for LBPD patients was 32.4 months (Group A) and 16.4 months (Group B) versus 12.5 months (Group A) and 7.7 months (Group B) for non-LBPD patients. Median overall survival (OS) in Group A was not reached (NR) in LBPD patients versus 24.4 months (95% confidence interval [CI] 12.1-NR); Group B median was 26.5 months (95% CI 18.7-35.5) in LBPD patients versus 14.7 months (95% CI 9.3-38.5) in non-LBPD patients. Median OS post-progression for Groups A and B was NR (95% CI 21.4-NR) and 14.6 months (95% CI 11.2-19.2) in LBPD patients, and 8.0 months (95% CI 1.5-NR) versus 5.3 months (95% CI 2.8-14.3) in non-LBPD patients.

Conclusions: Continuing LBPD is a viable treatment option for select patients with ALK-positive NSCLC who progressed on lorlatinib.
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http://dx.doi.org/10.1016/j.jtho.2021.12.011DOI Listing
January 2022

Outcomes According to ALK Status Determined by Central IHC or FISH in Patients with ALK-Positive NSCLC Enrolled in the Phase III ALEX Study.

J Thorac Oncol 2020 Oct 24. Epub 2020 Oct 24.

Massachusetts General Hospital, Boston, Massachusetts.

Introduction: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in-situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive non-small-cell lung cancer (NSCLC) in the ALEX study.

Methods: 303 treatment-naïve patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg. ALK status was assessed centrally using Ventana ALK (D5F3) CDx IHC and Vysis ALK Break Apart FISH Probe Kit. Primary endpoint: investigator-assessed PFS. Secondary endpoints of interest: objective response rate (ORR) and duration.

Results: Investigator-assessed PFS was significantly prolonged with alectinib versus crizotinib in ALK IHC-positive/FISH-positive tumors (n = 203, 67%) (HR 0.37, 95% CI: 0.25-0.56) and ALK IHC-positive/FISH-uninformative tumors (n = 61, 20%) (HR 0.39, 95% CI: 0.20-0.78), but not ALK IHC-positive/FISH-negative tumors (n = 39, 13%) (HR 1.33, 95% CI: 0.6-3.2). ORRs were higher with alectinib versus crizotinib in ALK IHC-positive/FISH-positive tumors 90.6% versus 81.4%; stratified odds ratio [OR] 2.22, 95% CI: 0.97-5.07) and ALK IHC-positive/FISH-uninformative tumors (96.0% versus 75.0%; OR 9.29, 95% CI: 1.05-81.88), but not ALK IHC-positive/FISH-negative tumors (28.6% versus 44.4%; OR 0.45, 95% CI: 0.12-1.74). Next-generation sequencing (NGS) was performed in 35/39 patients with ALK IHC-positive/FISH-negative tumors; no ALK fusion was identified in 20/35 (57.1%) patients by NGS, but 10/20 (50.0%) had partial response/stable disease.

Conclusion: Outcomes of patients with ALK IHC-positive/FISH-positive and ALK IHC-positive/FISH-uninformative NSCLC were similar to the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib.
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http://dx.doi.org/10.1016/j.jtho.2020.10.007DOI Listing
October 2020

Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms.

Cancer Cell 2021 11 7;39(11):1531-1547.e10. Epub 2021 Oct 7.

Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. Electronic address:

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.
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http://dx.doi.org/10.1016/j.ccell.2021.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578451PMC
November 2021

Efficacy of Taletrectinib (AB-106/DS-6051b) in NSCLC: An Updated Pooled Analysis of U.S. and Japan Phase 1 Studies.

JTO Clin Res Rep 2021 Jan 21;2(1):100108. Epub 2020 Oct 21.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Introduction: Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against G2032R solvent-front mutation.

Methods: Patients with NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety.

Results: A total of 22 patients with NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval [CI]: 4.1-33.8). A total of 18 patients with were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4-87.9) with a disease control rate of 100% (70.1-100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7-70.0) with a disease control rate of 88.3% (95% CI: 443.6-97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6-not reached) and 14.2 months (95% CI: 1.5-not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%).

Conclusions: Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474193PMC
January 2021

Plain language summary of the CROWN study comparing lorlatinib with crizotinib for people with untreated non-small cell lung cancer.

Future Oncol 2021 Dec 29;17(34):4649-4656. Epub 2021 Sep 29.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608.
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http://dx.doi.org/10.2217/fon-2021-0904DOI Listing
December 2021

Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in Fusion-Positive Lung Cancer.

Clin Cancer Res 2021 05 8;27(10):2899-2909. Epub 2021 Mar 8.

Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Purpose: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion ()-positive (ROS1) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1 NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1 disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib.

Experimental Design: Biopsies from patients with ROS1 NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing.

Results: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, mutations were identified in 38% and 46%, respectively. G2032R was the most commonly occurring mutation in approximately one third of cases. Additional mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1 causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1, ROS1, and ROS1 were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified amplification (4%), G12C (4%), amplification (4%), mutation (4%), and mutation (4%).

Conclusions: mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127383PMC
May 2021

A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor.

J Thorac Oncol 2021 05 3;16(5):850-859. Epub 2021 Feb 3.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Introduction: Capmatinib is approved for MET exon 14-altered NSCLC on the basis of activity in targeted therapy-naive patients. We conducted a phase 2 study to assess the efficacy of capmatinib in patients previously treated with a MET inhibitor.

Methods: Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping alterations received capmatinib 400 mg twice daily. The primary end point was the objective response rate. Secondary end points included progression-free survival, disease control rate (DCR), intracranial response rate, and overall survival. Circulating tumor DNA was analyzed to identify capmatinib resistance mechanisms.

Results: A total of 20 patients were enrolled between May 2016 and November 2019, including 15 patients with MET skipping alterations and five patients with MET amplification. All patients had received crizotinib; three had also received other MET-directed therapies. The median interval between crizotinib and capmatinib was 22 days (range: 4-374). Two patients (10%) achieved an objective response to capmatinib and 14 had stable disease, yielding a DCR of 80%. Among five patients who discontinued crizotinib for intolerance, the DCR was 83%, including two patients with the best tumor shrinkage of -25% and -28%. Intracranial DCR among four patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, the median progression-free survival and overall survival were 5.5 (95% confidence interval: 1.3-11.0) and 11.3 (95% confidence interval: 5.5-not reached) months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in postcrizotinib, precapmatinib plasma. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression on capmatinib.

Conclusions: Capmatinib has modest activity in crizotinib-pretreated MET-altered NSCLC, potentially owing to overlapping resistance mechanisms.
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http://dx.doi.org/10.1016/j.jtho.2021.01.1605DOI Listing
May 2021

Outcomes According to ALK Status Determined by Central Immunohistochemistry or Fluorescence In Situ Hybridization in Patients With ALK-Positive NSCLC Enrolled in the Phase 3 ALEX Study.

J Thorac Oncol 2021 02 24;16(2):259-268. Epub 2020 Oct 24.

Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

Introduction: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive NSCLC in the ALEX study.

Methods: A total of 303 treatment-naive patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg. ALK status was assessed centrally using Ventana ALK (D5F3) CDx IHC and Vysis ALK Break Apart FISH Probe Kit. Primary end point is investigator-assessed PFS. Secondary end points of interest are objective response rate and duration.

Results: Investigator-assessed PFS was significantly prolonged with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (n = 203, 67%) (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.25-0.56; p < 0.0001) and ALK IHC-positive and FISH-uninformative tumors (n = 61, 20%) (HR = 0.39, 95% CI: 0.20-0.78) but not in ALK IHC-positive and FISH-negative tumors (n = 39, 13%) (HR = 1.33, 95% CI: 0.6-3.2). Objective response rates were higher with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (90.6% versus 81.4%; stratified OR = 2.22, 95% CI: 0.97-5.07) and ALK IHC-positive and FISH-uninformative tumors (96.0% versus 75.0%; OR = 9.29, 95% CI: 1.05-81.88) but not in ALK IHC-positive and FISH-negative tumors (28.6% versus 44.4%; OR = 0.45, 95% CI: 0.12-1.74). Next-generation sequencing was performed in 35 of 39 patients with ALK IHC-positive and FISH-negative tumors; no ALK fusion was identified in 20 of 35 patients (57.1%) by next-generation sequencing, but 10 of 20 (50.0%) had partial response or stable disease.

Conclusions: Outcomes of patients with ALK IHC-positive and FISH-positive and ALK IHC-positive and FISH-uninformative NSCLC were similar to those of the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib.
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http://dx.doi.org/10.1016/j.jtho.2020.10.007DOI Listing
February 2021

First-Line Lorlatinib or Crizotinib in Advanced -Positive Lung Cancer.

N Engl J Med 2020 11;383(21):2018-2029

From the Massachusetts General Hospital Cancer Center (A.T.S.) and Pfizer (G.P.) - both in Boston; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (T.M.B.); European Institute of Oncology, IRCCS (F.M.), and Pfizer (A.P., A.M.C.) - both in Milan; Vall d'Hebron University Hospital and Institute of Oncology, International Oncology Bureau-Quirón, Barcelona (E.F.); National Cancer Center Hospital, Tokyo (Y.G.); Princess Margaret Cancer Centre, Toronto (G.L.); Toulouse University Hospital, Toulouse, France (J.M.); Seoul National University College of Medicine and Seoul National University Hospital, Seoul, South Korea (D.-W.K.); State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Hong Kong (T.M.); Pfizer, La Jolla, CA (H.T.); and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.).

Background: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with -positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced -positive NSCLC is unclear.

Methods: We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced -positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred.

Results: The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively.

Conclusions: In an interim analysis of results among patients with previously untreated advanced -positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.).
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http://dx.doi.org/10.1056/NEJMoa2027187DOI Listing
November 2020

Small cell transformation of fusion-positive lung cancer resistant to ROS1 inhibition.

NPJ Precis Oncol 2020 3;4:21. Epub 2020 Aug 3.

Department of Medicine, Massachusetts General Hospital, Boston, MA USA.

Histologic transformation from non-small cell to small cell lung cancer has been reported as a resistance mechanism to targeted therapy in -mutant and fusion-positive lung cancers. Whether small cell transformation occurs in other oncogene-driven lung cancers remains unknown. Here we analyzed the genomic landscape of two pre-mortem and 11 post-mortem metastatic tumors collected from an advanced, fusion-positive lung cancer patient, who had received sequential ROS1 inhibitors. Evidence of small cell transformation was observed in all metastatic sites at autopsy, with inactivation of and , and loss of fusion expression. Whole-exome sequencing revealed minimal mutational and copy number heterogeneity, suggestive of "hard" clonal sweep. Patient-derived models generated from autopsy retained features consistent with small cell lung cancer and demonstrated resistance to ROS1 inhibitors. This case supports small cell transformation as a recurring resistance mechanism, and underscores the importance of elucidating its biology to expand therapeutic opportunities.
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http://dx.doi.org/10.1038/s41698-020-0127-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400592PMC
August 2020

Association between circulating tumor DNA burden and disease burden in patients with ALK-positive lung cancer.

Cancer 2020 10 5;126(20):4473-4484. Epub 2020 Aug 5.

Division of Thoracic Imaging and Intervention, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.

Background: Plasma genotyping is an emerging approach for the identification of genetic alterations mediating resistance to anaplastic lymphoma kinase (ALK)-targeted therapy. The authors reviewed plasma genotyping and imaging findings to assess the correlation between circulating tumor DNA (ctDNA) burden and disease burden in patients with ALK-positive lung cancer.

Methods: The authors analyzed 97 plasma specimens from 75 patients with ALK-positive lung cancer to identify ALK and non-ALK alterations. Disease burden was estimated by tabulating lesions per organ and calculating lesion diameters, areas, and volumes. Disease burden was correlated with the allelic frequency (AF) of plasma alterations.

Results: The mean interval between plasma collection and imaging was 8 days. ctDNA was detected in approximately 85% of plasma specimens. An ALK fusion and ALK mutation were detected in 79% and 76%, respectively, of plasma specimens. Using the maximum plasma alteration AF and maximum ALK alteration AF as independent surrogates of ctDNA burden, a higher disease burden measurement on imaging was found to be associated with higher ctDNA burden. Total body and extrathoracic tumor volume but not intrathoracic tumor volume correlated with ctDNA burden. Of all the disease sites assessed, the ctDNA burden correlated most with involvement of the liver, bones, and adrenal glands. Despite being the defining alteration in ALK-positive lung cancer, isolated plasma ALK fusion AF did not perform as well as the maximum plasma alteration AF or maximum ALK alteration AF for correlating tumor burden.

Conclusions: In patients with ALK-positive lung cancer, the maximum plasma alteration AF and maximum ALK alteration AF correlate with the extrathoracic burden of disease and are more predictive of tumor burden compared with the ALK fusion AF alone.

Lay Summary: Analysis of genetic material shed from cancer cells into the circulation offers insights into the molecular composition of tumors. The circulating tumor DNA (ctDNA) varies over time and across individuals and is impacted by the distribution of disease. Herein, the authors estimated tumor burden on imaging and correlated it with ctDNA by calculating the maximum allelic frequency. The current study findings demonstrated that the greatest correlation exists between extrathoracic, extracranial tumor burden (particularly involvement of the liver, adrenal glands, or bones) and ctDNA burden, suggesting a biological basis for the interpatient and temporal intrapatient differences in ctDNA yield that have been described in previous studies.
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http://dx.doi.org/10.1002/cncr.33118DOI Listing
October 2020

BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.

Cancer Res 2020 09 20;80(18):3841-3854. Epub 2020 Jul 20.

Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.

Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the prelicensing protein, CDC6. Quantitative mass spectrometry and coimmunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Finally, BRG1-deficient lung cancers were sensitive to pharmacologic inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues. SIGNIFICANCE: These findings indicate that inhibition of ATR is a promising therapy for the 10% of non-small cell lung cancer patients harboring mutations in SMARCA4/BRG1. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3841/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501156PMC
September 2020

U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 09 26;26(18):4785-4794. Epub 2020 Jun 26.

Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, California.

Purpose: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib.

Patients And Methods: Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring / rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity.

Results: A total of 46 patients were enrolled. Steady-state peak concentration ( ) and exposure (AUC) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%-149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory NSCLC. One patient with differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive L2086F as an acquired taletrectinib-resistance mutation.

Conclusions: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1630DOI Listing
September 2020

Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer.

Lung Cancer 2020 06 10;144:10-19. Epub 2020 Mar 10.

University of Colorado, Aurora, CO, USA. Electronic address:

Objectives: To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily.

Materials And Methods: PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM).

Results: 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %).

Conclusions: Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.
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http://dx.doi.org/10.1016/j.lungcan.2020.02.011DOI Listing
June 2020

A Phase II Study of the Multikinase Inhibitor Ponatinib in Patients With Advanced, -Rearranged NSCLC.

JTO Clin Res Rep 2020 Sep 24;1(3):100045. Epub 2020 Apr 24.

Department of Medicine, Center for Thoracic Cancers, Massachusetts General Hospital, Boston, Massachusetts.

Introduction: rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of -rearranged NSCLC.

Methods: In this single-arm, multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, -rearranged NSCLC (NCT01813734). rearrangements were identified through fluorescence in situ hybridization or next-generation sequencing. Ponatinib was administered at a dose of 30 mg once daily. Patients without a documented objective response were eligible to dose-escalate ponatinib to 45 mg daily. The primary end point was objective response rate.

Results: Between August 2014 and December 2017, nine patients were enrolled. The median age was 58 years (range 49-73 y). Eight patients (89%) had a history of brain metastases. The median number of previous lines of therapy was three (range 1-5). Of the nine evaluated patients, five (55%) experienced tumor shrinkage from baseline, but no confirmed responses were observed (objective response rate 0%). The disease control rate was 55%. With a median follow-up of 9.33 months, the median progression-free survival and overall survival were 3.80 months (95% CI: 1.83-5.30) and 17.47 months (95% CI: 6.57-19.20), respectively. The most common treatment-related adverse events were rash (n = 5; 56%), constipation (n = 4; 44%), and diarrhea (n = 4; 44%). No treatment-related thromboembolic or cardiac events were observed. The study was stopped prematurely owing to slow accrual and lack of clinical activity.

Conclusions: Ponatinib has limited clinical activity in patients with -rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474450PMC
September 2020

Imaging Features and Patterns of Metastasis in Non-Small Cell Lung Cancer with Rearrangements.

Cancers (Basel) 2020 Mar 15;12(3). Epub 2020 Mar 15.

Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Rearranged during transfection proto-oncogene () fusions represent a potentially targetable oncogenic driver in non-small cell lung cancer (NSCLC). Imaging features and metastatic patterns of advanced fusion-positive (+) NSCLC are not well established. Our goal was to compare the imaging features and patterns of metastases in +, + and + NSCLC. Patients with +, +, or + NSCLC seen at our institution between January 2014 and December 2018 with available pre-treatment imaging were identified. The clinicopathologic features, imaging characteristics, and the distribution of metastases were reviewed and compared. We identified 215 patients with NSCLC harboring , , or gene fusion ( = 32; = 116; = 67). Patients with + NSCLC were older at presentation compared to + and + patients (median age: = 64 years; = 51 years, < 0.001; ROS = 54 years, = 0.042) and had a higher frequency of neuroendocrine histology ( = 12%; = 2%, = 0.025; = 0%, = 0.010). Primary tumors in + patients were more likely to be peripheral ( = 69%; = 47%, = 0.029; = 36%, = 0.003), whereas lobar location, size, and density were comparable across the three groups. + NSCLC was associated with a higher frequency of brain metastases at diagnosis compared to + NSCLC ( = 32%, = 10%; = 0.039. Metastatic patterns were otherwise similar across the three molecular subgroups, with high incidences of lymphangitic carcinomatosis, pleural metastases, and sclerotic bone metastases. + NSCLC shares several distinct radiologic features and metastatic spread with + and NSCLC. These features may suggest the presence of fusions and help identify patients who may benefit from further molecular genotyping.
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http://dx.doi.org/10.3390/cancers12030693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140075PMC
March 2020

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

Clin Cancer Res 2020 06 21;26(11):2535-2545. Epub 2020 Feb 21.

Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Purpose: Most -positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.

Experimental Design: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue ( = 101) or plasma ( = 106) specimens from patients with ALK-positive lung cancer to detect genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance.

Results: amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop amplification than those who had received next-generation ALK inhibitors after crizotinib ( = 0.019). Two tumor specimens harbored an identical rearrangement, one of which had concurrent amplification. Expressing in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both and amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired alterations achieved rapid responses to ALK/MET combination therapy.

Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired alterations may derive clinical benefit from therapies that target both ALK and MET.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269872PMC
June 2020

Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer.

Target Oncol 2020 02;15(1):55-65

Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain.

Background: Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood-brain barrier.

Objective: We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs.

Patients And Methods: In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ≥ 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach.

Results: Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2-3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n = 22)]. In patients who received ≥ 1 prior second-generation ALK TKI [EXP3B-5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively).

Conclusions: Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. CLINICALTRIALS.

Gov Identifier: NCT01970865.
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http://dx.doi.org/10.1007/s11523-020-00702-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028836PMC
February 2020

Resistance looms for KRAS inhibitors.

Nat Med 2020 02;26(2):169-170

Novartis Institutes of Biomedical Research, Cambridge, MA, USA.

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http://dx.doi.org/10.1038/s41591-020-0765-zDOI Listing
February 2020

Time To Response In Patients With Advanced Anaplastic Lymphoma Kinase ()-Positive Non-Small-Cell Lung Cancer (NSCLC) Receiving Alectinib In The Phase II NP28673 And NP28761 Studies.

Lung Cancer (Auckl) 2019 13;10:125-130. Epub 2019 Nov 13.

Division of Hematology-Medical Oncology, Department of Internal Medicine, University of California, Irvine School of Medicine, Orange, CA 92617, USA.

Introduction: Alectinib is a highly selective and potent ALK inhibitor, approved for the treatment of patients with metastatic + NSCLC based on results from the Phase II global NP28673 (NCT01801111) and North American NP28761 (NCT01871805) studies.

Methods: This exploratory analysis of two Phase II studies of alectinib (NP28673/NP28761) investigated time to systemic response (TTR) and time to central nervous system (CNS) response (TTCR) in patients with previously treated advanced anaplastic lymphoma kinase fusion gene-positive (+) non-small-cell lung cancer. Patients (n=225) received 600 mg oral alectinib twice daily and had scans every 6/8 weeks (NP28673/NP28761).

Results: For NP28673 and NP28761, respectively: median follow-up was 21.3 months/17.0 months; most responders (72.6%/82.9%) responded by the first disease assessment; median TTR was 8 weeks (95% confidence interval [CI]: 8.00-8.14)/6 weeks (95% CI: 5.86-6.14); median TTCR in responders with measurable baseline CNS disease was 8 weeks (95% CI: 7.86-10.29)/6 weeks (95% CI: 5.71-not evaluable). Similar results were observed regardless of measurable/non-measurable disease.

Discussion: These data suggest that alectinib achieves a rapid response in patients, both systemically and in the CNS.
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http://dx.doi.org/10.2147/LCTT.S209231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859466PMC
November 2019

Clinicopathologic Characteristics of BRG1-Deficient NSCLC.

J Thorac Oncol 2020 05 24;15(5):766-776. Epub 2020 Jan 24.

Center for Integrated Diagnostics, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Introduction: Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations.

Methods: Data sets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed.

Results: We detected SMARCA4 genomic alterations in 9% (n = 117 of 1422) and 11% (n = 3188 of 27,281) of NSCLCs in the institutional and Foundation Medicine data sets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine of 64 SMARCA4-mutant NSCLCs (45%) assessed for BRG1 expression reported loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, 84% (n = 26 of 31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n = 11) or chemotherapy plus immunotherapy (n = 5), median progression-free survival was 38 days and 35 days, respectively.

Conclusions: BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state.
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http://dx.doi.org/10.1016/j.jtho.2020.01.002DOI Listing
May 2020

Imaging Features and Metastatic Patterns of Advanced -Rearranged Non-Small Cell Lung Cancer.

AJR Am J Roentgenol 2020 04 30;214(4):766-774. Epub 2019 Dec 30.

Department of Radiology, Massachusetts General Hospital, 55 Fruit St, Founders 202, Boston, MA 02114.

rearrangements are an established targetable oncogenic driver in non-small cell lung cancer (NSCLC). The goal of this study was to determine the imaging features of the primary tumor and metastatic patterns in advanced -rearranged (+) NSCLC that may be different from those in -mutant (+) or wild-type (-/-) NSCLC. Patients with advanced +, +, or NSCLC were retrospectively identified. Two radiologists concurrently assessed the imaging features of the primary tumor and the distribution of metastases in these patients. We identified a cohort of 333 patients with metastatic NSCLC (119 cases, 116 cases, and 98 -/- cases). Compared with + and -/- NSCLC, the primary tumor in + NSCLC was more likely to be located in the lower lobes (53% of , 34% of , and 36% of -/- tumors; < 0.05), less likely to be subsolid (1% of +, 11% of , and 8% of -/- tumors; < 0.02), and less likely to have air bronchograms (7% of , 28% of , and 29% of -/- tumors; < 0.01). Compared with + and -/- tumors, + tumors had higher frequencies of distant nodal metastasis (20% of tumors vs 2% of and 9% of -/- tumors; < 0.05) and lymphangitic carcinomatosis (37% of tumors vs 12% of and 12% of -/- tumors; < 0.01), but + tumors had a lower frequency of brain metastasis compared with + tumors (24% vs 41%; = 0.01). Although there was no statistically significant difference in the frequencies of bone metastasis among the three groups, sclerotic bone metastases were more common in the + tumors (22% vs 7% of tumors and 6% of -/- tumors; < 0.01). Advanced + NSCLC has primary tumor imaging features and patterns of metastasis that are different from those of + or -/- wild type NSCLC at the time of initial presentation.
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http://dx.doi.org/10.2214/AJR.19.21982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558748PMC
April 2020

Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.

Lancet Oncol 2020 02 11;21(2):261-270. Epub 2019 Dec 11.

Ignyta, San Diego, CA, USA.

Background: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.

Methods: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).

Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred.

Interpretation: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC.

Funding: Ignyta/F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(19)30690-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811790PMC
February 2020

Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.

Lancet Oncol 2020 02 11;21(2):271-282. Epub 2019 Dec 11.

Department of Developmental Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.

Methods: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).

Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.

Interpretation: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.

Funding: Ignyta/F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(19)30691-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630PMC
February 2020

Final Overall Survival and Other Efficacy and Safety Results From ASCEND-3: Phase II Study of Ceritinib in ALKi-Naive Patients With ALK-Rearranged NSCLC.

J Thorac Oncol 2020 04 25;15(4):609-617. Epub 2019 Nov 25.

Department of Medicine and Pathology, Massachusetts General Hospital, Boston, Massachusetts.

Introduction: The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)-naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results.

Methods: Eligible patients (including those with asymptomatic or neurologically stable brain metastases) received oral ceritinib (750 mg/day, fasted). The primary end point was investigator-assessed overall response rate (ORR). Secondary end points were Blinded Independent Review Committee-assessed ORR; investigator- and Blinded Independent Review Committee-assessed overall intracranial response rate, duration of response, time to response, disease control rate, and progression-free survival (PFS); overall survival (OS); and safety. Exploratory end points included patient-reported outcomes.

Results: Of the 124 patients enrolled, 122 (98.4%) had received previous antineoplastic medications (31 patients [25.0%] received at least three regimens), and 49 (39.5%) had baseline brain metastases. The median follow-up time (data cutoff: January 22, 2018) was 52.1 (range, 48.4-60.1) months. The investigator-assessed ORR was 67.7% (95% confidence interval [CI]: 58.8-75.9), and the median PFS was 16.6 months (95% CI: 11.0-23.2). The median OS was 51.3 months (95% CI: 42.7-55.3). Most common adverse events (all grades, ≥60% of patients, all-causality) were diarrhea (85.5%), nausea (78.2%), and vomiting (71.8%). Overall, 18 patients (14.5%) had an adverse event leading to treatment discontinuation. Health-related quality of life was maintained during ceritinib treatment.

Conclusions: Ceritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies.
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http://dx.doi.org/10.1016/j.jtho.2019.11.006DOI Listing
April 2020

ALK Mutation Status Before and After Alectinib Treatment in Locally Advanced or Metastatic ALK-Positive NSCLC: Pooled Analysis of Two Prospective Trials.

J Thorac Oncol 2020 04 9;15(4):601-608. Epub 2019 Nov 9.

Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Introduction: The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies.

Methods: Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA from 187 patients post-crizotinib/pre-alectinib, and from 49 of these patients who subsequently progressed on alectinib.

Results: Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48 of 187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI]: 8.1-14.3) versus 5.6 months (95% CI: 4.5-10.9), respectively. Sixteen of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to alectinib (all partial responses); most of these ALK mutations were known to be sensitive to alectinib. Analysis of plasma samples obtained post-progression on alectinib revealed that 26 of 49 (53%) samples harbored 16 distinct ALK mutations, with known alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15 of 49 (31%) tumors.

Conclusions: Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy.
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http://dx.doi.org/10.1016/j.jtho.2019.10.015DOI Listing
April 2020

Computed Tomography Imaging Features and Distribution of Metastases in ROS1-rearranged Non-Small-cell Lung Cancer.

Clin Lung Cancer 2020 03 16;21(2):153-159.e3. Epub 2019 Oct 16.

Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA.

Background: ROS proto-oncogene 1 (ROS1) rearrangements are a known molecular target in non-small-cell lung cancer (NSCLC). Our goal was to determine whether ROS1-rearranged NSCLC has imaging features and patterns of metastasis, which differ from those of anaplastic lymphoma kinase (ALK)-rearranged or epidermal growth factor receptor (EGFR)-mutant NSCLC.

Patients And Methods: We retrospectively identified patients with metastatic ROS1-rearranged, ALK-rearranged, or EGFR-mutant NSCLC from January 2014 to June 2018 and included those with pretreatment imaging studies available. We assessed the imaging features of the primary tumor and the distribution of metastases in these patients. The Wilcoxon rank-sum test and Fisher exact test were used to compare the imaging features.

Results: We identified 257 patients (167 women and 90 men; median age, 56 years; range, 19-90 years) with metastatic NSCLC (ROS1, 53; ALK, 87; EGFR, 117). Compared with ALK-rearranged or EGFR-mutant NSCLC, ROS1-rearranged NSCLC was less likely to present with extrathoracic metastases (ROS1, 49%; ALK, 75%; EGFR, 72%; P < .01), including brain metastases (ROS1, 9%; ALK, 25%; EGFR, 40%; P < .04). Compared with EGFR-mutant NSCLC, ROS1-rearranged tumors were more likely to exhibit imaging features of lymphangitic carcinomatosis (ROS1, 42%; EGFR, 12%; P < .01) and less likely to have air bronchograms in the primary tumor (ROS1, 2%; EGFR, 28%; P < .01). ROS1-rearranged tumors were also more likely to present with distant nodal metastases (ROS1, 15%; EGFR, 2%; P < .01) and sclerotic-type bone metastases (ROS1, 17%; EGFR, 6%; P < .01).

Conclusion: Although considerable overlap exists in the imaging features of ROS1-rearranged, ALK-rearranged, and EGFR-mutant NSCLC, we found that ROS1-rearranged NSCLC has certain distinct imaging features and patterns of spread.
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http://dx.doi.org/10.1016/j.cllc.2019.10.006DOI Listing
March 2020

Pooled overall survival and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small-cell lung cancer.

Lung Cancer 2020 01 14;139:22-27. Epub 2019 Oct 14.

Massachusetts General Hospital Cancer Center, Yawkey 7B, 32 Fruit Street, Boston, MA, USA. Electronic address:

Objectives: A pooled analysis of two open-label phase II studies of alectinib (NP28673 [NCT01801111] and NP28761 [NCT01871805]) demonstrated clinical activity in patients with advanced, anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) previously treated with crizotinib. Longer-term and final pooled analyses of overall survival (OS) and safety data from the two studies are presented here.

Patients And Methods: The pooled population totaled 225 patients (NP28673: n = 138, NP28761: n = 87) who received 600 mg oral alectinib twice daily until disease progression, death, or withdrawal. OS was defined as the time from date of first treatment to date of death, regardless of cause. OS was estimated using Kaplan-Meier methodology, with 95% confidence intervals (CIs) determined using the Brookmeyer-Crowley method. Safety was assessed through adverse event (AE) reporting.

Results: Baseline characteristics were generally comparable between the studies. At final data cutoff (October 27, 2017 [NP28673], October 12, 2017 [NP28761]; median pooled follow-up time, ∼21 months), 53.3% of patients had died, 39.1% were alive and in follow-up, and 7.6% had withdrawn consent or were lost to follow-up. Alectinib demonstrated a median OS of 29.1 months (95% CI 21.3-39.0). No new or unexpected safety findings were observed. The most common all-grade AEs included constipation (39.1%), fatigue (35.1%), peripheral edema (28.4%), myalgia (26.2%), and nausea (24.0%).

Conclusion: Updated results from this pooled analysis further demonstrate that alectinib has robust clinical activity and a manageable safety profile in patients with advanced, ALK+ NSCLC pretreated with crizotinib.
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http://dx.doi.org/10.1016/j.lungcan.2019.10.015DOI Listing
January 2020

Efficacy of Platinum/Pemetrexed Combination Chemotherapy in ALK-Positive NSCLC Refractory to Second-Generation ALK Inhibitors.

J Thorac Oncol 2020 02 26;15(2):258-265. Epub 2019 Oct 26.

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Introduction: The current standard initial therapy for advanced ALK receptor tyrosine kinase (ALK)-positive NSCLC is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third-generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in cases that are refractory to second-generation TKIs.

Methods: This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to one or more second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy.

Results: Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11 of 37 patients; 95% confidence interval [CI]: 15.9% - 47.0%), with median duration of response of 6.4 months (95% CI: 1.6 months - not reached). The median progression-free survival for the entire cohort was 4.3 months (95% CI: 2.9 - 5.8 months). Progression-free survival was longer in patients who received platinum/pemetrexed in combination with an ALK TKI compared to those who received platinum/pemetrexed alone (6.8 months vs. 3.2 months, respectively; hazard ratio = 0.33; p = 0.025).

Conclusions: Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.
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http://dx.doi.org/10.1016/j.jtho.2019.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058505PMC
February 2020

Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial.

Lancet Oncol 2019 12 25;20(12):1691-1701. Epub 2019 Oct 25.

University of California Irvine, Irvine, CA, USA.

Background: Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity against most known resistance mutations in ALK and ROS1. We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive non-small-cell lung cancer (NSCLC).

Methods: In this open-label, single-arm, phase 1-2 trial, we enrolled patients (aged ≥18 years) with histologically or cytologically confirmed advanced ROS1-positive NSCLC, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 2 or less (≤1 for phase 1 only) from 28 hospitals in 12 countries worldwide. Lorlatinib 100 mg once daily (escalating doses of 10 mg once daily to 100 mg twice daily in phase 1 only) was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was overall and intracranial tumour response, assessed by independent central review. Activity endpoints were assessed in patients who received at least one dose of lorlatinib. This study is ongoing and is registered with ClinicalTrials.gov, NCT01970865.

Findings: Between Jan 22, 2014, and Oct 2, 2016, we assessed 364 patients, of whom 69 with ROS1-positive NSCLC were enrolled. 21 (30%) of 69 patients were TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and eight (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. The estimated median duration of follow-up for response was 21·1 months (IQR 15·2-30·3). 13 (62%; 95% CI 38-82) of 21 TKI-naive patients and 14 (35%; 21-52) of 40 patients previously treated with crizotinib as their only TKI had an objective response. Intracranial responses were achieved in seven (64%; 95% CI 31-89) of 11 TKI-naive patients and 12 (50%; 29-71) of 24 previous crizotinib-only patients. The most common grade 3-4 treatment-related adverse events were hypertriglyceridaemia (13 [19%] of 69 patients) and hypercholesterolaemia (ten [14%]). Serious treatment-related adverse events occurred in five (7%) of 69 patients. No treatment-related deaths were reported.

Interpretation: Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent.

Funding: Pfizer.
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http://dx.doi.org/10.1016/S1470-2045(19)30655-2DOI Listing
December 2019
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