Publications by authors named "Justin F Gainor"

129 Publications

Adjuvant PD-L1 blockade in non-small-cell lung cancer.

Authors:
Justin F Gainor

Lancet 2021 Oct 20;398(10308):1281-1283. Epub 2021 Sep 20.

Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)02100-0DOI Listing
October 2021

Clinical and Imaging Features of Non-Small Cell Lung Cancer with G12C KRAS Mutation.

Cancers (Basel) 2021 Jul 16;13(14). Epub 2021 Jul 16.

Department of Radiology, Division of Thoracic Imaging and Intervention, Massachusetts General Hospital, Boston, MA 02114, USA.

KRAS G12C mutations are important oncogenic mutations that confer sensitivity to direct G12C inhibitors. We retrospectively identified patients with KRAS+ NSCLC from 2015 to 2019 and assessed the imaging features of the primary tumor and the distribution of metastases of G12C NSCLC compared to those of non-G12C KRAS NSCLC and NSCLC driven by oncogenic fusion events (RET, ALK, ROS1) and EGFR mutations at the time of initial diagnosis. Two hundred fifteen patients with KRAS+ NSCLC (G12C: 83; non-G12C: 132) were included. On single variate analysis, the G12C group was more likely than the non-G12C KRAS group to have cavitation (13% vs. 5%, = 0.04) and lung metastasis (38% vs. 21%; = 0.043). Compared to the fusion rearrangement group, the G12C group had a lower frequency of pleural metastasis (21% vs. 41%, = 0.01) and lymphangitic carcinomatosis (4% vs. 39%, = 0.0001) and a higher frequency of brain metastasis (42% vs. 22%, = 0.005). Compared to the EGFR+ group, the G12C group had a lower frequency of lung metastasis (38% vs. 67%, = 0.0008) and a higher frequency of distant nodal metastasis (10% vs. 2%, = 0.02). KRAS G12C NSCLC may have distinct primary tumor imaging features and patterns of metastasis when compared to those of NSCLC driven by other genetic alterations.
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http://dx.doi.org/10.3390/cancers13143572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304953PMC
July 2021

Lung cancer.

Lancet 2021 08 21;398(10299):535-554. Epub 2021 Jul 21.

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

Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide with an estimated 2 million new cases and 1·76 million deaths per year. Substantial improvements in our understanding of disease biology, application of predictive biomarkers, and refinements in treatment have led to remarkable progress in the past two decades and transformed outcomes for many patients. This seminar provides an overview of advances in the screening, diagnosis, and treatment of non-small-cell lung cancer and small-cell lung cancer, with a particular focus on targeted therapies and immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/S0140-6736(21)00312-3DOI Listing
August 2021

Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study.

Lancet Diabetes Endocrinol 2021 08 9;9(8):491-501. Epub 2021 Jun 9.

Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.

Background: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers.

Methods: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis.

Findings: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event.

Interpretation: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer.

Funding: Blueprint Medicines.
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http://dx.doi.org/10.1016/S2213-8587(21)00120-0DOI Listing
August 2021

Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study.

Lancet Oncol 2021 07 9;22(7):959-969. Epub 2021 Jun 9.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC.

Methods: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis.

Findings: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population.

Interpretation: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC.

Funding: Blueprint Medicines.
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http://dx.doi.org/10.1016/S1470-2045(21)00247-3DOI Listing
July 2021

Characteristics and Outcomes of Lung Cancers Detected on Low-Dose Lung Cancer Screening CT.

Cancer Epidemiol Biomarkers Prev 2021 Aug 9;30(8):1472-1479. Epub 2021 Jun 9.

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

Background: Lung cancer screening (LCS) with low-dose CT (LDCT) was implemented in the United States following the National Lung Screening Trial (NLST). The real-world benefits of implementing LCS are yet to be determined with outcome-oriented data. The study objective is to investigate the characteristics and outcomes of screening-detected lung cancers.

Methods: This single-institution retrospective study included LCS patients between June 2014 and December 2019. Patient demographics, number of screening rounds, imaging features, clinical workup, disease extent, histopathology, treatment, complications, and mortality outcomes of screening-detected lung cancers were extracted and compared with NLST data.

Results: LCS LDCTs (7,480) were performed on 4,176 patients. The cancer detection rate was 3.8%, higher than reported by NLST (2.4%, < 0.0001), and cancers were most often found in patients ≥65 years (62%), older than those in NLST (41%, < 0.0001). The patients' ethnicity was similar to NLST, = 0.87. Most LCS-detected cancers were early stage I tumors (71% vs. 54% in NLST, < 0.0001). Two thirds of cancers were detected in the first round of screening (67.1%) and were multifocal lung cancers in 15%. As in NLST, the complication rate after invasive workup or surgery was low (24% vs. 28% in NLST, = 0.32). Over a median follow-up of 3.3 years, the mortality rate was 0.45%, lower than NLST (1.33%, < 0.0001).

Conclusions: LCS implementation achieved a higher cancer detection rate, detection of early-stage cancers, and more multifocal lung cancers compared with the NLST, with low complications and mortality.

Impact: The real-world implementation of LCS has been successful for detection of lung cancer with favorable outcomes.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1847DOI Listing
August 2021

Intracranial Efficacy of Selpercatinib in Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial.

Clin Cancer Res 2021 Aug 4;27(15):4160-4167. Epub 2021 Jun 4.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for fusion-positive non-small cell lung cancers (NSCLC).

Patients And Methods: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced -altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.

Results: Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.

Conclusions: Selpercatinib has robust and durable intracranial efficacy in patients with fusion-positive NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447251PMC
August 2021

Temporal Trends in Inpatient Oncology Census Before and During the COVID-19 Pandemic and Rates of Nosocomial COVID-19 Among Patients with Cancer at a Large Academic Center.

Oncologist 2021 08 18;26(8):e1427-e1433. Epub 2021 May 18.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted health care systems. However, to date, the trend of hospitalizations in the oncology patient population has not been studied, and the frequency of nosocomial spread to patients with cancer is not well understood. The objectives of this study were to evaluate the impact of COVID-19 on inpatient oncology census and determine the nosocomial rate of COVID-19 in patients with cancer admitted at a large academic center.

Materials And Methods: Medical records of patients with cancer diagnosed with COVID-19 and admitted were reviewed to evaluate the temporal trends in inpatient oncology census during pre-COVID-19 (January 2019 to February 2020), COVID-19 (March to May 2020), and post-COVID-19 surge (June to August 2020) in the region. In addition, nosocomial infection rates of SARS-CoV-2 were reviewed.

Results: Overall, the daily inpatient census was steady in 2019 (median, 103; range, 92-118) and until February 2020 (median, 112; range, 102-114). However, there was a major decline from March to May 2020 (median, 68; range, 57-104), with 45.4% lower admissions during April 2020. As the COVID-19 surge eased, the daily inpatient census over time returned to the pre-COVID-19 baseline (median, 103; range, 99-111). One patient (1/231, 0.004%) tested positive for SARS-CoV-2 13 days after hospitalization, and it is unclear if it was nosocomial or community spread.

Conclusion: In this study, inpatient oncology admissions decreased substantially during the COVID-19 surge but over time returned to the pre-COVID-19 baseline. With aggressive infection control measures, the rates of nosocomial transmission were exceedingly low and should provide reassurance to those seeking medical care, including inpatient admissions when medically necessary.

Implications For Practice: The COVID-19 pandemic has had a major impact on the health care system, and cancer patients are a vulnerable population. This study observes a significant decline in the daily inpatient oncology census from March to May 2020 compared with the same time frame in the previous year and examines the potential reasons for this decline. In addition, nosocomial rates of COVID-19 were investigated, and rates were found to be very low. These findings suggest that aggressive infection control measures can mitigate the nosocomial infection risk among cancer patients and the inpatient setting is a safe environment, providing reassurance.
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http://dx.doi.org/10.1002/onco.13807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242879PMC
August 2021

Assessment of a Contralateral Esophagus-Sparing Technique in Locally Advanced Lung Cancer Treated With High-Dose Chemoradiation: A Phase 1 Nonrandomized Clinical Trial.

JAMA Oncol 2021 Jun;7(6):910-914

Department of Radiation Oncology, Massachusetts General Hospital, Boston.

Importance: Severe acute esophagitis occurs in up to 20% of patients with locally advanced lung cancer treated with chemoradiation therapy to at least 60 Gy once daily and represents a dose-limiting toxic event associated with poor outcomes.

Objective: To assess whether formalized sparing of the contralateral esophagus (CE) is associated with reduced risk of severe acute esophagitis.

Design, Setting, And Participants: This single-center phase 1 nonrandomized clinical trial assessing an empirical CE-sparing technique enrolled patients from July 2015 to January 2019. In total, 27 patients with locally advanced non-small cell lung carcinoma (with or without solitary brain metastasis) or limited-stage small cell lung carcinoma with gross tumor within 1 cm of the esophagus were eligible.

Interventions: Intensity-modulated radiation therapy to 70 Gy at 2 Gy/fraction concurrent with standard chemotherapy with or without adjuvant durvalumab. The esophageal wall contralateral to gross tumor was contoured as an avoidance structure to guide a steep dose falloff gradient. Target coverage was prioritized over CE sparing, and 99% of internal and planning target volumes had to be covered by 70 Gy and at least 63 Gy, respectively.

Main Outcomes And Measures: The primary end point was the rate of at least grade 3 acute esophagitis as assessed by Common Terminology Criteria for Adverse Events, version 4.

Results: Of 27 patients enrolled, 25 completed chemoradiation therapy. Nineteen patients had non-small cell lung carcinoma, and 6 had small cell lung carcinoma. The median age at diagnosis was 67 years (range, 51-81 years), and 15 patients (60%) were men. Thirteen patients (52%) had stage IIIA cancer, 10 (40%) had stage IIIB cancer, and 2 (8%) had stage IV cancer. The median CE maximum dose was 66 Gy (range, 44-71 Gy); the median volume of CE receiving at least 55 Gy was 1.4 cm3 (range, 0-5.3 cm3), and the median volume of CE receiving at least 45 Gy was 2.7 cm3 (range, 0-9.2 cm3). The median combined percentage of lung receiving at least 20 Gy was 25% (range, 11%-37%). The median follow-up was 33.3 months (range, 11.1-52.2 months). Among the 20 patients who had treatment breaks of 0 to 3 days and were thus evaluable for the primary end point, the rate of at least grade 3 esophagitis was 0%. Other toxic events observed among all 25 patients included 7 (28%) with grade 2 esophagitis, 3 (12%) with at least grade 2 pneumonitis (including 1 with grade 5), and 2 (8%) with at least grade 3 cardiac toxic event (including 1 with grade 5). There was no isolated local tumor failure. The 2-year progression-free survival rate was 57% (95% CI, 33%-75%), and the 2-year overall survival rate was 67% (95% CI, 45%-82%).

Conclusions And Relevance: This phase 1 nonrandomized clinical trial found that the CE-sparing technique was associated with reduced risk of esophagitis among patients treated uniformly with chemoradiation therapy (to 70 Gy), with no grade 3 or higher esophagitis despite tumor within 1 cm of the esophagus. This technique may be translated into clinical practice.

Trial Registration: ClinicalTrials.gov Identifier: NCT02394548.
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http://dx.doi.org/10.1001/jamaoncol.2021.0281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033505PMC
June 2021

Clinical Acquired Resistance to KRAS Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation.

Cancer Discov 2021 Aug 6;11(8):1913-1922. Epub 2021 Apr 6.

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

Mutant-selective KRAS inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in -mutant cancers, including non-small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRAS inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (), all of which converge to reactivate RAS-MAPK signaling. Notably, a novel mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein-drug interactions and confers resistance to these inhibitors in engineered and patient-derived cancer models. Interestingly, a novel, functionally distinct tricomplex KRAS active-state inhibitor RM-018 retained the ability to bind and inhibit KRAS and could overcome resistance. SIGNIFICANCE: In one of the first reports of clinical acquired resistance to KRAS inhibitors, our data suggest polyclonal RAS-MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRAS inhibitor...
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http://dx.doi.org/10.1158/2159-8290.CD-21-0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338755PMC
August 2021

An early look at selective RET inhibitor resistance: new challenges and opportunities.

Br J Cancer 2021 May 23;124(11):1757-1758. Epub 2021 Mar 23.

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

Two RET inhibitors, selpercatinib and pralsetinib, recently received approval for the treatment of advanced RET fusion-positive lung cancer. Acquired resistance to these inhibitors will be a major challenge. We have shown that resistance can emerge due to recurrent RET kinase domain mutations and, in most cases, due to RET-independent mechanisms.
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http://dx.doi.org/10.1038/s41416-021-01344-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144197PMC
May 2021

COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials.

Nat Rev Clin Oncol 2021 05 15;18(5):313-319. Epub 2021 Mar 15.

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility.
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http://dx.doi.org/10.1038/s41571-021-00487-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957448PMC
May 2021

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

Clin Cancer Res 2021 May 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

Patterns and prognostic significance of cutaneous immune-related adverse events in non-small cell lung cancer.

Eur J Cancer 2021 04 16;147:13-16. Epub 2021 Feb 16.

Department of Dermatology, Massachusetts General Hospital & Harvard Medical School, 50 Staniford Street, Boston MA 02114, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2021.01.022DOI Listing
April 2021

Endocrine immune-related adverse events: a double-edged sword?

Transl Lung Cancer Res 2021 Jan;10(1):13-17

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.21037/tlcr-2020-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867773PMC
January 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

Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer: Implications for Oncogene-Driven Lung Cancer.

Cancer J 2020 Nov/Dec;26(6):517-524

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly defined by genetic alterations in oncogenic drivers. Targeted therapies have transformed the management of oncogene-driven lung cancers, with targeted agents now approved in the United States for 7 distinct molecular alterations. Nonetheless, acquired resistance remains an ongoing challenge, underscoring the need for alternative therapeutic approaches. Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have emerged as important therapies in the management of advanced NSCLC, but the role of these agents in patients with oncogenic driver mutations remains unclear. Here, we focus on epidermal growth factor receptor-mutant and anaplastic lymphoma kinase-rearranged NSCLC as paradigms to explore the role of immune checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview of the clinical data examining programmed death ligand 1 (PD-L1) inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor combinations, as well as combinations of PD-(L)1 inhibitors and chemotherapy.
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http://dx.doi.org/10.1097/PPO.0000000000000491DOI Listing
September 2021

Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, Presentation, and Alternative Diagnostic Considerations.

JTO Clin Res Rep 2021 Jan 12;2(1):100124. Epub 2020 Nov 12.

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.

Introduction: Lung cancer is associated with severe coronavirus disease 2019 (COVID-19) infections. Symptom overlap between COVID-19 and lung cancer may complicate diagnostic evaluation. We aimed to investigate the incidence, symptoms, differential diagnosis, and outcomes of COVID-19 in patients with lung cancer.

Methods: To determine an at-risk population for COVID-19, we retrospectively identified patients with lung cancer receiving longitudinal care within a single institution in the 12 months (April 1, 2019 to March 31, 2020) immediately preceding the COVID-19 pandemic, including an "active therapy population" treated within the last 60 days of this period. Among patients subsequently referred for COVID-19 testing, we compared symptoms, laboratory values, radiographic findings, and outcomes of positive versus negative patients.

Results: Between April 1, 2019 and March 31, 2020, a total of 696 patients received longitudinal care, including 406 (58%) in the active therapy population. Among 55 patients referred for COVID-19 testing, 24 (44%) were positive for COVID-19, representing a cumulative incidence of 3.4% (longitudinal population) and 1.5% (active therapy population). Compared with patients who were COVID-19 negative, those who were COVID-19 positive were more likely to have a supplemental oxygen requirement (11% versus 54%,  = 0.005) and to have typical COVID-19 pneumonia imaging findings (5 versus 56%,  = 0.001). Otherwise, there were no marked differences in presenting symptoms. Among patients who were COVID-19 negative, alternative etiologies included treatment-related toxicity (26%), atypical pneumonia (22%), and disease progression (22%). A total of 16 patients positive for COVID-19 (67%) required hospitalization, and seven (29%) died from COVID-related complications.

Conclusions: COVID-19 was infrequent in this lung cancer population, but these patients experienced high rates of morbidity and mortality. Oncologists should maintain a low threshold for COVID-19 testing in patients with lung cancer presenting with acute symptoms.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659804PMC
January 2021

Detection of Extrapulmonary Malignancy During Lung Cancer Screening: 5-Year Analysis at a Tertiary Hospital.

J Am Coll Radiol 2020 Dec 12;17(12):1609-1620. Epub 2020 Oct 12.

Director of Quality and Safety and Head of Thoracic Imaging for Oncology, Division of Thoracic Imaging and Intervention, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Purpose: The aims of this study were to determine the prevalence and outcomes of extrapulmonary malignancies identified on lung cancer screening (LCS) and to determine the cost associated with the investigation of these lesions.

Methods: This retrospective study included 7,414 low-dose CT studies performed between June 2014 and December 2019 on 4,160 patients as part of an established LCS program. Patients with indeterminate extrapulmonary lesions were identified, and the diagnostic workup, management, and outcomes of the lesions were determined. Costs related to diagnostic evaluation were estimated using 2020 total facility relative value units and the 2020 Medicare conversion factor. Out-of-pocket costs were extracted from billing records.

Results: There were 20 extrapulmonary malignancies among 241 reported lesions in 225 patients (mean age, 66.1 ± 6.4 years; 109 men, 116 women). The prevalence of extrapulmonary malignancy was 20 of 4,160 (0.48%). Early-stage cancers were detected in 13 of 20 (65%). No cancer-specific mortality was observed. The predictive value for malignancy varied by organ (P = .03) and was highest in the chest wall and axilla (36.4%), followed by bone (25%). The average cost on the basis of Medicare reimbursement for diagnosis of an extrapulmonary malignancy on LCS was $1,316.03 ($6.33 per participant and $109.21 per indeterminate incidental lesion). Most patients (203 of 225 [90.2%]) did not have out-of-pocket costs related to diagnostic workup. In those who did, the median cost was $160.60 (range, $75-$606.76).

Conclusions: Low-dose CT for LCS detects extrapulmonary malignancy with high predictive value for certain locations. There is cost associated in the workup related to these incidental lesions, but most malignancies are detected at early stages and have good outcomes.
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http://dx.doi.org/10.1016/j.jacr.2020.09.032DOI Listing
December 2020

Deep Learning to Estimate RECIST in Patients with NSCLC Treated with PD-1 Blockade.

Cancer Discov 2021 01 21;11(1):59-67. Epub 2020 Sep 21.

Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Real-world evidence (RWE), conclusions derived from analysis of patients not treated in clinical trials, is increasingly recognized as an opportunity for discovery, to reduce disparities, and to contribute to regulatory approval. Maximal value of RWE may be facilitated through machine-learning techniques to integrate and interrogate large and otherwise underutilized datasets. In cancer research, an ongoing challenge for RWE is the lack of reliable, reproducible, scalable assessment of treatment-specific outcomes. We hypothesized a deep-learning model could be trained to use radiology text reports to estimate gold-standard RECIST-defined outcomes. Using text reports from patients with non-small cell lung cancer treated with PD-1 blockade in a training cohort and two test cohorts, we developed a deep-learning model to accurately estimate best overall response and progression-free survival. Our model may be a tool to determine outcomes at scale, enabling analyses of large clinical databases. SIGNIFICANCE: We developed and validated a deep-learning model trained on radiology text reports to estimate gold-standard objective response categories used in clinical trial assessments. This tool may facilitate analysis of large real-world oncology datasets using objective outcome metrics determined more reliably and at greater scale than currently possible..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981277PMC
January 2021

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

Progresses Toward Precision Medicine in -altered Solid Tumors.

Clin Cancer Res 2020 12 14;26(23):6102-6111. Epub 2020 Jul 14.

Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.

(rearranged during transfection) gene encodes a receptor tyrosine kinase essential for many physiologic functions, but aberrations are involved in many pathologies. While loss-of-function mutations are associated with congenital disorders like Hirschsprung disease and CAKUT, gain-of-function mutations and rearrangements are critical drivers of tumor growth and proliferation in many different cancers. -altered ( ) tumors have been hitherto targeted with multikinase inhibitors (MKI) having anti- activities, but they inhibit other kinase targets more potently and show limited clinical activities. The lack of target specificity and consequently increased side effects, responsible for dose reduction and drug discontinuation, are critical limitations of MKIs in the clinics. New selective inhibitors, selpercatinib and pralsetinib, are showing promising activities, improved response rates, and more favorable toxicity profiles in early clinical trials. This review critically discusses the oncogenic activation of and its role in different kinds of tumors, clinical features of tumors, clinically actionable genetic alterations and their diagnosis, and the available data and results of nonselective and selective targeting of .
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1587DOI Listing
December 2020

Association Between Immune-Related Adverse Events and Clinical Outcomes to Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Blockade in SCLC.

JTO Clin Res Rep 2020 Nov 15;1(4):100074. Epub 2020 Jul 15.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Introduction: The development of immune-related adverse events (irAEs) has been associated with improved efficacy of immune checkpoint inhibitors in patients with urothelial cancer, melanoma, and NSCLC. Whether this association exists in patients with SCLC is currently unknown.

Methods: We conducted a multicenter retrospective study to evaluate the relationship between irAEs and immunotherapy efficacy in SCLC. To account for the lead-time bias resulting from the time-dependent nature of irAEs, the development of irAEs was considered as a time-varying covariate in univariate and multivariate Cox proportional hazard models.

Results: Of the 183 patients treated with immunotherapy, 73 (39.9%) experienced at least one irAE. A total of 42 patients (22.9%) had grade 1 to 2 irAEs, whereas 31 patients (16.9%) had grade 3 to 4 irAEs. The median time of onset to the first irAE was 24 days (interquartile range: 14-55). The baseline clinicopathologic features were well-balanced between patients with and without irAEs. At a median follow-up of 24 months (95% confidence interval [CI]: 17.0-31.6), the median progression-free survival was significantly longer in the irAE group than the non-irAE group (3.8 versus 1.3 mo, < 0.0001). The median overall survival was also significantly longer among patients with irAEs than patients without irAEs (13.8 versus 2.9 mo, < 0.0001). When analyzed as a time-varying covariate, the development of irAEs was associated with a significant improvement in progression-free survival (hazard ratio: 0.44 [95% CI: 0.29-0.66], < 0.001) and overall survival (hazard ratio: 0.47 [95% CI: 0.32-0.71], < 0.001) in multivariate models.

Conclusions: The development of irAEs is associated with improved clinical outcomes for immunotherapy in patients with advanced SCLC.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474257PMC
November 2020

Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.

Lancet Oncol 2020 06 7;21(6):786-795. Epub 2020 May 7.

Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. Electronic address:

Background: Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection.

Methods: This open-label, multicentre, single-arm, phase 2 trial was done at three hospitals in the USA. Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1, and a history of smoking exposure. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100 mg/m) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1, of each 21-day cycle. Patients without disease progression after two cycles proceeded to receive two further cycles, which were then followed by surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting participants.

Findings: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12·9 months (IQR 6·2-22·9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response. The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths.

Interpretation: Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection.

Funding: Genentech and Celgene.
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http://dx.doi.org/10.1016/S1470-2045(20)30140-6DOI 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

Expanding Access to Lung Cancer Clinical Trials by Reducing the Use of Restrictive Exclusion Criteria: Perspectives of a Multistakeholder Working Group.

Clin Lung Cancer 2020 07 26;21(4):295-307. Epub 2020 Feb 26.

WSCollaborative, McLean, VA. Electronic address:

Low rates of adult patient participation have been a persistent problem in cancer clinical trials and have continued to be a barrier to efficient drug development. The routine use of significant exclusion criteria has contributed to this problem by limiting participation in studies and creating significant clinical differences between the study cohorts and the real-world cancer patient populations. These routine exclusions also unnecessarily restrict opportunities for many patients to access potentially promising new therapies during clinical development. Multiple efforts are underway to broaden eligibility criteria, allowing more patients to enroll in studies and generating more robust data regarding the effect of novel therapies in the population at large. Focusing specifically on lung cancer as an example, a multistakeholder working group empaneled by the LUNGevity Foundation identified 14 restrictive and potentially outdated exclusion criteria that appear frequently in lung cancer clinical trials. As a part of the project, the group evaluated data from multiple recent lung cancer studies to ascertain the extent to which these 14 criteria appeared in study protocols and played a role in excluding patients (screen failures). The present report describes the working group's efforts to limit the use of these routine exclusions and presents clinical justifications for reducing the use of 14 criteria as routine exclusions in lung cancer studies, potentially expanding trial eligibility and improving the generalizability of the results from lung cancer trials.
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http://dx.doi.org/10.1016/j.cllc.2020.02.008DOI Listing
July 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

A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors.

J Immunother Cancer 2020 03;8(1)

Sarah Cannon Research Institute, Nashville, Tennessee, USA.

Background: Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.

Methods: In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).

Results: Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.

Conclusions: Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.

Trial Registration Number: NCT02404441.
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http://dx.doi.org/10.1136/jitc-2020-000530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073791PMC
March 2020
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