Publications by authors named "Anna F Farago"

43 Publications

Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic Fusion-Positive Non-Small-Cell Lung Cancer.

J Clin Oncol 2021 Apr 1;39(11):1253-1263. Epub 2021 Mar 1.

Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France.

Purpose: Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 () are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in fusion-positive NSCLC.

Methods: The efficacy-evaluable population included adults with locally advanced or metastatic fusion-positive NSCLC with or without CNS metastases who received entrectinib ≥ 600 mg orally once per day. Co-primary end points were objective response rate (ORR) assessed by blinded independent central review and duration of response (DoR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety.

Results: In total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found.

Conclusion: Entrectinib continued to demonstrate a high level of clinical benefit for patients with fusion-positive NSCLC, including patients with CNS metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.03025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078299PMC
April 2021

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

Clin Cancer Res 2021 Mar 7;27(6):1695-1705. Epub 2021 Jan 7.

Division of Gastrointestinal Cancers, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Purpose: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion-associated colorectal cancer.

Experimental Design: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results.

Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in and wild-type tumors and were enriched in right-sided and mismatch repair-deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled V600E-mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an L1196Q gatekeeper mutation. The second patient, whose tumor contained an fusion, continues to benefit from entrectinib after 9 months of therapy.

Conclusions: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in and wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-4073DOI Listing
March 2021

The Art of Oncology: COVID-19 Era.

Oncologist 2020 11 10;25(11):997-1000g. Epub 2020 Sep 10.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2020-0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405267PMC
November 2020

Larotrectinib, a selective tropomyosin receptor kinase inhibitor for adult and pediatric tropomyosin receptor kinase fusion cancers.

Future Oncol 2020 Mar 4;16(9):417-425. Epub 2020 Mar 4.

Harvard Medical School, Boston, MA 02115, USA.

Gene fusions involving , and are oncogenic drivers across a wide variety of cancer types. Inhibitors of the chimeric TRKA/B/C protein kinases encoded by these fusions are now available, including larotrectinib, a potent and highly selective oral drug. Integrated data from three trials demonstrate substantial clinical activity of larotrectinib in patients with many different types of cancers harboring fusions. Larotrectinib has received accelerated approval from both the US FDA and the EMA. Resistance mutations have been observed in the kinase domains of the fusion genes and development of next-generation tropomyosin receptor kinase inhibitors designed to overcome such resistance mutations is being actively pursued in clinical trials and ongoing drug discovery efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2019-0647DOI Listing
March 2020

Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.

Lancet Oncol 2020 04 24;21(4):531-540. Epub 2020 Feb 24.

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address:

Background: The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.

Methods: Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).

Findings: Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.

Interpretation: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.

Funding: Bayer and Loxo Oncology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30856-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497841PMC
April 2020

New Approaches to SCLC Therapy: From the Laboratory to the Clinic.

J Thorac Oncol 2020 04 1;15(4):520-540. Epub 2020 Feb 1.

University of Virginia, Charlottesville, Virginia.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2020.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263769PMC
April 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.
View Article and Find Full Text PDF

Download full-text PDF

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

Identification of DHODH as a therapeutic target in small cell lung cancer.

Sci Transl Med 2019 11;11(517)

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with extremely poor prognosis. No targetable genetic driver events have been identified, and the treatment landscape for this disease has remained nearly unchanged for over 30 years. Here, we have taken a CRISPR-based screening approach to identify genetic vulnerabilities in SCLC that may serve as potential therapeutic targets. We used a single-guide RNA (sgRNA) library targeting ~5000 genes deemed to encode "druggable" proteins to perform loss-of-function genetic screens in a panel of cell lines derived from autochthonous genetically engineered mouse models (GEMMs) of SCLC, lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC). Cross-cancer analyses allowed us to identify SCLC-selective vulnerabilities. In particular, we observed enhanced sensitivity of SCLC cells toward disruption of the pyrimidine biosynthesis pathway. Pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in this pathway, reduced the viability of SCLC cells in vitro and strongly suppressed SCLC tumor growth in human patient-derived xenograft (PDX) models and in an autochthonous mouse model. These results indicate that DHODH inhibition may be an approach to treat SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aaw7852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401885PMC
November 2019

Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study.

Clin Cancer Res 2019 12 10;25(23):6958-6966. Epub 2019 Sep 10.

Ohio State University, Columbus, Ohio.

Purpose: Although extensive-stage small-cell lung cancer (SCLC) is highly responsive to first-line therapy, virtually all patients develop resistance with short survival. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting delta-like 3 protein (DLL3). This open-label, single-arm, phase II study (TRINITY) assessed safety and efficacy of Rova-T in patients with DLL3-expressing SCLC in the third-line and beyond (3L+) setting.

Patients And Methods: Patients with DLL3-expressing SCLC (determined by mouse antibody immunohistochemistry [IHC] assay), and ≥2 prior regimens, received 0.3 mg/kg Rova-T once every 6 weeks for two cycles. During study, a rabbit antibody IHC assay was developed and used for the final analysis, with DLL3-positive and DLL3-high defined as ≥25% and ≥75% of tumor cells positive for DLL3, respectively. The primary endpoints were objective response rate (ORR) and overall survival (OS).

Results: Among 339 patients enrolled, 261 (77%) had two prior lines of therapy and 78 (23%) had ≥3. DLL3-high and DLL3-positive tumors by rabbit IHC were seen in 238 (70%) and 287 (85%) patients, respectively. The remaining 52 (15%) were DLL3-negative only by rabbit IHC or had missing results. ORR was 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. The most common adverse events (AE) were fatigue, photosensitivity reaction, and pleural effusion. Grade 3-5 AEs were seen in 213 (63%) patients.

Conclusions: Rova-T is the first targeted agent in SCLC to use DLL3, a novel biomarker. However, results demonstrate modest clinical activity in 3L+ SCLC, with associated toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-1133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105795PMC
December 2019

Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer.

Cancer Discov 2019 10 15;9(10):1372-1387. Epub 2019 Aug 15.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of PARP have modest single-agent activity. We performed a phase I/II trial of combination olaparib tablets and temozolomide (OT) in patients with previously treated SCLC. We established a recommended phase II dose of olaparib 200 mg orally twice daily with temozolomide 75 mg/m daily, both on days 1 to 7 of a 21-day cycle, and expanded to a total of 50 patients. The confirmed overall response rate was 41.7% (20/48 evaluable); median progression-free survival was 4.2 months [95% confidence interval (CI), 2.8-5.7]; and median overall survival was 8.5 months (95% CI, 5.1-11.3). Patient-derived xenografts (PDX) from trial patients recapitulated clinical OT responses, enabling a 32-PDX coclinical trial. This revealed a correlation between low basal expression of inflammatory-response genes and cross-resistance to both OT and standard first-line chemotherapy (etoposide/platinum). These results demonstrate a promising new therapeutic strategy in SCLC and uncover a molecular signature of those tumors most likely to respond. SIGNIFICANCE: We demonstrate substantial clinical activity of combination olaparib/temozolomide in relapsed SCLC, revealing a promising new therapeutic strategy for this highly recalcitrant malignancy. Through an integrated coclinical trial in PDXs, we then identify a molecular signature predictive of response to OT, and describe the common molecular features of cross-resistant SCLC...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-19-0582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319046PMC
October 2019

Treatment with Next-Generation ALK Inhibitors Fuels Plasma Mutation Diversity.

Clin Cancer Res 2019 11 29;25(22):6662-6670. Epub 2019 Jul 29.

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

Purpose: Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary mutations. Here, we investigated utility of plasma genotyping for identifying resistance mutations at relapse on next-generation ALK TKIs.

Experimental Design: We analyzed 106 plasma specimens from 84 patients with advanced -positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify mutations.

Results: By genotyping plasma, we detected an mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 mutations (24% vs. 2%, = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an mutation in 22 (76%), including 14 (48%) with ≥2 mutations. The most frequent combinations of mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new mutations on lorlatinib.

Conclusions: resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of resistance mutations leading to treatment-refractory compound mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-1436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858956PMC
November 2019

Unexpected Synergy Reveals New Therapeutic Strategy in SCLC.

Trends Pharmacol Sci 2019 05 8;40(5):295-297. Epub 2019 Apr 8.

Massachusetts General Hospital Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address:

DNA damage repair (DDR) inhibition and immune checkpoint blockade (ICB) have each individually shown modest clinical activity in small cell lung cancer (SCLC). Recently, Sen and colleagues (Cancer Discov. 2019;https://doi.org/10.1158/2159-8290.CD-18-1020) demonstrated that DDR inhibition can activate the stimulator of interferon genes (STING) innate immune pathway, providing strong rationale for combining DDR inhibition and ICB to treat SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tips.2019.03.005DOI Listing
May 2019

Expediting Comprehensive Molecular Analysis to Optimize Initial Treatment of Lung Cancer Patients With Minimal Smoking History.

J Thorac Oncol 2019 05 18;14(5):835-843. Epub 2019 Jan 18.

Massachusetts General Hospital, Center for Integrated Diagnostics, Boston, Massachusetts.

Introduction: Lung cancer patients with tumors harboring actionable alterations can achieve very durable responses to first-line targeted therapy. However, identifying targetable alterations using next-generation sequencing (NGS) is a complex and time-intensive process. As actionable genetic alterations are enriched in lung cancers arising in patients with limited smoking history, we designed a workflow to expedite NGS testing for this group.

Methods: We developed a protocol to allow for next-day extraction of nucleic acids from frozen tissue. Specimens were designated as high priority during sequencing. We determined the interval between biopsy and NGS results to evaluate whether the workflow reduced the pre-analytical period and in-laboratory turnaround time and allowed for rapid initiation of genotype-matched therapy.

Results: Between January 2017 and May 2018, 21 patients participated in the expedited sequencing program. The median interval between biopsy and NGS results was 10.7 days. Six patients received results within 1 week of biopsy. Performing molecular analysis on frozen tissue and prioritizing sequencing and analysis of these specimens reduced the pre-analytical period from 3.5 to 1.3 days (p < 0.0001) and shortened in-laboratory turnaround time by 3 days (11.8 versus 8.4 business days, p < 0.0001). Ninety-three percent of patients with an actionable molecular alteration received first-line targeted therapy. The median time-to-initiation of treatment was 19.7 days from biopsy.

Conclusions: Sequencing and analyzing nucleic acids from frozen tissue is a practical strategy for shortening the time to matched therapy. The significant advantage of upfront treatment with targeted therapies in subsets of lung cancer patients provides rationale for developing workflows that accelerate comprehensive molecular analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2018.12.032DOI Listing
May 2019

EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes.

J Clin Oncol 2019 02 14;37(4):278-285. Epub 2018 Dec 14.

1 Massachusetts General Hospital, Boston, MA.

Purpose: Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.

Methods: We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.

Results: We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.

Conclusion: There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.01585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001776PMC
February 2019

Clinical Utility of Rapid Genotyping in Advanced Lung Cancer.

JCO Precis Oncol 2018 24;2018. Epub 2018 Jul 24.

Massachusetts General Hospital, Boston, MA.

Purpose: Targeted therapy is the cornerstone of treatment of advanced -mutant non-small-cell lung cancer (NSCLC). Next-generation sequencing (NGS), the preferred method for genotyping, typically requires several weeks. Here, we assessed workflows designed to rapidly identify patients with actionable mutations and reduce time to initiation (TTI) of epidermal growth factor receptor (EGFR)-directed therapy.

Patients And Methods: We performed rapid testing for L858R mutations and exon 19 deletions on paraffin-embedded or frozen section biopsy specimens from newly diagnosed patients with metastatic NSCLC by using an -specific assay (rapid test). To determine clinical utility, we assessed concordance with NGS results, turnaround time, and TTI of EGFR therapy, and we evaluated reimbursement data.

Results: Between January 2015 and September 2017, we performed 243 rapid tests and identified mutations in 43 patients (18%). With NGS results as a reference, sensitivity and specificity of the rapid polymerase chain reaction assay were 98% and 100%, respectively. The median turnaround time for NGS was 14 days, compared with 7 days for rapid testing ( < .001). In the rapid group, 95% of patients received an EGFR inhibitor in the first-line setting. The median TTI of EGFR therapy was significantly shorter in the rapid cohort when compared with 121 historical cases (22 37 days; = .01). Escalation of the initiative into an interdisciplinary ultra-rapid next-day frozen-section workflow for highly symptomatic patients (n = 8) resulted in a reduction in the median (± standard deviation) turnaround time to 1 ± 0.4 days and allowed several patients to initiate therapy within 1 week of biopsy. An extended 9-month clinical evaluation phase confirmed operational sustainability (turnaround times: ultra-rapid, 0.81 ± 0.4 days; rapid, 3 ± 1.5 days), and a 63% reimbursement rate indicated financial sustainability.

Conclusion: Rapid genotyping facilitates earlier initiation of EGFR-directed therapies without compromising NGS workflows.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200882PMC
http://dx.doi.org/10.1200/PO.17.00299DOI Listing
July 2018

ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line.

Future Oncol 2019 Jan 26;15(3):231-239. Epub 2018 Oct 26.

Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.

Lurbinectedin is an inhibitor of active transcription of protein-coding genes, causing DNA-break accumulation, apoptosis and modulation of the tumor microenvironment. Early-phase clinical trials indicate promising activity of lurbinectedin in small-cell lung cancer. Here, we describe the rationale and design of ATLANTIS (NCT02566993), an open-label, randomized, multicenter Phase III study to compare the efficacy of lurbinectedin and doxorubicin combination with standard-of-care chemotherapy, investigator's choice of cyclophosphamide/doxorubicin/vincristine or topotecan, in patients with small-cell lung cancer that has progressed following one line of platinum-based chemotherapy. Patients are randomized in a 1:1 ratio. The primary end point is overall survival and key secondary end points include progression-free survival, best tumor response and duration of response, each assessed by independent review committee.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2018-0597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331752PMC
January 2019

Third-Line Nivolumab Monotherapy in Recurrent SCLC: CheckMate 032.

J Thorac Oncol 2019 02 10;14(2):237-244. Epub 2018 Oct 10.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Introduction: For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC.

Methods: In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety.

Results: Between December 4, 2013, and November 30, 2016, 109 patients began receiving third- or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5-19.5) with a median duration of response of 17.9 months (range 3.0-42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events.

Conclusions: Nivolumab monotherapy provided durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third- or later-line treatment for this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050700PMC
February 2019

Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in -Mutant Non-Small Cell Lung Cancer.

Cancer Discov 2018 12 25;8(12):1598-1613. Epub 2018 Sep 25.

Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.

BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in -mutant non-small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone. Susceptibility to BH3 mimetics that target either MCL1 or BCL-xL was determined by the differential binding of proapoptotic BCL2 proteins to MCL1 or BCL-xL, respectively. The efficacy of dual MEK + MCL1 blockade was augmented by prior transient exposure to BCL-xL inhibitors, which promotes the binding of proapoptotic BCL2 proteins to MCL1. This suggests a novel strategy for integrating BH3 mimetics that target different BCL2 family proteins for -mutant NSCLC. SIGNIFICANCE: Defining the molecular basis for MCL1 versus BCL-xL dependency will be essential for effective prioritization of BH3 mimetic combination therapies in the clinic. We discover a novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and subsequently exploit apoptotic dependencies of -mutant NSCLCs treated with MEK inhibitors...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-0277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279543PMC
December 2018

Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an Gene Fusion.

JCO Precis Oncol 2018 23;2018. Epub 2018 Jul 23.

Memorial Sloan Kettering Cancer Center, New York NY.

Purpose: Gene rearrangements involving can generate fusion oncoproteins containing the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small cell lung cancer (NSCLC), with frequency previously estimated to be <1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of fusion-positive NSCLCs are not well characterized.

Methods: We compiled a database of NSCLC cases harboring fusions. We characterized the clinical, molecular, and histologic features of these cases with central review of histology.

Results: We identified 11 NSCLC cases harboring gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data, forming the study cohort. Fusions involved (7 cases) and (4 cases), with 5 and 2 distinct fusion partners, respectively. Cohort patients were 55% male, with a median age at diagnosis of 47.6 years (range 25.3-86.0) and a median pack year history of 0 (range 0-58). 73% of patients had metastatic disease at diagnosis. No concurrent alterations in , , , , or other known oncogenic drivers were identified. Nine cases were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features; one was squamous cell carcinoma; and one was neuroendocrine carcinoma. By collating data on 4872 consecutively screened NSCLC cases from unique patients, we estimate a frequency of fusions in NSCLC of 0.23% (95% CI 0.11-0.40).

Conclusion: fusions occur in NSCLCs across genders, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for fusions using a multiplexed NGS-based fusion assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132056PMC
http://dx.doi.org/10.1200/PO.18.00037DOI Listing
July 2018

Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC.

J Thorac Oncol 2018 10 20;13(10):1530-1538. Epub 2018 Jun 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced ALK-rearranged NSCLC, establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has shown substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown.

Methods: A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib-refractory ALK-positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes.

Results: Twenty-two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression-free survival was 4.4 months (95% confidence interval [CI]: 1.8-5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8-6.2 months). Among 9 patients in this study who underwent post-alectinib/pre-brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best overall response to brigatinib.

Conclusions: Brigatinib has limited clinical activity in alectinib-refractory ALK-positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib-resistant ALK-positive NSCLC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341982PMC
October 2018

Current standards for clinical management of small cell lung cancer.

Transl Lung Cancer Res 2018 Feb;7(1):69-79

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.

Small cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine carcinoma. Despite over 30 years of clinical research, little progress has been made in the management of SCLC, and outcomes remain poor. Here, we review the current clinical standards for management of SCLC and the data supporting these strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr.2018.01.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835595PMC
February 2018

Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts.

Cancer Discov 2018 05 26;8(5):600-615. Epub 2018 Feb 26.

Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.

Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy. Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-17-0935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369413PMC
May 2018

Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.

N Engl J Med 2018 02;378(8):731-739

From Memorial Sloan Kettering Cancer Center (A. Drilon, J.F.H., R.B., M.L., D.M.H.) and Weill Cornell Medical College (A. Drilon, D.M.H.), New York; University of Texas Southwestern Medical Center-Children's Health, Dallas (T.W.L.); Stanford Cancer Center, Stanford University, Palo Alto (S.K.), Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California (L.M.), and UCLA David Geffen School of Medicine (N.F.), Los Angeles, and Loxo Oncology, South San Francisco (B.B.T., K.E., S.C., N.C.K., M.C.C.) - all in California; Dana-Farber-Boston Children's Cancer and Blood Disorders Center (S.G.D.), Dana-Farber Cancer Institute (G.D.D., M.N.), Ludwig Center at Harvard (G.D.D.), and Massachusetts General Hospital (A.F.F.) - all in Boston; the Finsen Center, Rigshospitalet, Copenhagen (U.N.L.); University of Colorado, Aurora (R.C.D.); St. Jude Children's Research Hospital, Memphis (A.S.P.), and Vanderbilt University, Nashville (J.B.) - both in Tennessee; Cincinnati Children's Hospital Medical Center, Cincinnati (B.T.); University Hospitals of Cleveland Medical Center (A. Dowlati) and Taussig Cancer Institute, Cleveland Clinic (D.P.S.S.), Cleveland; University of Pennsylvania Perelman School of Medicine, Department of Otorhinolaryngology and Head and Neck Surgery, and the Abramson Cancer Center (M.S.B.), and Fox Chase Cancer Center (W.S.E.-D.), Philadelphia; University of Washington-Seattle Cancer Care Alliance (C.B.), Seattle Children's Hospital (E.R.R.), and Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center (D.S. Hawkins), Seattle; University of Texas M.D. Anderson Cancer Center, Houston (F.M.-B., D.S. Hong); Inova Schar Cancer Institute, Falls Church, VA (J.D.); START Madrid, Centro Integral Oncológico Clara Campal, Madrid (V.B.); Nemours Children's Hospital, Orlando (R.N.), and Memorial Cancer Institute-Florida International University, Miami (L.E.R.) - both in Florida; Oregon Health and Science University, Portland (M.T.); and WVU Cancer Institute, West Virginia University, Morgantown (P.C.M.).

Background: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.

Methods: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.

Results: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.

Conclusions: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1714448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857389PMC
February 2018

Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

JCO Precis Oncol 2018 23;2018. Epub 2018 Jan 23.

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

Purpose: rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer.

Methods: Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies.

Results: At progression, we detected an fusion in plasma from 19 (86%) of 22 patients, and identified resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between mutation calls. mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib.

Conclusions: Plasma genotyping by NGS is an effective method for detecting fusions and mutations in patients progressing on ALK TKIs. The correlation between plasma mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785105PMC
http://dx.doi.org/10.1200/PO.17.00160DOI Listing
January 2018

Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in -Positive Non-Small-Cell Lung Cancer.

JCO Precis Oncol 2017 16;2017. Epub 2017 Aug 16.

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

Purpose: The ROS1 tyrosine kinase is activated through gene rearrangements in 1-2% of non-small cell lung cancer (NSCLC), conferring sensitivity to treatment with the ALK/ROS1/MET inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among -positive patients are limited.

Patients And Methods: We reviewed clinical and radiographic imaging data of patients with - and -positive NSCLC in order to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we also analyzed repeat biopsies from a cohort of -positive patients progressing on crizotinib.

Results: We identified 39 and 196 patients with advanced and positive NSCLC, respectively. -positive patients had significantly lower rates of extrathoracic metastases ( 59.0%, 83.2%, =0.002), including lower rates of brain metastases ( 19.4%, 39.1%; = 0.033), at initial metastatic diagnosis. Despite similar overall survival between and positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; =0.786), positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; <0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. mutations included: G2032R (41%), D2033N (6%), and S1986F (6%).

Conclusions: Compared to rearrangements, rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, underscoring the need to develop novel ROS1 inhibitors with activity against these resistant mutants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766287PMC
http://dx.doi.org/10.1200/PO.17.00063DOI Listing
August 2017

Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care.

Cell Rep 2017 Dec;21(11):3298-3309

Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA. Electronic address:

Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745232PMC
December 2017

Beyond and and gene rearrangements in non-small cell lung cancer.

Transl Lung Cancer Res 2017 Oct;6(5):550-559

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

The discovery of gene rearrangements involving the receptor tyrosine kinase genes and has revolutionized management of the subset of non-small cell lung cancers characterized by these alterations. The oncogenic fusion proteins expressed in these tumors drive cancer cell growth and survival, and targeted inhibition of this signaling can lead to dramatic and durable responses in patients. While the best characterized gene fusions in non-small cell lung cancer (NSCLC) involve and , fusions involving other kinases including , , and are now established as additional targetable drivers. Here we review data supporting the roles of these fusions as oncogenic drivers, and the potential for targeting these fusions for improved clinical outcomes. These discoveries should encourage multiplexed molecular profiling of lung cancers using next-generation platforms which identify these gene fusions in order to expand treatment options for patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr.2017.08.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653525PMC
October 2017

Unlocking the Mystery of Small-Cell Lung Cancer Transformations in EGFR Mutant Adenocarcinoma.

J Clin Oncol 2017 09 10;35(26):2987-2988. Epub 2017 Jul 10.

Anna F. Farago, Zofia Piotrowska, and Lecia V. Sequist, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2017.73.5696DOI Listing
September 2017

Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor.

NPJ Precis Oncol 2017 20;1(1). Epub 2017 Mar 20.

2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.

Glioneuronal tumors constitute a histologically diverse group of primary central nervous system neoplasms that are typically slow-growing and managed conservatively. Genetic alterations associated with glioneuronal tumors include mutations and oncogenic fusions. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in (34%) and oncogenic fusions (30%), consistent with previously published reports. In addition, we discovered novel oncogenic fusions involving members of the gene family in a subset of our cohort. One-patient with exon 13 fused to exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient's targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1, and (anaplastic lymphoma kinase) inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41698-017-0009-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871889PMC
March 2017

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).

Cancer Discov 2017 04 9;7(4):400-409. Epub 2017 Feb 9.

Ignyta, Inc., San Diego, California.

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring , or gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with -rearranged lung cancer. Gene fusions of , and (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-16-1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380583PMC
April 2017