Publications by authors named "Pasi A Janne"

348 Publications

Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites.

J Med Chem 2021 Oct 20. Epub 2021 Oct 20.

Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.

Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00848DOI Listing
October 2021

Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial.

JAMA Oncol 2021 Oct 14:e214761. Epub 2021 Oct 14.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Metastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations.

Objective: To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC.

Design, Setting, And Participants: This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort).

Interventions: Mobocertinib 160 mg once daily.

Main Outcomes And Measures: The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety.

Results: Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash.

Conclusions And Relevance: In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.

Trial Registration: ClinicalTrials.gov Identifier: NCT02716116.
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http://dx.doi.org/10.1001/jamaoncol.2021.4761DOI Listing
October 2021

A structural model of a Ras-Raf signalosome.

Nat Struct Mol Biol 2021 Oct 8;28(10):847-857. Epub 2021 Oct 8.

D. E. Shaw Research, New York, NY, USA.

The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the human mitogen-activated protein kinase (MAPK) pathway, which is implicated in many cancers, multiple K-Ras proteins are thought to assemble at the cell membrane with Ras effector proteins from the Raf family. Here we propose an atomistic structural model for such an assembly. Our starting point was an asymmetric guanosine triphosphate-mediated K-Ras dimer model, which we generated using unbiased molecular dynamics simulations and verified with mutagenesis experiments. Adding further K-Ras monomers in a head-to-tail fashion led to a compact helical assembly, a model we validated using electron microscopy and cell-based experiments. This assembly stabilizes K-Ras in its active state and presents composite interfaces to facilitate Raf binding. Guided by existing experimental data, we then positioned C-Raf, the downstream kinase MEK1 and accessory proteins (Galectin-3 and 14-3-3σ) on and around the helical assembly. The resulting Ras-Raf signalosome model offers an explanation for a large body of data on MAPK signaling.
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http://dx.doi.org/10.1038/s41594-021-00667-6DOI Listing
October 2021

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

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

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

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

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

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

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

EGFR inhibition enhances the cellular uptake and antitumor-activity of the HER3 antibody drug conjugate HER3-DXd.

Cancer Res 2021 Sep 21. Epub 2021 Sep 21.

Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in EGFR-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pre-treatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2426DOI Listing
September 2021

Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer.

Cancer Discov 2021 Sep 21. Epub 2021 Sep 21.

Medicine, Memorial Sloan Kettering Cancer Center.

HER3 is expressed in the majority of EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase 1, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated NSCLC with prior EGFR TKI therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg IV Q3W, the confirmed ORR by BICR (RECIST v1.1) was 39% (95% CI, 26.0-52.4), and median PFS was 8.2 (4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade {greater than or equal to}3 TEAE were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treating a broad range of drug-resistant cancers.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0715DOI Listing
September 2021

Trastuzumab Deruxtecan in -Mutant Non-Small-Cell Lung Cancer.

N Engl J Med 2021 Sep 18. Epub 2021 Sep 18.

From Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (B.T.L.); the Netherlands Cancer Institute, Amsterdam (E.F.S); the National Cancer Center Hospital, Tokyo (Y.G.), Kindai University Hospital, Osaka (K.N.), and the National Cancer Center East, Kashiwa (H.U.) - all in Japan; Centre Hospitalier Universitaire, Toulouse (J.M.), Centre Léon Bérard, Lyon (M.P.), and the Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif (D.P.) - all in France; Karmanos Cancer Institute, Detroit (M.N.); the University of California, San Diego, Moores Cancer Center, San Diego (L.B.); Moffitt Cancer Center, Tampa, FL (A.N.S.); Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (E.F.); University of Colorado, Aurora (J.M.P.); Hospital Universitario 12 de Octubre, H12O-Centro Nacional de Investigaciones Oncológicas (CNIO) Lung Cancer Clinical Research Unit, and Complutense University, Madrid (L.P.-A.); Daiichi Sankyo, Basking Ridge, NJ (K.S., R.S., Y.C., S.A., P.V., J.S.); and Dana-Farber Cancer Institute and the Belfer Center for Applied Cancer Science, Boston (P.A.J.).

Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with -mutant NSCLC have not been investigated extensively.

Methods: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic -mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.

Results: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different mutation subtypes, as well as in patients with no detectable HER2 expression or amplification.

Conclusions: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated -mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).
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http://dx.doi.org/10.1056/NEJMoa2112431DOI Listing
September 2021

Prediction Model for Tumor Volume Nadir in EGFR-mutant NSCLC Patients Treated With EGFR Tyrosine Kinase Inhibitors.

J Thorac Imaging 2021 Sep 15. Epub 2021 Sep 15.

Departments of Imaging Medical Oncology, Dana Farber Cancer Institute Departments of Radiology Medicine, Brigham and Women's Hospital Department of Biostatistics, Harvard Chan School of Public Health, Boston, MA.

Purpose: In patients with advanced non-small cell lung cancer (NSCLC) and oncogenic driver mutations treated with effective targeted therapy, a characteristic pattern of tumor volume dynamics with an initial regression, nadir, and subsequent regrowth is observed on serial computed tomography (CT) scans. We developed and validated a linear model to predict the tumor volume nadir in EGFR-mutant advanced NSCLC patients treated with EGFR tyrosine kinase inhibitors (TKI).

Materials And Methods: Patients with EGFR-mutant advanced NSCLC treated with EGFR-TKI as their first EGFR-directed therapy were studied for CT tumor volume kinetics during therapy, using a previously validated CT tumor measurement technique. A linear regression model was built to predict tumor volume nadir in a training cohort of 34 patients, and then was validated in an independent cohort of 84 patients.

Results: The linear model for tumor nadir prediction was obtained in the training cohort of 34 patients, which utilizes the baseline tumor volume before initiating therapy (V0) to predict the volume decrease (mm3) when the nadir volume (Vp) was reached: V0-Vp=0.717×V0-1347 (P=2×10-16; R2=0.916). The model was tested in the validation cohort, resulting in the R2 value of 0.953, indicating that the prediction model generalizes well to another cohort of EGFR-mutant patients treated with EGFR-TKI. Clinical variables were not significant predictors of tumor volume nadir.

Conclusion: The linear model was built to predict the tumor volume nadir in EGFR-mutant advanced NSCLC patients treated with EGFR-TKIs, which provide an important metrics in treatment monitoring and therapeutic decisions at nadir such as additional local abrasive therapy.
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http://dx.doi.org/10.1097/RTI.0000000000000615DOI Listing
September 2021

Amivantamab: Treating Exon 20-Mutant Cancers With Bispecific Antibody-Mediated Receptor Degradation.

J Clin Oncol 2021 Oct 2;39(30):3403-3406. Epub 2021 Aug 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1200/JCO.21.01494DOI Listing
October 2021

Plasma ctDNA Response Is an Early Marker of Treatment Effect in Advanced NSCLC.

JCO Precis Oncol 2021 17;5. Epub 2021 Feb 17.

Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA.

Plasma circulating tumor DNA (ctDNA) analysis is routine for genotyping of advanced non-small-cell lung cancer (NSCLC); however, early response assessment using plasma ctDNA has yet to be well characterized.

Materials And Methods: Patients with advanced -mutant NSCLC across three phase I NCI osimertinib combination trials were analyzed in this study, and an institutional cohort of patients with , , and -mutant advanced NSCLC receiving systemic treatment was used for validation. Plasma was collected before treatment initiation and serially before each cycle of therapy, and key driver mutations in ctDNA were characterized by droplet digital polymerase chain reaction. Timing of plasma versus imaging response was compared in a separate cohort of patients with -mutant NSCLC treated with osimertinib. Across cohorts, we also studied ctDNA variability before treatment start.

Results: In the NCI cohort, 14/16 (87.5%) patients exhibited ≥ 90% decrease in mutation abundance by the first on-treatment timepoint (20-28 days from treatment start) with minimal subsequent change. Similarly, 47/56 (83.9%) patients with any decrease in the institutional cohort demonstrated ≥ 90% decrease in mutation abundance by the first follow-up draw (7-30 days from treatment start). All 16 patients in the imaging cohort with radiographic partial response showed best plasma response within one cycle, preceding best radiographic response by a median of 24 weeks (range: 3-147 weeks). Variability in ctDNA levels before treatment start was observed.

Conclusion: Plasma ctDNA response is an early phenomenon, with the majority of change detectable within the first cycle of therapy. These kinetics may offer an opportunity for early insight into treatment effect before standard imaging timepoints.
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http://dx.doi.org/10.1200/PO.20.00419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232122PMC
February 2021

Acquired Resistance to KRAS Inhibition in Cancer.

N Engl J Med 2021 06;384(25):2382-2393

From Dana-Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women's Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge - all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) - all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).

Background: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS). The mechanisms of acquired resistance to these therapies are currently unknown.

Methods: Among patients with -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS inhibitors.

Results: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the allele. Acquired bypass mechanisms of resistance included amplification; activating mutations in , , , and ; oncogenic fusions involving , , , , and ; and loss-of-function mutations in and . In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of mutations that confer resistance to KRAS inhibitors.

Conclusions: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).
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http://dx.doi.org/10.1056/NEJMoa2105281DOI Listing
June 2021

Kinase drug discovery 20 years after imatinib: progress and future directions.

Nat Rev Drug Discov 2021 07 17;20(7):551-569. Epub 2021 May 17.

Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Harvard University, Boston, MA, USA.

Protein kinases regulate nearly all aspects of cell life, and alterations in their expression, or mutations in their genes, cause cancer and other diseases. Here, we review the remarkable progress made over the past 20 years in improving the potency and specificity of small-molecule inhibitors of protein and lipid kinases, resulting in the approval of more than 70 new drugs since imatinib was approved in 2001. These compounds have had a significant impact on the way in which we now treat cancers and non-cancerous conditions. We discuss how the challenge of drug resistance to kinase inhibitors is being met and the future of kinase drug discovery.
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http://dx.doi.org/10.1038/s41573-021-00195-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127496PMC
July 2021

Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.

Cancer Discov 2021 Oct 29;11(10):2488-2505. Epub 2021 Apr 29.

Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with p.H167_N173del. Expression of this EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These EIDs are sensitive to FGFR inhibition , and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1669DOI Listing
October 2021

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for -Mutant Lung Cancer.

Int J Mol Sci 2021 Mar 16;22(6). Epub 2021 Mar 16.

Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA 02215, USA.

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma () mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that is "undruggable", (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by downstream effector functions. Better insights into structural biochemistry allowed researchers to develop direct (G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct inhibition and project future opportunities and challenges of dual and immune checkpoint inhibition. This strategy is supported by preclinical models which show that (G12C) inhibitors can turn some immunologically "cold" tumors into "hot" ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of as a transforming oncogene, we are on the verge of approval of the first -targeted drug combinations, thus therapeutically unifying Paul Ehrlich's century-old "magic bullet" vision with Rudolf Virchow's cancer inflammation theory.
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http://dx.doi.org/10.3390/ijms22063025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002337PMC
March 2021

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond.

Expert Opin Biol Ther 2021 Jul 1;21(7):811-824. Epub 2021 Apr 1.

International Breast Cancer Center, Quiron Group, Barcelona, Spain.

Introduction: Despite the substantial improvements made in human epidermal growth factor receptor 2 (HER2)-targeted therapies since the approval of trastuzumab more than 20 years ago, there is still considerable unmet need in patients with HER2-expressing breast cancer (BC) and other solid tumors. Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate approved for the treatment of metastatic breast cancer (BC) and gastric cancer (GC) and is under active investigation in other solid tumors, including non-small cell lung cancer, colorectal cancer, and HER2-low tumors.

Areas Covered: The current treatment and investigational landscape of HER2-positive and HER2-low metastatic BC (mBC) and the preclinical and clinical trials investigating T-DXd. To identify relevant literature, a search was performed on English-language publications and congress abstracts.

Expert Opinion: T-DXd is likely to become the standard of care for second-line treatment of HER2-positive mBC, and it may play a role in the treatment of hormone receptor-positive and triple-negative mBC with HER2-low expression. Because it was recently approved in the United States and Japan to treat HER2-positive metastatic GC, it holds promise for the treatment of other HER2-positive solid tumors, including colorectal cancer, non-small cell lung cancer, and HER2-low BC.
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http://dx.doi.org/10.1080/14712598.2021.1890710DOI Listing
July 2021

Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity.

Cancer Discov 2021 Aug 11;11(8):1952-1969. Epub 2021 Mar 11.

Translational Pathology, Bristol Myers Squibb, Trenton, New Jersey.

Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC I subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338750PMC
August 2021

Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with Exon 20 Insertion Mutations from a Phase I/II Trial.

Cancer Discov 2021 Jul 25;11(7):1688-1699. Epub 2021 Feb 25.

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

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting gene mutations, including exon 20 insertions (ex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 ex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse ex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with ex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced ex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295177PMC
July 2021

Thirty Years of HER3: From Basic Biology to Therapeutic Interventions.

Clin Cancer Res 2021 Jul 19;27(13):3528-3539. Epub 2021 Feb 19.

Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

HER3 is a pseudokinase member of the EGFR family having a role in both tumor progression and drug resistance. Although HER3 was discovered more than 30 years ago, no therapeutic interventions have reached clinical approval to date. Because the evidence of the importance of HER3 is accumulating, increased amounts of preclinical and clinical trials with HER3-targeting agents are emerging. In this review article, we discuss the most recent HER3 biology in tumorigenic events and drug resistance and provide an overview of the current and emerging strategies to target HER3.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254743PMC
July 2021

ERK Inhibitor LY3214996-Based Treatment Strategies for -Driven Lung Cancer.

Mol Cancer Ther 2021 04 3;20(4):641-654. Epub 2021 Feb 3.

Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with -mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of -mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and-equally important-to identify biomarkers for patient stratification.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026682PMC
April 2021

Phase IB Study of Osimertinib in Combination with Navitoclax in -mutant NSCLC Following Resistance to Initial Therapy (ETCTN 9903).

Clin Cancer Res 2021 03 29;27(6):1604-1611. Epub 2020 Dec 29.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Osimertinib is an effective therapy in -mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of -mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance.

Patients And Methods: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced -mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily.

Results: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia.

Conclusions: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976451PMC
March 2021

Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy.

Clin Cancer Res 2021 02 17;27(4):1019-1028. Epub 2020 Nov 17.

Syndax Pharmaceuticals, Inc., Waltham, Massachusetts.

Purpose: New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1) blockade to overcome resistance. We report outcomes in patients with anti-programmed cell death ligand-1 [PD-(L)1]-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601.

Patients And Methods: The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase II expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described.

Results: Of 76 treated patients, 71 were evaluable for efficacy. immune-regulated RECIST-assessed ORR was 9.2% [95% confidence interval (CI): 3.8-18.1], which did not meet the prespecified threshold for positivity. Median duration of response was 10.1 months (95% CI: 3.9-not estimable), progression-free survival (PFS) at 6 months was 22%, median PFS was 2.8 months (95% CI: 1.5-4.1), and median overall survival was 11.7 months (95% CI: 7.6-13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and gene expression were not associated with benefit. Treatment-related grade ≥3 adverse events occurred in 41% of patients.

Conclusions: In anti-PD-(L)1-experienced patients with NSCLC, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit, with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887114PMC
February 2021

Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion-Positive Lung Cancer by Combining Selpercatinib with Crizotinib.

Clin Cancer Res 2021 01 20;27(1):34-42. Epub 2020 Oct 20.

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

Purpose: The proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.

Patients And Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have amplification associated with resistance to selpercatinib. We validated activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP).

Results: amplification was identified in posttreatment biopsies in 4 patients with fusion-positive NSCLC treated with selpercatinib. In at least one case, amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.

Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting -amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009613PMC
January 2021

Plasma IL-6 changes correlate to PD-1 inhibitor responses in NSCLC.

J Immunother Cancer 2020 10;8(2)

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Background: Blood-based biomarkers of anti-solid tumor immune checkpoint blockade (ICB) response are lacking. We hypothesized that changes in systemic cytokine levels with the initial doses of programmed cell death protein 1 (PD-1) pathway inhibitors would correlate with clinical responses. New ultrasensitive ELISA technology enables quantitation of plasma proteins in sub-picogram-per-milliliter concentrations.

Methods: We measured plasma cytokines by ultrasensitive single-molecule array assays in patients with non-small-cell lung carcinoma before and during treatment with anti-PD-1 therapy. Association with best overall response and progression-free survival (PFS) was assessed by Kruskall-Wallis test and Kaplan-Meier plots with log-rank test, respectively.

Results: A decrease in interleukin 6 (IL-6) levels was associated with improved PFS (n=47 patients, median PFS: 11 vs 4 months, HR 0.45 (95% CI 0.23 to 0.89), p=0.04). The extent of change in IL-6 differed between best overall response categories (p=0.01) and correlated with changes in C reactive protein levels. We also explored plasma cytokine levels in relation to immune-related adverse effects and observed some correlation.

Conclusions: This study suggests the presence of a systemic, proteomic reflection of successful ICB outside the tumor microenvironment with plasma decreases in IL-6 and CRP.
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http://dx.doi.org/10.1136/jitc-2020-000678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537334PMC
October 2020

Turnaround Time of Plasma Next-Generation Sequencing in Thoracic Oncology Patients: A Quality Improvement Analysis.

JCO Precis Oncol 2020 21;4. Epub 2020 Sep 21.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.

Purpose: Genomic analysis of plasma cell-free DNA has become a widespread tool for advanced non-small-cell lung cancer care. Whereas accuracy has been reported on widely, its usefulness is also tied tightly to its turnaround time (TAT), which is not well studied.

Methods: We studied the TAT of commercial plasma next-generation sequencing (NGS; Guardant360) for 533 results from 461 patients at our center between August 2016 and October 2019. The study received institutional review board approval as a quality improvement study; therefore, the results of the test and clinical setting were not analyzed.

Results: TAT from blood draw to result (median of 9 days) was slightly longer than the TAT from laboratory receipt to result, a median of 7 days. Testing volume at our center increased three-fold over the time of the study. During this period, clinical TAT decreased from an initial median of 12 days to a median of 8 days in 2018, but more recently the median increased slightly to 9 days. During the most recent 12 months, 231 (95%) of 247 cases resulted within 14 days from blood draw, with delayed results usually because of billing, whereas 44 cases (18%) resulted within 7 days of blood draw. Studying 92 cases drawn in the most recent 3-month period, the median time of result receipt was 4:01 pm Eastern Time/1:01 pm Pacific Time; 39 results (43%) were returned after 5:00 pm Eastern Time.

Conclusion: In a large single-institution experience, we find that plasma NGS results can routinely be expected within 2 weeks, but uncommonly result within 1 week, supporting the need for new strategies to incorporate plasma NGS into the initial genotyping of advanced non-small-cell lung cancer.
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http://dx.doi.org/10.1200/PO.20.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529535PMC
September 2020

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.
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http://dx.doi.org/10.1172/jci.insight.137869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455065PMC
August 2020

KRAS Preferentially Signals through MAPK in a RAF Dimer-Dependent Manner in Non-Small Cell Lung Cancer.

Cancer Res 2020 09 30;80(17):3719-3731. Epub 2020 Jun 30.

Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

Assembly of RAS molecules into complexes at the cell membrane is critical for RAS signaling. We previously showed that oncogenic KRAS codon 61 mutations increase its affinity for RAF, raising the possibility that KRAS, the most common KRAS mutation at codon 61, upregulates RAS signaling through mechanisms at the level of RAS assemblies. We show here that KRAS exhibits preferential binding to RAF relative to PI3K in cells, leading to enhanced MAPK signaling in models and human NSCLC tumors. X-ray crystallography of KRAS:GTP revealed that a hyperdynamic switch 2 allows for a more stable interaction with switch 1, suggesting that enhanced RAF activity arises from a combination of absent intrinsic GTP hydrolysis activity and increased affinity for RAF. Disruption of KRAS assemblies by the RAS oligomer-disrupting D154Q mutation impaired RAF dimerization and altered MAPK signaling but had little effect on PI3K signaling. However, KRAS oligomers but not KRAS oligomers were disrupted by RAF mutations that disrupt RAF-RAF interactions. KRAS cells show enhanced sensitivity to RAF and MEK inhibitors individually, whereas combined treatment elicited synergistic growth inhibition. Furthermore, KRAS tumors in mice exhibited high vulnerability to MEK inhibitor, consistent with cooperativity between KRAS and RAF oligomerization and dependence on MAPK signaling. These findings support the notion that KRAS and functionally similar mutations may serve as predictive biomarkers for targeted therapies against the MAPK pathway. SIGNIFICANCE: These findings show that oncogenic KRAS forms a cooperative RAS-RAF ternary complex, which renders RAS-driven tumors vulnerable to MEKi and RAFi, thus establishing a framework for evaluating RAS biomarker-driven targeted therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0448DOI Listing
September 2020

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

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

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

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

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

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

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

Targeting Dysregulation in Cancer.

Cancer Discov 2020 07 12;10(7):922-934. Epub 2020 Jun 12.

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

Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including gene amplification, mutation, rearrangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specific, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent malignancies, and highlight emerging challenges in acquired drug resistance in these cancers. SIGNIFICANCE: Increasing evidence supports the use of MET-targeting therapies in biomarker-selected cancers that harbor molecular alterations in MET. Diverse mechanisms of resistance to MET inhibitors will require the development of novel strategies to delay and overcome drug resistance.
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http://dx.doi.org/10.1158/2159-8290.CD-19-1446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781009PMC
July 2020
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