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PURPOSEThe impact of the intratumoral microbiome on immune checkpoint inhibitor (ICI) efficacy in patients with non-small-cell lung cancer (NSCLC) is unknown. Preclinically, intratumoral Escherichia is associated with a proinflammatory tumor microenvironment and decreased metastases. We sought to determine whether intratumoral Escherichia is associated with outcome to ICI in patients with NSCLC.PATIENTS AND METHODSWe examined the intratumoral microbiome in 958 patients with advanced NSCLC treated with ICI by querying unmapped next-generation sequencing reads against a bacterial genome database. Putative environmental contaminants were filtered using no-template controls (n = 2,378). The impact of intratumoral Escherichia detection on overall survival (OS) was assessed using univariable and multivariable analyses. The findings were further validated in an external independent cohort of 772 patients. Escherichia fluorescence in situ hybridization (FISH) and transcriptomic profiling were performed.RESULTSIn the discovery cohort, read mapping to intratumoral Escherichia was associated with significantly longer OS (16 v 11 months; hazard ratio, 0.73 [95% CI, 0.59 to 0.92]; P = .0065) in patients treated with single-agent ICI, but not combination chemoimmunotherapy. The association with OS in the single-agent ICI cohort remained statistically significant in multivariable analysis adjusting for prognostic features including PD-L1 expression ( P = .023). Analysis of an external validation cohort confirmed the association with improved OS in univariable and multivariable analyses of patients treated with single-agent ICI, and not in patients treated with chemoimmunotherapy. Escherichia localization within tumor cells was supported by coregistration of FISH staining and serial hematoxylin and eosin sections. Transcriptomic analysis correlated Escherichia-positive samples with expression signatures of immune cell infiltration.CONCLUSIONRead mapping to potential intratumoral Escherichia was associated with survival to single-agent ICI in two independent cohorts of patients with NSCLC.

Purpose: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with EGFR mutations., Methods: Eligible patients had EGFR mutations (T790M or rare activating) and received osimertinib 80 mg once daily. Patients with lung cancer with EGFR T790M were excluded. The primary end point was objective response rate (ORR), and the secondary end points were 6-month progression-free survival (PFS), overall survival, and toxicity., Results: A total of 19 patients were enrolled: 17 were evaluable for toxicity and 13 for efficacy. The median age of the 13 included in the efficacy analysis was 63 years, 62% had Eastern Cooperative Oncology Group performance status 1, and 31% received >three previous systemic therapies. The most common tumor type was brain cancers (54%). The ORR was 15.4% (n = 2 of 13; 90% CI, 2.8 to 41.0) and 6-month PFS was 16.7% (90% CI, 0 to 34.4). The two confirmed RECIST responses were observed in a patient with neuroendocrine carcinoma not otherwise specified ( EGFR exon 20 S768T and exon 18 G719C mutation) and a patient with low-grade epithelial carcinoma of the paranasal sinus ( EGFR D770_N771insSVD). The most common (>20%) treatment-related adverse events were diarrhea, thrombocytopenia, and maculopapular rash., Conclusion: In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Purpose: Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor ( EGFR )-mutated non-small-cell lung cancer (NSCLC)., Methods: This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR- mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data., Results: Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations., Conclusion: After tumor progression with EGFR TKI therapy and PBC in patients with EGFR -mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR- mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

Purpose: Although several agents targeting epidermal growth factor receptor ( EGFR ) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines., Methods: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy., Results: Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day., Conclusion: Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Purpose: The identification of novel oncogenic driver alterations and novel mechanisms of acquired resistance (AR) is the key for further development of personalized therapy. The current study investigates the potential role of YES1 amplification as a primary driver of tumorigenesis and of YES1/YAP1 amplifications as mediators of AR to ALK and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)., Methods: Models of ectopic expression were established and characterized for YES1 and YAP1 in human bronchial epithelial cells and ALK fusion-positive (ALK+) and EGFR -mutant lung adenocarcinoma cell lines. MSK-IMPACT data for all lung adenocarcinoma cases and for ALK and EGFR TKI AR cases were surveyed for YES1 and YAP1 amplification., Results: We report response to SRC family kinase (SFK) inhibition in a patient whose lung cancer exhibited YES1 amplification, without any well-established primary driver alteration, suggesting that YES1 amplification can also function as a primary oncogenic driver. To investigate the possibility of YES1 as a primary driver in tumorigenesis, we established preclinical models of YES1 overexpression using human bronchial epithelial cells and normal human breast epithelial cells. We showed that YES1 overexpression conferred sensitivity to SFK TKIs and promoted EGF-independent growth in a YAP1-dependent manner. Analysis of clinical genomic sequencing data from cases of AR to EGFR and ALK inhibitors revealed acquired amplification of YAP1 in four cases. EGFR -mutant and ALK fusion-positive cells overexpressing YES1 or YAP1 were resistant to EGFR and ALK TKIs, respectively, but were sensitive to dual inhibition of the primary driver and YES1., Conclusion: Our results demonstrate the therapeutic potential of SFK inhibition in primary tumorigenesis and AR driven by YES1/YAP1 signaling.

Patients with EGFR- mutant lung cancer have no approved targeted therapies after disease progression on first-line osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Preclinical studies suggest that tumors with both EGFR -sensitizing alteration and acquired second-site EGFR resistance alterations after treatment with osimertinib retain sensitivity to second-generation EGFR TKIs. We hypothesized that dacomitinib, a pan-human epidermal growth factor receptor TKI, may be effective in this setting., Methods: In this phase II study, patients who had progressed on first-line osimertinib were treated with dacomitinib 45 mg orally daily until disease progression or intolerability. The primary end point was objective response rate., Results: We enrolled 12 patients. Two partial responses were documented (17% objective response rate; 95% CI, 5 to 45). The median progression-free survival was 1.8 months (95% CI, 1.6 to not reached). One patient with an original sensitizing EGFR G719A mutation and one patient without molecular testing available had partial responses, whereas 0 of the 3 patients with second-site acquired EGFR resistance mutations (two C797S and one G724S) met the response criteria. The patient with EGFR G719A has an ongoing response at 17 months, which exceeds prior time on osimertinib (11 months)., Conclusion: In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit., (© 2021 by American Society of Clinical Oncology.)

Inhibition of the MEK/ERK pathway is critical for Bcl-2-like protein 11 (BIM)-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-induced apoptosis, and dysregulation of this pathway may be a mechanism of acquired resistance. Therefore, MEK inhibition with trametinib and an EGFR TKI may resensitize tumors with acquired resistance. Limited targeted therapies are available after progression on EGFR TKIs, and it is in this setting that we completed a phase I/II study of erlotinib and trametinib., Methods: Patients with metastatic EGFR -mutant lung adenocarcinoma and acquired resistance to an EGFR TKI received combination erlotinib 75 mg and trametinib 1.5 mg daily until progression or unacceptable side effects. The primary objective was objective response rate determined using RECIST version 1.1., Results: Twenty-three patients were accrued; patients had received a median of two lines of prior TKI therapy (61% prior osimertinib), and 48% had acquired EGFR T790M. We confirmed one partial response (1/23, 4%, 95% CI, 0 to 22). The median progression-free survival was 1.8 months, and the median overall survival was 21 months. Diarrhea (87%), acneiform rash (87%), and fatigue (52%) were the most common treatment-related adverse events. Two patients who had tumor shrinkage both harbored a BRAF fusion., Conclusion: Addition of trametinib to erlotinib in the acquired resistance setting in an unselected population is not efficacious. Future studies should focus on targeted therapies in molecularly selected populations. Acquired BRAF fusions in patients with EGFR -sensitizing mutations may be a molecular subset where EGFR and MEK combination therapy could be studied further., (© 2021 by American Society of Clinical Oncology.)

Purpose: Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy., Materials and Methods: Patients with metastatic non-small-cell lung cancer (NSCLC) or mismatch repair deficiency (MMRD) carcinoma treated with PD-1 monotherapy were evaluated independently. Absolute and percent change of each target lesion were quantified at each computed tomography scan using RECIST. Patterns of progression were predefined as systemic or mixed and were correlated with clinical outcomes., Results: A total of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma were examined. Individual target lesion responses aligned with best overall response of each patient (85% NSCLC and 93% MMRD lesions responded in patients with partial response/complete response). In responding patients, timing of response was uniform (73% NSCLC and 76% MMRD lesions responded synchronously), and deeper responses were associated with prolonged progression-free survival and overall survival. By contrast, at progression, mixed progression was common (45% of NSCLC and 53% of MMRD) and associated with improved survival compared with those who experienced systemic progression (NSCLC hazard ratio [HR], 0.58; P = .001; MMRD HR, 0.40; P = .07). Organ sites had differential responses, with lymph node and liver metastasis among the most and least responsive, respectively., Conclusion: Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.

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.

Metastases to the central nervous system (CNS) are associated with considerable morbidity and mortality in patients with cancer. Historically, very few systemic therapies have shown efficacy in this patient population. Emerging data are now demonstrating that whole-brain radiation therapy, previously considered the mainstay of treatment of brain metastases, is associated with high rates of neurotoxicity. In this new era of targeted therapy and immunotherapy, clinical outcomes are improving, and patients are living longer. Despite these improvements, there is an urgent need to design central nervous system-penetrant compounds that target the genetic mutations enriched in brain metastases and to bring these to clinical trials.

Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center Michael Offin Consulting or Advisory Role: PharmaMar Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck Sharp & Dohme Maria E. Arcila Honoraria: Invivoscribe Consulting or Advisory Role: AstraZeneca Travel, Accommodations, Expenses: AstraZeneca, Invivoscribe, Raindance Technologies Charles M. Rudin Consulting or Advisory Role: Bristol-Myers Squibb, AbbVie, Seattle Genetics, Harpoon Therapeutics, Genentech/Roche, AstraZeneca, Ascentage Pharma, Bicycle Therapeutics, Celgene, Daiichi Sankyo, Ipsen, Loxo, PharmaMar, Elucida Oncology, Bridge Medicines Research Funding: AbbVie/Stemcentrx (Inst), Viralytics (Inst), Merck (Inst), Daiichi Sankyo (Inst) Alexander Drilon Honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, Peerview Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer HealthCare Pharmaceuticals, Tyra Biosciences, Verastem, Takeda/ARIAD/ Millennium Pharmaceuticals, BerGenBio, MORE Health Patents, Royalties, Other Intellectual Property: Wolters Kluwer (royalties for Pocket Oncology) Other Relationship: Merck, GlaxoSmithKline, TEVA Pharmaceuticals Industries, Taiho Pharmaceutical Helena A. Yu Consulting or Advisory Role: AstraZeneca, Eli Lilly Research Funding: Clovis Oncology (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Eli Lilly (Inst), Novartis (Inst), Pfizer (Inst), Daiichi Sankyo (Inst) Travel, Accommodations, Expenses: Eli Lilly Other Relationship: Astellas Pharma Gregory J. Riely Research Funding: Novartis (Inst), Roche/Genentech (Inst), Millennium Pharmaceuticals (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Infinity Pharmaceuticals (Inst), ARIAD Pharmaceuticals (Inst), Mirati Therapeutics (Inst), Merck (Inst) Patents, Royalties, Other Intellectual Property: Patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases (Inst) Travel, Accommodations, Expenses: Merck Sharp & Dohme Romel Somwar Research Funding: Helsinn Healthcare Travel, Accommodations, Expenses: Helsinn Healthcare Marc Ladanyi Honoraria: Bristol-Myers Squibb Consulting or Advisory Role: National Comprehensive Cancer Network/ AstraZeneca Tagrisso RFP Advisory Committee, Takeda Pharmaceuticals, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Merck (I), Merck Research Funding: Loxo (Inst), Helsinn Therapeutics Travel, Accommodations, Expenses: Bristol-Myers Squibb No other potential conflicts of interest were reported.

Purpose: Liquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor ( EGFR ) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non-small-cell lung cancer treated with rociletinib., Methods: Tissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples., Results: Positive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) than tissue alone (83%) among matched samples (n = 177). The ability to identify mutations in plasma was strongly associated with M stage ( P < .001); rate of T790M detection for patients with M1a/M0 disease increased from 54% for plasma alone to 85% when urine and plasma were both examined. Objective response rates of patients who were T790M positive were comparable between tumor (34%), plasma (32%), and urine (37%)., Conclusion: Clinical response to rociletinib was comparable irrespective of whether T790M status was identified by liquid or tissue biopsy. Combined, urine and plasma identified a higher percentage of patients who were T790M positive than tumor genotyping alone and improved detection of T790M, particularly in the absence of distant metastases. These findings support the noninvasive analysis of urine and plasma before tumor rebiopsy when assessing T790M status.

The practice of precision medicine for patients with metastatic non-small cell lung cancer (NSCLC), particularly those patients with adenocarcinoma histology (the predominant subtype of NSCLC), has become the accepted standard of care worldwide. Implementation of prospective tumor molecular profiling and rational therapeutic decision-making based on the presence of recurrently detected oncogenic "driver" alterations in the tumor genome has revolutionized the way that lung cancer is diagnosed and treated in the clinic. Over the past two decades, there has been a deluge of therapeutically actionable driver alterations and accompanying small molecule inhibitors to target these drivers. Herein, we synthesize a large and rapidly growing body of literature regarding therapeutic inhibition of driver mutations. We focus on established targets, including EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, HER2, and neurotrophic tyrosine kinase receptor (NTRK), with a particular emphasis on the sequencing of small molecule inhibitors in these genetically defined cohorts of patients with lung cancer.

Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Michael Offin No relationship to disclose Romel Somwar Research Funding: Helsinn Healthcare Travel, Accommodations, Expenses: Helsinn Healthcare Natasha Rekhtman No relationship to disclose Ryma Benayed No relationship to disclose Jason C. Chang No relationship to disclose Andrew Plodkowski No relationship to disclose Allan J.W. Lui No relationship to disclose Juliana Eng No relationship to disclose Marc Rosenblum No relationship to disclose Bob T. Li Consulting or Advisory Role: Roche, BIosceptre International, ThermoFisher Scientific, Mersana, Guardant Health Research Funding: Roche (Inst), Genentech (Inst), Illumina (Inst), BioMed Valley Discoveries (Inst), AstraZeneca (Inst), GRAIL (Inst) Gregory J. Riely Research Funding: Novartis (Inst), Roche (Inst), Genentech (Inst), Millenium (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Infinity Pharmaceuticals (Inst), ARIAD (Inst) Patents, Royalties, Other Intellectual Property: Patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases (Inst) Travel, Accommodations, Expenses: Merck Sharp & Dohme Charles M. Rudin Consulting or Advisory Role: Bristol-Myers Squibb, Abbvie, Seattle Genetics, Harpoon Therapeutics, Genentech, Roche, AstraZeneca Mark G. Kris Consulting or Advisory Role: AstraZeneca, Regeneron William Travis Speakers’ Bureau: Genentech Alexander Drilon Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech, Roche, Takeda, Helsinn Therapeutics, BeiGene Maria E. Arcila Consulting or Advisory Role: AstraZeneca Travel, Accommodations, Expenses: AstraZeneca, Invivoscribe, Raindance Technologies Marc Ladanyi Honoraria: Merck (I) Consulting or Advisory Role: National Comprehensive Cancer Network, Boehringer Ingelheim, AstraZeneca (Tagrisso RFP Advisory Committee) Research Funding: Loxo (Inst) Helena A. Yu Consulting or Advisory Role: AstraZeneca Research Funding: Astellas Pharma, Incyte, Lilly Oncology, Novartis, Daiichi, AstraZeneca

Competing Interests: Identification and Functional Characterization of EGFR V769M, a Novel Germline Variant Associated With Multiple Lung AdenocarcinomasThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc.Matthew D. HellmannConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, MedImmune, Novartis, Janssen Research Funding: Bristol-Myers Squibb, GenentechTakuo HayashiNo relationship to discloseBoris RevaNo relationship to discloseHelena A. YuConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly Research Funding: Clovis Oncology, AstraZeneca, Astellas Pharma, Incyte Pharmaceuticals, LillyGregory J. RielyConsulting or Advisory Role: Novartis, Genentech Research Funding: Novartis (Inst), Genentech (Inst), Millennium Pharmaceuticals (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Infinity Pharmaceuticals (Inst), ARIAD Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases (Inst) Travel, Accommodations, Expenses: NovartisPrasad S. AdusumilliNo relationship to discloseWilliam D. TravisNo relationship to discloseOlivia WilkinsNo relationship to discloseNicole BramlettaTravel, Accommodations, Expenses: AstraZenecaRaghu ChandramohanNo relationship to discloseMegan Harlan FleischutNo relationship to discloseMark G. KrisConsulting or Advisory Role: AstraZeneca, ARIAD Pharmaceuticals, Genentech Research Funding: Puma Biotechnology (Inst), Genentech (Inst)Mark E. RobsonHonoraria: AstraZeneca Consulting or Advisory Role: McKesson, AstraZeneca Research Funding: AstraZeneca (Inst), AbbVie (Inst), Biomarin (Inst), Medivation (Inst), Tesaro (Inst) Travel, Accommodations, Expenses: AstraZenecaMaria E. ArcilaConsulting or Advisory Role: AstraZeneca Travel, Accommodations, Expenses: AstraZeneca, Invivoscribe, Raindance TechnologiesPaul K. PaikHonoraria: Celgene, Bristol-Myers Squibb, Lilly, ARIAD Pharmaceuticals Consulting or Advisory Role: Celgene, Lilly, ARIAD Pharmaceuticals, Bristol-Myers Squibb Research Funding: Celgene, EMD Serono Travel, Accommodations, Expenses: EMD SeronoMarc LadanyiHonoraria: Merck (I) Consulting or Advisory Role: NCCN/Boehringer Ingelheim Afatinib Targeted Therapy Advisory Committee, NCCN/AstraZeneca Tagrisso RFP Advisory Committee Research Funding: Loxo Pharmaceuticals (Inst)

Purpose: AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment., Patients and Methods: All patients had developed acquired resistance after treatment with erlotinib and underwent repeat tumor biopsies before study entry to assess for EGFR T790M. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximum-tolerated dose. The primary end point of the phase II trial was complete plus partial response rate., Results: In phase I (n = 18), three patients were treated in each cohort, except the highest-dose cohort (AUY922 70 mg and erlotinib 150 mg), which expanded to six patients because of a dose-limiting toxicity (ie, junctional cardiac rhythm). Common drug-related adverse events were diarrhea, skin rash, hyperglycemia, and night blindness. All patients treated at maximum-tolerated dose (n = 25) were evaluable for response. The partial response rate was 16% (four of 25 patients; 95% CI, 5% to 36%) and was independent of tumor T790M status., Conclusion: Partial responses were observed, but the duration of treatment with AUY922 and erlotinib was limited by toxicities, especially night blindness. This phase II study of AUY922 and erlotinib did not meet its primary end point., (© 2015 by American Society of Clinical Oncology.)