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Preferred first-line treatment for patients with metastatic EGFR-mutant lung cancer is osimertinib, yet it is not known if patient outcomes may be improved by identifying and intervening upon molecular markers associated with therapeutic resistance.All patients with metastatic EGFR-mutant lung cancer treated with first-line osimertinib at Memorial Sloan Kettering Cancer Center (n=327) were identified. Available pre-treatment and post-progression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free and overall survival were estimated using Kaplan Meier methods.Using multivariate analysis, baseline atypical EGFR (mPFS 5.8 mo, p0.001) and concurrent TP53/RB1 alterations (mPFS 10.5 mo, p=0.015) were associated with shorter progression-free survival on first-line osimertinib. Of 95 patients with post-progression biopsies, acquired resistance mechanisms were identified in 52% (off-target n=24, histological transformation n=14, on-target n=12), with MET amplification (n=9), small cell lung transformation (n=7) and acquired EGFR amplification (n=7) the most frequently identified mechanisms. While there was no difference in post-progression survival based on identified resistance (p=0.07), patients with subsequent second-line therapy tailored to post-progression biopsy results had improved post-progression survival (HR 0.09, p=0.006). Paired post-progression tumors had higher tumor mutational burden (p=0.008) and further dominant APOBEC mutational signatures (p=0.07) compared to pre-treatment samples.Patients with EGFR-mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation based on identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pre-treatment genomic alterations.

Purpose: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. Patients and Methods: We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. Results: Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%–88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%–58%). Conclusions: We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

PURPOSE Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT. PATIENTS AND METHODS We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non–small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs). RESULTS Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; P < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; P = .029). There was no difference in the rate of grade 3 and 4 TAEs ( P = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months). CONCLUSION Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non–small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.

Supplemental Figure 1. Dose modifications of Combination Osimertinib and Dacomitinib (initial therapy study).

Supplemental Figure 4. A. Median progression-free survival and B. Overall survival for patients enrolled in the acquired resistance study

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has significantly prolonged progression-free survival (PFS) in patients with EGFR-mutant lung cancer, including those with brain metastases. However, despite striking initial responses, osimertinib-treated patients eventually develop lethal metastatic relapse, often to the brain. Although osimertinib-refractory brain relapse is a major clinical challenge, its underlying mechanisms remain poorly understood. Using metastatic models of EGFR-mutant lung cancer, we show that cancer cells expressing high intracellular S100A9 escape osimertinib and initiate brain relapses. Mechanistically, S100A9 upregulates ALDH1A1 expression and activates the retinoic acid (RA) signaling pathway in osimertinib-refractory cancer cells. We demonstrate that the genetic repression of S100A9, ALDH1A1, or RA receptors (RAR) in cancer cells, or treatment with a pan-RAR antagonist, dramatically reduces brain metastasis. Importantly, S100A9 expression in cancer cells correlates with poor PFS in osimertinib-treated patients. Our study, therefore, identifies a novel, therapeutically targetable S100A9–ALDH1A1–RA axis that drives brain relapse.Significance:Treatment with the EGFR TKI osimertinib prolongs the survival of patients with EGFR-mutant lung cancer; however, patients develop metastatic relapses, often to the brain. We identified a novel intracellular S100A9–ALDH1A1–RA signaling pathway that drives lethal brain relapse and can be targeted by pan-RAR antagonists to prevent cancer progression and prolong patient survival.This article is highlighted in the In This Issue feature, p. 873

Supplementary Figure from Targeting S100A9–ALDH1A1–Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686–95. ©2018 AACR.See related commentary by Wilson and Politi, p. 676.This article is highlighted in the In This Issue feature, p. 663

PDF file - 29K

Breakdown of RET and ROS1 fusion positive patients

Retreatment Cohort - Initial irAEs: Clinical Characteristics and Features

Supplementary Fig 3

Co-occurring Level 1-3 alterations by MSK-IMPACT in 52 patients

Large-scale genomic characterization of squamous cell lung cancers (SQCLC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance. We performed comprehensive genomic profiling (including next-generation sequencing) of 79 stage IV SQCLCs and analyzed differences in the clinical characteristics of two major SQCLC subtypes: FGFR1 amplified and PI3K aberrant. Patients with PI3K-aberrant tumors had aggressive disease marked by worse survival (median overall survival, 8.6 vs. 19.1 months, P < 0.001), higher metastatic burden (>3 organs, 18% vs. 3%, P = 0.025), and greater incidence of brain metastases (27% vs. 0% in others, P < 0.001). We performed whole-exome and RNA sequencing on paired brain metastases and primary lung cancers to elucidate the metastatic process to brain. SQCLC primaries that gave rise to brain metastases exhibited truncal PTEN loss. SQCLC brain metastases exhibited a high degree of genetic heterogeneity and evidence of clonal differences between their primary sites.Significance: We performed next-generation sequencing of metastatic SQCLCs and primary lung–brain metastasis pairs, identifying PI3K-aberrant tumors as an aggressive subset associated with brain metastases. We identified genetic heterogeneity between lung primaries–brain metastases as well as clonal populations that may highlight alterations important in the metastatic process. Cancer Discov; 5(6); 610–21. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 565

PDF file - 92K, Effects of HER2 overexpression on the sensitivity of HCC827 cells to EGFR TKIs

PDF file - 91K, Levels of HER2 affect the sensitivity of EGFR-mutant NSCLC cells to EGFR TKIs

Supplementary Table 2. Frequency of selected genes in SQ-MAP vs. TCGA. Supplementary Table 3. Clinical characteristics of patients with resected brain metastases. Supplementary Table 4. Genes exhibiting clonal evolution from primary lung tumors and matched brain metastases. Data from PP1 and PP4 are shown. Supplementary Table 5. List of 279 oncogenes and tumor suppressors covered by the Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) assay. Supplementary Table 6. Computational estimates of tumor purity (fractional) from whole-exome sequencing data for the paired lung primary and brain metastasis tumor samples compared to pathological evaluation of tumor purity in the same samples.

Supplementary Table 1. Complete list of somatic mutations and copy number alterations detected by IMPACT in 79 stage IV SQCLC patients with clinical annotation.

Supplementary Fig 2

Table S1

Types of Clinical trials patients enrolled to according to level 1-4 and UMD assigned samples

Supplementary Table S1: List of actionable genes and potential matched therapy Supplementary Table S2: List of co-occurring Level 1-4 mutations Supplementary Table S3: EGFR mutations identified and associated therapy Supplementary Table S4: List of 410 genes in MSK-IMPACT assay

PDF file - 1601K, Representative case harboring a 9pb insertion mutation V769_D770insASV

Supplementary Tables and Figures

PDF file - 76K, Comprehensive list of mutations tested by mass spectrometry (Sequenom)

Figures S1, S2, S3, S4, and S5

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Patients with Advanced NSCLC Treated at MSKCC with Immunotherapy From April 2011 to May 2016

Supplementary Fig 5

This document contains Supplementary Figures 1-6 and Supplementary Table 1. Supplementary Figure 1. Sequencing reads of EGFR-KDD in index patient with lung adenocarcinoma. Supplementary Figure 2. cDNA sequence of EGFR-KDD. Supplementary Figure 3. Sequencing reads identifying EGFR-KDD in a lung adenocarcinoma tumor from The Cancer Genome Atlas. Supplementary Figure 4. Autophosphorylation of endogenous EGFR-KDD in A1235 cells. Supplementary Figure 5. Colony formation of NR6 cells expressing EGFR variants. Supplementary Figure 6. Efficacy of EGFR TKIs in endogenous and ectopic models of the EGFR-KDD. Supplementary Table 1. Results of MTT curve fitting from Prism.

Breakdown of MAP2K1, RAF1, ARAF, FGFR3-TACC3 fusion and CDKN2A loss patients

Retreatment Cohort - Recurrent irAEs: Characteristics of The Recurrent Immune-Related Toxicity

This document contains Supplementary Methods, Supplementary Figure Legends, and Supplementary Table Legend.

Time From First Dose of Immunotherapy to Date of The Initial irAE

PDF file - 61K, Summary of all cases tested for EGFR exon 20 insertions

Patient 1 Concurrent EGFR and KRAS mutations in a patient identified by MSK-IMPACT

Median number of mutations in samples sequenced by MSK-IMPACT in patients with a Level 1-4 alteration or assigned to the unknown mitogenic driver cohort.

Supplementary Methods

Supplementary Table 1

Overall Survival for Patients in the Retreatment Cohort

Supplementary Figure 1. Copy number pattern in paired lung cancer primaries and brain metastases from patients PP1, PP2, and PP4. Red, blue, and white indicate gain, loss, neutral states, respectively. The total number of shared cytobands (percent shared) between the primary and brain metastases are indicated at the bottom. Supplementary Figure 2A. Genome-wide copy number profile of the PP1 brain metastasis (A) and lung primary (B). Total log-copy ratio (logR) in the tumor versus normal and minor allele frequency (MAF) in the tumor are plotted. Yellow line represents joint segmentation of logR and MAF. Supplementary Figure 2B. Genome-wide copy number profile of the PP4 brain metastasis (A) and lung primary (B). Supplementary Figure 2C. Genome-wide copy number profile of the PP2 brain metastasis (A) and lung primary (B). Pooled normal was used to generate the logR plot. Supplementary Figure 2D. Genome-wide copy number profile of the PP3 brain metastasis (A) and PP5 brain metastasis (B).

PDF file - 66K, Summary of all mutations identified through clinical and extended mass spectrometry genotyping (n=1500)

Supplementary Fig 6

Supplementary Figure 3. Photomicrographs of chromosome 5p FISH from PP1-PP4 brain metastases. Red signals correspond to 5p13.

Supplementary Figure 4. Heatmap of mRNA expression for clustered protocadherin gene families. A. gamma cluster and B. beta cluster in 178 TCGA lung squamous cell carcinomas and 5 MSKCC brain metastasis samples. Yellow ticks under the dendrogram indicate the brain metastasis samples.

Supplementary Fig 4

Patient 2 Concurrent EGFR and KRAS mutations in a patient identified by MSK-IMPACT

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

Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non–small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1–2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093–9. ©2018 AACR.