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Cyclin‑dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy are the current standard of care used in the first‑line treatment of hormone receptor‑positive/HER2‑negative metastatic breast cancer (BC). Although CDK4/6 inhibitors mainly target the cell cycle, emerging evidence has indicated further potential roles of CDKs other than regulating cell cycle progression. The G

Increased insight into the mutational landscape of squamous cell lung cancers (LUSCs) in the past decade has not translated into effective targeted therapies for patients with this disease. NRF2, encoded by NFE2L2, and its upstream regulator, KEAP1, control key aspects of redox balance and are frequently mutated in NSCLCs.Here, we describe the specific potent activity of TAK-228, a TORC1/2 inhibitor, in NSCLC models harboring NRF2-activating alterations and results of a phase 2 clinical trial of TAK-228 in patients with advanced NSCLC harboring NRF2-activating alterations including three cohorts (NFE2L2-mutated LUSC, KEAP1-mutated LUSC, KRAS/NFE2L2- or KEAP1-mutated NSCLC).TAK-228 was most efficacious in a LUSC cohort with NFE2L2 alterations; the overall response rate was 25% and median progression-free survival was 8.9 months. Additional data suggest that concurrent inhibition of glutaminase with the glutaminase inhibitor CB-839 might overcome metabolic resistance to therapy in these patients.TAK-228 has single-agent activity in patients with NRF2-activated LUSC. This study reframes oncogenic alterations as biologically relevant based on their downstream effects on metabolism. This trial represents, to the best of our knowledge, the first successful attempt at metabolically targeting NSCLC and identifies a promising targeted therapy for patients with LUSC, who are bereft of genotype-directed therapies.

Purpose: Gemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic antitumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLC) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the antitumor activity in patients with advanced SQCLCs. Patients and Methods: This was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1,000 mg/m2) plus ABP (100 mg/m2) in a 3-week on, 1-week off schedule during stage I and a 2-week on, 1-week off schedule in stage II. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy. Results: Thirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient [ORR 59%; 95% confidence interval (CI), 42%–74%]. Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI, 6.7–10.5) months. There were no unexpected toxicities. Conclusions: Gemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable with carboplatin plus taxane plus pembrolizumab.

PURPOSE Broad-panel sequencing of tumors facilitates routine care of people with cancer as well as clinical trial matching for novel genome-directed therapies. We sought to extend the use of broad-panel sequencing results to survival stratification and clinical outcome prediction. METHODS By using sequencing results from a cohort of 1,054 patients with advanced lung adenocarcinomas, we developed OncoCast, a machine learning tool for survival risk stratification and biomarker identification. RESULTS With OncoCast, we stratified this patient cohort into four risk groups on the basis of tumor genomic profile. Patients whose tumors harbored a high-risk profile had a median survival of 7.3 months (95% CI, 5.5 to 10.9 months) compared with a low-risk group with a median survival of 32.8 months (95% CI, 26.3 to 38.5 months) with a hazard ratio of 4.6 ( P < .001), far superior to any individual gene predictor or standard clinical characteristics. We found that comutations of both STK11 and KEAP1 are strong determinants of unfavorable prognosis with currently available therapies. In patients with targetable oncogenes (eg, EGFR, ALK, ROS1) who received targeted therapies, the tumor genetic background additionally differentiated survival with mutations in TP53 and ARID1A, which contributed to a higher risk score for shorter survival. CONCLUSION A mutational profile derived from broad-panel sequencing presents an effective genomic stratification for patient survival in advanced lung adenocarcinoma. OncoCast is available as a public resource that facilitates the incorporation of mutational data to predict individual patient prognosis and compare risk characteristics of patient populations.

Combination of bendamustine (B) and rituximab (R) has been associated with opportunistic infections (OI) in case reports. This retrospective analysis evaluated the incidence, risk factors, and types of infectious complications (IC) in adults with CD20+ non-Hodgkin lymphoma who received ≥2 cycles of B and either R or ofatumumab. Infection data were collected up to 1-year post-B-based treatment. Potential risk factors for IC were assessed using univariate analysis with Fisher's exact test. Four-hundred and sixteen patients were included. Incidence of IC and OI was 20 and 6%, respectively. Viral (

532 Background: Limited compelling prospective and retrospective data regarding the added benefit of anti-HER2 therapy in the management of small, node-negative HER2-positive breast cancer (HER2+BC) exists, in part due to differences in outcome reporting, unmatched analyses, and a lack of head-to-head comparisons. As a result, national guideline committees find themselves unable to confidently recommend anti-HER2 therapy and clinicians are left to exercise clinical judgement on whether the use of anti-HER2 therapy should be considered for such patients. Methods: Our team performed a multi-institutional retrospective analysis using the ASCO CancerLinQ database, with a focus on clinical data from small, node-negative HER2+BC patients diagnosed between 2010 to 2021. We compared clinical outcomes between those who received adjuvant trastuzumab therapy, with or without chemotherapy, to those who did not, with our primary outcomes being invasive disease-free survival (iDFS) and overall survival (OS). We performed both a univariate and multivariate analysis, using a Cox proportional hazard model to control for factors including age, ethnicity, body mass index, hormone status, tumor grade, histology type, BRCA status, region, and smoking history. Additionally, a three-arm univariate analysis was performed comparing untreated patients to trastuzumab alone versus combination therapy. Results: In total, 1206 patients met inclusion criteria, including 779 patients who received trastuzumab with or without chemotherapy. We found a statistically significant improvement in both iDFS (HR 0.73, p = 0.01) and OS (HR 0.63, p = 0.027) on univariate analysis for those receiving anti-HER2 therapy. Similarly on multivariate analysis, iDFS (HR 0.75, p = 0.030) and OS (HR 0.61, p = 0.029) were improved in those who received therapy, regardless of tumor size. Our three-arm univariate analysis involving no treatment (n = 427), trastuzumab monotherapy (n = 169), and combination therapy (n = 578) found that iDFS was significantly improved for both treatment arms compared to observation alone (p = 0.006), whereas OS trended towards significance in the treatment arms but did not reach this target (p = 0.061). No significant difference was noted between treatment arms. Conclusions: Our analysis found a statistically significant improvement in iDFS and OS when patients with small, node negative, HER2+BC received adjuvant anti-HER2 therapy with or without chemotherapy as compared to observation. From our univariate three-arm comparison, it appears that trastuzumab provides the majority of benefit to patients in terms of DFS, but this result is exploratory. Further investigation is warranted, including meta-analyses to better characterize the degree of benefit seen with anti-HER2 treatment. For now, this data adds to evidence suggesting added benefit with therapy over observation.

Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

The CLL-IPI is a risk-weighted prognostic model for previously untreated patients with chronic lymphocytic leukemia (CLL), but has not been evaluated in patients with relapsed CLL or on novel therapies. We evaluated the CLL-IPI in 897 patients with relapsed/refractory CLL in 3 randomized trials testing idelalisib (PI3Kδ inhibitor). The CLL-IPI identified patients as low (2.2%), intermediate (12.8%), high (48.7%), and very high (36.2%) risk, and was prognostic for survival (log-rank p65, β2-microglobulin >3.5mg/L, unmutated immunoglobulin heavy chain variable region gene, and deletion 17p/TP53 mutation were independently prognostic, but Rai I-IV or Binet B/C was not. The CLL-IPI is prognostic for survival in relapsed CLL and with idelalisib therapy. However, low/intermediate risk is uncommon, and regression parameters of individual factors in this risk-weighted model appear different in relapsed CLL. Reassessment of the weighting of the individual variables might optimize the model in this setting.

Introduction In ret proto-oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%–32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%–58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)–rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3–2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0–4.9 months). Conclusions Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

BACKGROUND: MET exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced MET exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized. PATIENTS AND METHODS: Patients with MET exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was carried out and TMB was calculated by estimation from targeted next-generation sequencing panels. RESULTS: We identified 147 patients with MET exon 14-altered lung cancers. PD-L1 expression of 0%, 1%–49%, and ≥50% were 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers was lower than that of unselected non-small-cell lung cancers (NSCLCs) in both independently evaluated cohorts: 3.8 versus 5.7 mutations/megabase (P

Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing. Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1. Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo. Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108–18. ©2018 AACR.

Purpose Treatment of advanced non–small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non–small-cell lung cancer treated with anti–programmed death-1 or anti–programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number–altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES. Results Estimates of TMB by targeted NGS correlated well with WES (ρ = 0.86; P < .001). TMB was greater in patients with DCB than with NDB ( P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1%; P < .001; hazard ratio, 1.38; P = .024). The fraction of copy number–altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs. Conclusion Targeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.

Background: Venetoclax (Ven; BH3 mimetic) and Obinutuzumab (O; CD20 antibody) is an approved, fixed-duration regimen (one year) that induces undetectable minimum residual disease (uMRD) and durable remissions in treatment naïve patients (pts) with chronic lymphocytic leukemia (CLL; Fischer NEJM 2019). In the CLARITY trial of venetoclax-ibrutinib (BTK inhibitor; BTKi) in relapsed or refractory CLL, peripheral blood (PB) MRD response kinetics predicted bone marrow (BM) uMRD and were associated with progression-free survival (Rawstron EHA 2020). We explored MRD as a biomarker to direct treatment duration in an investigator-initiated phase 2 trial of Zanubrutinib (BTKi) and O-Ven (BOVen). We hypothesize that early MRD kinetics will identify a defined cohort of pts with delayed BM MRD clearance, and early recurrent detectable MRD after discontinuation of treatment in pts attaining uMRD. Methods: In this multicenter, phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment (iwCLL), ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelets (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) and immunosequencing (MRD-IS; Adaptive ClonoSEQ) with uMRD defined as ≤10 -4 for flow and ≤10 -5 for IS. Treatment consisted of 8-24 cycles with duration determined by prespecified MRD criteria. Beginning on C7D1 then every 2 cycles, pts with PB uMRD-FC had BM within 14 days. If BM uMRD, PB MRD was repeated after two additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy and entered posttreatment surveillance. Response was assessed per iwCLL. Adverse events (AE) were assessed per CTCAE v5. MRD-IS failure free survival (FFS) was calculated from end-of-treatment (EOT) to the date of detectable MRD-IS (≥10 -5) using the Kaplan-Meier method. Results: The study accrued 39 pts (03/19-10/19): median age 59 years (23-73), 3:1 male predominance, 28/39 (72%) IGHV unmutated, 5/39 (12.8%) del(17p)/TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy. At a median follow up of 26+ months (mo; 4.5-30.5+), 95% (35/37) pts achieved uMRD-FC in PB, among whom 33 (94%) also achieved uMRD-IS. BM uMRD-FC was seen in 89% (33/37) at a median time of 8 mo (6-16), all of whom met prespecified MRD criteria and discontinued therapy after a median of 10 mo (8-18). Three pts discontinued therapy with persistent detectable BM MRD after 24 cycles. The most common AEs were neutropenia (51%), thrombocytopenia (44%), diarrhea (44%), infusion related reaction (41%) and bruising (41%). The most common grade ≥3 AE was neutropenia (15%). No laboratory or clinical TLS occurred (Howard definition). A ≥400-fold reduction in PB MRD-IS after 4 cycles (ΔMRD400) was selected using the Youden Index and was highly predictive of attaining BM uMRD in ≤8mo (sensitivity 88% [21/24], specificity 100% [11/11], PPV 100% [21/21], NPV 79% [11/14]. As a result, the median duration of therapy was shorter among patients who achieved ΔMRD400 (8 vs 13 mo). Of 33 pts who met prespecified uMRD criteria and stopped therapy, 31 (94%) remain uMRD-FC following a median 15 mo (0-20) from EOT, and 2 pts had recurrent MRD (1 with PD recaptured PB uMRD with retreatment). Of 33 pts who discontinued therapy after achieving the prespecified MRD endpoint, MRD-IS was evaluated every 3 months in 31 pts for a median of 12 mo (range, 3-18) from EOT. MRD-IS FFS was longer in pts who achieved ΔMRD400 (log rank p Conclusion: BOVen achieved frequent, durable uMRD. All pts completed therapy (median 10 mo treatment), including 89% (33/37) who met the prespecified PB/BM uMRD endpoint. With a median posttreatment follow-up of 15 mo, 31 (94%) remain uMRD-FC. ΔMRD400 identified a cohort of pts (40%) with delayed BM MRD clearance and earlier MRD recurrence, despite longer treatment duration. ΔMRD400 warrants further study as a predictive biomarker for treatment duration. Figure 1 Figure 1. Disclosures Soumerai: Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; BostonGene: Research Funding; GlaxoSmithKline: Research Funding. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding. Dogan: Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Hochberg: Leuko: Consultancy; Intervention Insights: Consultancy. Abramson: Bluebird Bio: Consultancy; Morphosys: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Kite Pharma: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; GLG Pharma: Consultancy; Dava Oncology: Honoraria; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Life Sciences: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Seattle Genetics: Consultancy; Bayer: Research Funding; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Matasar: Rocket Medical: Consultancy, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; BeiGene: Consultancy; Lygenesis: Honoraria; Nektar: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Rheos: Honoraria; Magenta: Honoraria; Pluto: Honoraria; WindMIL: Honoraria; Priothera: Honoraria. Kumar: Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Seattle Genetics: Research Funding. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Thompson: VJHemOnc: Honoraria; MJH Life Sciences: Honoraria; Curio Science: Honoraria. Roshal: Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jacob: Adaptive Biotechnologies: Current Employment. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Novartis: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; AstraZeneca: Honoraria; MethylGene: Research Funding; Pharmacyclics: Honoraria; Amgen: Honoraria; MEI Pharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; SecuraBio: Honoraria; Janssen: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria; NCCN: Other; LFR: Other. OffLabel Disclosure: Zanubrutinib is administered off-label in combination with venetoclax and obinutuzumab for patients with CLL/SLL.

BACKGROUND In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)–mutant lung cancers with untreated brain metastases. METHODS Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors). RESULTS Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue. CONCLUSIONS Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2017. © 2017 American Cancer Society.

Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04).Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

RET rearrangements are identified in 1% to 2% of non-small-cell lung cancers (NSCLCs).1,2 In patients with advanced, RET-rearranged lung cancers, systemic therapy can be highly active. We demonstrated previously that pemetrexed-based chemotherapy can achieve an objective response rate of 45% and a median progression-free survival (PFS) of 19 months.3 Furthermore, the activity of targeted therapy has improved dramatically with the introduction of selective RET inhibitors to the clinic. In early-phase testing, objective response rates with LOXO-2924 and BLU-6675 are 68% (26 of 38) and 50% (seven of 14), respectively. These outcomes exceed the modest activity observed previously with multikinase inhibitors such as cabozantinib6 and vandetanib.7 In contrast, the activity of immunotherapy in RET-rearranged lung cancers has not been well characterized. This represents a clear unmet need, given that all prior regulatory approvals of immune checkpoint inhibitors, either alone or in combination with chemotherapy, and in stage III or IV disease, have technically included patients with RET-rearranged lung cancers.8,9 Furthermore, although increasing levels of programmed death-ligand 1 (PD-L1) expression and high tumor mutational burden (TMB) have been associated with benefit from immune checkpoint blockade,10 the immunophenotype of RET-rearranged lung cancers and the role of PD-L1 and TMB status in relation to benefit with immunotherapy remain poorly described. We set out to characterize these factors.

BACKGROUND Mutations in human epidermal growth factor receptor 2 (HER2; also known as ERBB2) are found in approximately 2% of lung adenocarcinomas. The frequency and clinical course of brain metastases in this oncogenic subset are ill defined. METHODS Baseline and subsequent development of brain metastases was evaluated in consecutive patients with HER2-mutant (n = 98), epidermal growth factor receptor (EGFR)-mutant (n = 200), and KRAS-mutant lung cancers (n = 200). RESULTS At metastatic diagnosis, the odds ratio (ORs) for brain metastases was similar for patients whose tumors harbored HER2 mutations (19%) in comparison with patients with KRAS mutations (24%; OR for HER2 vs KRAS, 0.7; P = .33) but lower compared to patients with EGFR mutations (31%; OR for HER2 vs EGFR, 0.5; P = .03). Patients with lung cancer and HER2 mutations developed more brain metastases on treatment than patients with KRAS mutations (28% vs 8%; hazard ratio [HR], 5.2; P

Summary Background Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies. Methods In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0–1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination. Findings The derived model consisted of four factors (one point each; serum β2-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin Interpretation We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need. Funding Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.

KRAS G12D-mutant/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-κB pathway that can be down-regulated by the proteasome inhibitor bortezomib. Two exceptional responders were observed on prior clinical trials of bortezomib, both of whom had KRAS G12D-mutant NSCLC, prompting the initiation of this single-center phase 2 trial. Patients with advanced KRAS G12D-mutant NSCLC were eligible. Bortezomib was administered at 1.3 mg/m2 subcutaneously (days 1, 4, 8, 11; 21-d cycle) until progression or unacceptable toxicity. The primary objective was best objective response (RECIST v1.1). Sixteen patients with KRAS G12D-mutant lung adenocarcinomas were treated. Patients had a median pack year smoking history of 4 (range 0–45). A partial response (PR) was observed in one patient (−66% from baseline) and stable disease in five patients on the first stage of this study (overall response rate of 6%, 95% CI: 0.2–30.2), and further patients were not accrued. The median progression-free survival was 1 mo (95% CI: 1–6). The median overall survival was 13 mo (95% CI: 6–NA). The most common treatment-related adverse events were fatigue (38%) and diarrhea (26%). TP53 status did not predict response on exploratory testing. Of note, the patient with a PR had a unique subtype of lung adenocarcinoma—invasive mucinous adenocarcinomas (IMA)—and had rapid clinical improvement and substantial disease regression, which was also previously observed in two other patients with advanced KRAS G12D-mutant lung cancer with IMAs who received bortezomib on separate clinical trials. Exceptional responses to bortezomib can be achieved in KRAS G12D-mutant NSCLCs. KRAS G12D mutation alone, however, is not a robust predictor of response. Further evaluation should only be performed after further elucidation of other factors such as co-occurring alterations and histologic subtype such as IMA that may predict sensitivity to therapy.

Background Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. Patients and methods This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. Results Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92–21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). Conclusions Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.

Ipilimumab induces durable remission in about 15–20% of patients with metastatic melanoma. However, reliable predictors of response to ipilimumab are currently lacking. Whole-body metabolic tumor volume (wMTV) has been shown to be a strong prognostic factor in a variety of malignancies treated with chemotherapy, but few results have been reported for patients treated with immunotherapy. The purpose of this study was to investigate the prognostic value of wMTV and other metabolic parameters from baseline 18F-FDG PET/CT scans in patients with melanoma being treated with ipilimumab. The prognostic impact of wMTV, as well as mean standardized uptake values and total lesion glycolysis, was evaluated in 142 consecutive patients with melanoma treated with single-agent ipilimumab therapy. Metabolic parameters were dichotomized by their respective medians and correlated with overall survival (OS). In addition, the prognostic value of metabolic parameters combined with known clinical prognostic factors was evaluated in multivariate analyses. The median OS time in all patients was 14.7 months (95% CI 10.45–18.93 months). wMTV was a strong independent prognostic factor for OS (p = 0.001). The median survival in patients with a metabolic volume above the median was 10.8 months (95% CI 5.88–15.81 months) as compared with 26.0 months (95% CI 3.02–49.15 months) in patients with an MTV below the median. A multivariate model including wMTV and known clinical prognostic factors, such as age and the presence of brain metastases, further improved the identification of patient subgroups with different OS times. wMTV appears to be a strong independent prognostic factor in melanoma patients treated with ipilimumab, and can be determined semiautomatically from routine 18F- FDG PET/CT scans. wMTV, combined with clinical prognostic factors, could be used to personalize immunotherapy and in future clinical studies.

Introduction HER2 mutations occur in 1–3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor. Methods We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival. Results We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval [CI] 4–33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5–10); median time on treatment was 3 months (range 1–30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18–53 months). Conclusions Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted.

Purpose Human epidermal growth factor receptor 2 ( HER2, ERBB2)–activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial. Patients and Methods Patients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry. Results We treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane, and extracellular domains. Concurrent HER2 amplification was observed in two patients. HER2 immunohistochemistry ranged from 0 to 2+ and did not predict response, and responders had low HER2 protein expression measured by mass spectrometry. The median progression-free survival was 5 months (95% CI, 3 to 9 months). Toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated hepatic transaminases. No patient stopped therapy as a result of toxicity or died on study. Conclusion Ado-trastuzumab emtansine is an active agent in patients with HER2-mutant lung cancers. This is the first positive trial in this molecular subset of lung cancers. Further use and study of this agent are warranted.

Context BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). Objectives To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). Design This was a pilot trial that enrolled from June 2014 to January 2016. Setting Academic cancer center. Patients Patients with RAIR, BRAF mutant thyroid cancer. Intervention Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. Main outcome measure The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. Results Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). Conclusions Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

Introduction The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs. Methods Tumor tissues from 23 patients with WHO Type B2/B3 thymoma (n = 12) and thymic carcinoma (n = 11) were identified and clinical outcomes were annotated. The expression of membranous PD-L1 on tumor cells, CD3+ and CD8+ tumor infiltrating lymphocytes (TILs), co-stimulatory (CD137, GITR, ICOS), and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) were assessed semi-quantitatively using immunohistochemistry. Results PD-L1 positivity (≥ 25% of tumor membrane expression) was frequent in TETs (15/23, 65%), more common in thymomas compared to thymic carcinomas (p

OBJECTIVES: Thyroid transcription factor 1 (TTF-1) is routinely tested in the diagnostic evaluation of suspected lung cancers, is commonly expressed by lung adenocarcinomas, and may modulate lung cancer biology. We examined the role of TTF-1 as a predictive and prognostic marker in patients with advanced lung adenocarcinomas. MATERIALS AND METHODS: We analyzed clinical, pathologic, and molecular features, treatments received, and overall survival obtained from the medical records of 479 consecutive patients at a single site with stage IV lung adenocarcinomas and evaluable TTF-1 expression. TTF-1 expression was determined by immunohistochemistry using antibody 8G7G3/1. RESULTS AND CONCLUSION: TTF-1 expression was evaluable in 479 (75%) of all patients reviewed, and was positive in 383 (80%, 95% CI 76 to 83%). Clinicopathologic features were similar between TTF-1 positive and TTF-1 negative tumors, except EGFR mutations were more common in TTF-1 positive cases (24% vs 6%, p/= 80% (HR 0.62, p=0.0003) and receipt of first-line combination chemotherapy or targeted therapy (HR relative to single agent chemotherapy 0.59, p=0.05 and 0.51, p=0.05 respectively). Both patients with TTF-1 positive and TTF-1 negative cancers had longer durations of initial therapy when treated with pemetrexed-based chemotherapy. In patients with advanced lung adenocarcinomas, TTF-1 expression is associated with better survival but is not predictive of distinct benefit from pemetrexed-based chemotherapy.

e18025 Background: Rituximab (R), available as an intravenous (IV; R-IV) infusion or subcutaneous (SC; R-SC) injection, is used in the treatment of follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). This study evaluated real-world practice efficiency changes associated with the adoption of R-SC by studying differences in chair time by route of administration. Methods: We conducted a retrospective analysis of practice care delivery measures before and after adoption of R-SC at Memorial Sloan Kettering Cancer Center (MSKCC). Data for patients (pts) with FL, DLBCL, or CLL receiving R-based therapy from September 2016 to September 2018 were extracted from the electronic medical record. A linear mixed effect multivariate model with random intercept was used to analyze the association between treatment type (R-IV vs R-SC) and chair time (defined as the difference in pt room-in and room-out times) in the year prior to and following R-SC adoption at MSKCC. Model covariates included treatment time and location, therapy type (monotherapy vs combination), and pt demographics. Given the prolonged infusion time, patients’ first dose of R-IV was excluded from the analysis. Results: Data were collected during 6744 visits (3018 visits prior to R-SC adoption and 3726 after) for 1503 pts receiving R. Pts receiving R-IV combination therapy had a mean chair time of 203 minutes (min); overall, R-SC injection reduced chair time by a mean of 92 min (p < 0.001 vs R-IV). Monotherapy, regardless of route, reduced chair time by a mean of 30 min (p < 0.001) compared with combination therapy, and mean chair time was further reduced by 39 min (p < 0.001) for R-SC pts receiving monotherapy. Reductions in chair time increased over time following initial adoption of R-SC (p = 0.042), and were greater at the lymphoma-specific site than multispecialty oncology infusion centers (p < 0.001). Conclusions: Adoption of R-SC results in substantial time savings for both the pt and health system as measured by reduced chair time and improved pt throughput. Given increasing constraints on infusion chair space, increased utilization of R-SC may improve practice efficiency and pt access to care.

1565 Background: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare subtype of T-cell lymphoma, developing in in the fluid or capsule surrounding breast implants, primarily or exclusively in those with textured surfaces. Several prior series have estimated the risk of BIA- ALCL at 1/6920 - 1/3800 women in retrospectively defined cohorts (from diagnosed cases within national or pathology databases), approximating the population at risk from sales records or other estimates (Sirinvasa 2017; Loch-Wilkinson 2017; de Boer 2018). Methods: A prospective cohort study was conducted in the population that underwent breast reconstruction by a single surgeon at Memorial Sloan Kettering Cancer Center (MSKCC) from April 1993 to December 2017. Patients had long-term follow-up, and events related to implants were prospectively recorded. We identified all cases of BIA-ALCL by cross-checking data from internal clinical records, pathology records, and outside reports. Incidence rate per person-years and cumulative incidence when accounting for competing risk were calculated. 134 women who received smooth-surface implants were excluded from the analysis, since these implants have not been associated with BIA-ALCL. Results: From 1993 to 2017, 3546 patients underwent 6023 breast reconstructions using textured surface implants. All reconstructions were performed by a single surgeon (PGC) on patients enrolled in this study. To identify BIA-ALCL occurrence, clinical and pathological data were assessed from a prospective database. Median follow-up was 7 years (range, 3 days - 24.7 years). Eight women developed ALCL after a median exposure of 11.2 years (range, 8.3-15.8 years). Overall risk of BIA-ALCL in this cohort was 0.294 cases per 1000 person-years (1/443 women). Conclusions: This study, evaluating the risk of women with textured breast implants from a prospective database with long-term follow-up, demonstrated that the incidence rate of BIA-ALCL may be higher than previously reported. These results can help inform implant choice for women undergoing breast reconstruction.

9086 Background: Osimertinib (osi) demonstrated improved progression-free survival (PFS) over erlotinib as initial treatment (trmt) for EGFR-mutant (EGFR+) lung cancers. The addition of bevacizumab (bev) to erlotinib as initial trmt resulted in improved PFS compared to erlotinib alone (16 vs 10 months, HR 0.41). The phase 1 study of osi and bev confirmed the ability to combine osi and bev at full doses. Methods: The phase 2 study is assessing safety and efficacy of the combination. The primary endpoint is PFS at 12 months; secondary endpoints include overall response (ORR), overall survival (OS), and CNS PFS. All pts had interval CNS as well as systemic imaging. Pre-treatment and post-progression (PD) tumor tissue and interval plasma samples are being collected to identify mechanisms of resistance (MOR) and for biomarker assessment. Results: From Nov 2016 to May 2018, 49 pts were enrolled, including 6 pts from the phase 1. Median age: 60; Women 69%; Never-smokers 65%. 13 pts had CNS metastases (9 untreated, 5 measurable) prior to study initiation. 49 pts are eligible for response; 34/49 pts had a confirmed partial response (PR)(ORR 69%). PFS at 12 months is 0.70 (95% CI: 0.57-0.84), with 8/49 pts on study without PD for less than 12 months. All pts with measurable CNS disease had a PR in the CNS; PD in the CNS was uncommon (17%). 24 pts remain on study without PD; 2 are being treated beyond PD. Reasons for study discontinuation include PD (n = 16), resection of all sites of disease (n = 3), withdrawal of consent (n = 3), unrelated death (n = 2), toxicity (n = 1). The most frequent trtmt-related adverse events (any grade) were thrombocytopenia (61%), diarrhea (57%), hypertension (55%), and rash (47%). 24% required a dose reduction of osi, 18% discontinued bev and median doses of bev was 17. 9 pts have paired pre-trtmt and post-progression tissue biopsies; MOR identified include squamous cell (n = 2) and small cell (n = 1) transformation, PTEN loss, and CCNE amplification. Conclusions: Combination osi and bev was well-tolerated and efficacy to date supports further evaluation. Results of secondary endpoints including PFS, mechanisms of resistance, cfDNA data are forthcoming. A randomized study of osi compared to osi and bev is planned (EA5182). Supported by AstraZeneca Clinical trial information: NCT02803203.

Introduction: Several prognostic models for overall survival (OS) in chronic lymphocytic leukemia (CLL) have been developed, but none were derived for patients (pts) with relapsed or refractory (R/R) CLL treated in the era of novel agents. We used a comprehensive approach to derive and validate a novel risk model for OS in 2,475 pts with R/R CLL who received therapy in randomized phase 3 trials evaluating ibrutinib (IBR), idelalisib (IDELA), and venetoclax (VEN) vs control arms, or the Mayo Clinic CLL Database (MCCD). Methods: In collaboration with Janssen, Gilead, Pharmacyclics, and Genentech/Roche, the analysis included 2,475 pts from 6 multicenter randomized phase 3 trials or the MCCD. Trials included were: IBR plus bendamustine-rituximab (BR) vs placebo plus BR (HELIOS: NCT01611090), IBR vs ofatumumab (RESONATE: NCT01578707), IDELA plus BR vs placebo plus BR (Study 115: NCT01569295); IDELA plus rituximab vs placebo plus rituximab (Study 116: NCT01539512); IDELA plus ofatumumab vs ofatumumab (Study 119: NCT01659021); VEN plus rituximab vs BR (MURANO: NCT02005471). All pts had R/R CLL and required treatment by iwCLL criteria. The model-building dataset (n=969) included pts from HELIOS and RESONATE, and was randomly assigned to the IBR/chemoimmunotherapy (CIT) training dataset (n=727) and IBR/CIT internal-validation dataset(n=242). Three independent external validation datasets included IDELA/CIT (n=897), VEN/CIT (n=389), and MCCD (n=220). We applied univariate and multivariate analyses (MVA) to 28 candidate clinical/laboratory and genetic prognostic factors to derive the risk model in the training dataset. The primary endpoint was OS. We assessed the need for separate models for targeted agents by interactions with treatment in univariate analyses. We proceeded to develop a single model for all pts with R/R CLL, as only one candidate factor (del(13q), interaction p value We evaluated cutoffs for dichotomized covariates and for definition of risk groups after the final factors were selected. We fit a Cox regression on the training and internal/external validation datasets using the risk categories as the covariate to test the difference among the groups, and calculated the C-statistic as a measure of discrimination. Results: Of 11 selected factors with a significant univariate effect on OS (p We excluded number of prior therapies from the model, reasoning that its optimal cutoff might change with advances in CLL therapies. IGHV did not remain significant (p=0.0592) in MVA of 5 remaining prognostic factors. Notably, del(17p) was not independently prognostic for OS. The final risk model consisted of 4 prognostic factors: B2M ≥5 mg/L, LDH elevated, HGB Our risk model was prognostic for OS in the IBR/CIT training dataset (C-statistic 0.74 [95% CI 0.60-0.85]; log-rank p Conclusions: We present the first validated risk model for OS in R/R CLL in the era of targeted therapies. Our model consists of 4 readily available factors (B2M ≥5 mg/L, LDH elevated, HGB Figure. Figure. Disclosures Darif: Jannsen: Employment. Londhe:Jannsen: Employment. Xing:Gilead Sciences, Inc.: Employment. Mun:Genentech: Employment, Equity Ownership. Kay:Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Furman:Loxo Oncology: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Incyte: Consultancy, Other: DSMB; Acerta: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Hillmen:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Novartis: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Seymour:AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding. Jones:Celgene: Employment, Equity Ownership. Ferrante:Jannsen: Employment. Dreiling:Gilead: Employment. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Stark:Genentech: Employment. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Howes:Janssen: Employment. James:Pharmacyclics: Employment. Bhargava:Gilead: Employment. Zelenetz:Novartis/Sandoz: Consultancy; Abbvie: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding.

7520Background: Bruton’s tyrosine kinase (BTK) and PI3K inhibitors synergize effectively in both in vitro and in vivo models of B-cell non-Hodgkin lymphoma (Griner, et al, PNAS, 2014; Erdmann et al...

9049Background: Routine next generation sequencing (NGS) testing for patients with lung cancer allows the rapid identification of a broad array of targetable molecular drivers. We hypothesized that...

9042Background: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade. The impact of TMB on outcomes with targeted therapies has not been explored. We hypothesized th...

9081Background: HER2 mutations are oncogenic drivers in 3% of lung cancers. Here we describe the frequency and course of patients with HER2 mutant lung cancers with spread to brain and compare resu...

e21234Background: Liquid biopsy of circulating tumor DNA (ctDNA) by next generation sequencing (NGS) is widely adopted in clinical practice. ctDNA shedding across different lung cancer histologies,...

9034Background: In patients with RET-rearranged lung cancers, multikinase inhibitors (e.g. cabozantinib and vandetanib) and specific (e.g. pemetrexed-containing) chemotherapy regimens have documented activity. In contrast, PD-L1 expression, tumor mutational burden (TMB), and the treatment outcomes of immunotherapy are not well characterized in this genomic subset. Methods: Patients with a pathologically confirmed diagnosis of lung cancer harboring a RET rearrangement were identified between January 2012 and December 2017. PD-L1 expression was determined by IHC (E1L3N Clone). TMB was calculated in tumors that underwent NGS (Mutations/Mb, MSK-IMPACT). Objective response rate (ORR) to immunotherapy was evaluated by RECIST. Results: 74 patients with RET-rearranged lung cancers were identified. The median age was 63 (range 34-80 years), 55% were women, and 68% were never smokers. The majority (97%) had adenocarcinoma and 85% had metastatic disease. In patients with sufficient tissue for analysis, tumor PD-L1 e...

e20568Background: LCNEC is a biologically heterogeneous disease comprised of distinct subgroups characterized by genomic signatures of either SCLC or NSCLC (e.g. RB1 loss or retained). We assessed ...

9060Background: HER2 mutations are present in 3% of lung cancers. Response to immune checkpoint blockade (ICB) in this subset of lung cancers is unknown. We evaluate the landscape of PD-L1 and tumo...

9003Background: Treatment with PD-(L)1 inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of steroids may reduce efficacy of PD-(L)1 blockade. On-treatme...

e24181Background: Targeting HER2 alterations including mutation, amplification and protein overexpression has been an active area of new drug development. However, the relationships between these H...

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.

Importance Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well. Objective To estimate the burden of germline variants identified through routine clinical tumor sequencing. Design, Setting, and Participants Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014. Main Outcomes and Measures The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors. Results The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual’s cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non–cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99.9%; 95% CI, 99.6%-99.9%). Conclusions and Relevance Germline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations.

9029 Background: Little data is available to guide clinical management of individuals with less common oncogenic drivers such as exon 18 mutations (ex18m) in EGFR. To better understand the impact of these rare mutations on treatment outcomes, we reviewed clinicopathologic data in patients (pts) with ex18m treated with tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancers. Methods: Pts with EGFR ex18m were detected via molecular diagnostics using Sequenom™, FoundationOne™ or MSK IMPACT™ NGS testing from 2003-2016. We reviewed their clinical data for molecular alterations in EGFR, treatment outcomes in response to TKI (time on treatment) and median overall survival (OS). Results: We identified mutations in EGFR ex18m in 63 pts. Median age at diagnosis was 68; 63% were women; 29% never smokers. Overall, 74 ex18m were found in 63 pts, including: G719A = 38, G719S = 11, G719C = 8, E709K = 6, E709_T710delinsD = 6, E709A = 3, G719D = 2. E709 and G719 co-mutations in ex18 were found in 9 pts, and 1 pt was found to have 3 separate tumors, each with a distinct ex18m. 29/63 (46%) patients with ex18m had a co-occurring EGFR mutation: 9 with another ex18m; 20 with ex19-21m. Using our IMPACT NGS, the median number of co-mutations was 8 (range 1-17). Two out of 63 pts had a pre-treatment T790M mutation. The 25 pts with non-metastatic disease presented in the following stages: IA = 19; IB = 3; IIB = 1; IIIA = 2; IIIB = 2. 34/38 pts with metastatic disease were treated with the following first-line EGFR-TKIs: erlotinib = 28, afatinib = 5, osimertinib = 1. Median duration on TKI treatment in months was: erlotinib = 10 mo, (range 1-25), afatinib = 3 mo (range 2-9), osimertinib = 4 mo. Median OS from the date of diagnosis of metastatic disease was 22 months (95% CI 18-29). In comparison, a similar cohort of pts with sensitizing EGFR exon19del/L858R mutations had a median OS of 31 months (95% CI 28-33) (Naidoo Cancer2015). Conclusions: Almost half of ex18m occur concurrently with another EGFR mutation. Overall, ex18m pts have a shorter median OS when compared to similar patient cohorts. EGFR-TKIs appear to be an effective treatment for pts with ex18m in EGFR-mutant lung cancers.

9071 Background: Human epidermal growth factor 2 ( HER2, ERBB2) mutations have been identified as oncogenic drivers in 3% of lung cancers. Afatinib is an irreversible tyrosine kinase inhibitor of HER1 (EGFR), HER2 and HER4 and has been described in case reports to have activity in HER2-mutant lung cancers. However, there is little data to inform the clinical use of afatinib. Methods: We reviewed patients with metastatic HER2-mutant lung cancers treated with afatinib among 7 institutions between 2009 and 2016. The primary endpoint was investigator assessed overall response rate using RECIST v1.1. Other data collected included types of HER2mutations, duration of afatinib treatment and overall survival. Results: We identified 27 patients with metastatic HER2-mutant lung cancers treated with afatinib. Median age at diagnosis was 63 (range 40 to 84); majority were men (n = 16; 59%) and never-smokers (n = 18; 67%). All tumors were adenocarcinomas, and the majority were Stage IV at initial diagnosis (n = 16; 59%). A 12-base pair (bp) in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 16 patients (59%). In addition, there were three 9-bp insertions, two 3-bp insertions and two single bp substitutions (L755F and D769H) in exon 20; two single bp substitutions (S310F) in exon 8; one exon 17 V659E mutation; and one single-nucleotide polymorphism (Ile655Val). Median duration on afatinib was 2 months (range 1 to 27); median line of prior treatment was 3 (range 1 to 6). Eight patients had previously received trastuzumab prior to afatinib and one concurrently with afatinib. Overall response rate was 15% (n = 4; 95% CI 4 to 34%); the four partial responses lasted 5, 5, 6 and 10 months. The 3 longest partial responders had a 12-bp insertion in exon 20 (YVMA); the remaining partial responder had a 9-bp insertion in exon 20. Median overall survival from diagnosis date of metastatic disease was 23 months (95% CI 18 to 62). Conclusions: Afatinib produced partial responses in 15% of patients with metastatic HER2-mutant lung cancers, including insertion YVMA. Our findings confirm the activity of afatinib and provide data supporting a framework for its use in the care of patients with HER2-mutant lung cancers.

e20673 Background: Third generation (3rd gen) epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat EGFR T790M-mediated resistance to EGFR TKIs by inhibiting EGFR T790M, as well as EGFR L858R and EGFR exon 19 deletions. The mechanisms of resistance to third-generation EGFR TKIs are largely unknown and clinical cross-resistance among 3rd gen EGFR TKIs has not been routinely evaluated. Osimertinib is an FDA-approved irreversible 3rd gen EGFR TKI. In patients with EGFR T790M mutant NSCLC, the response rate (ORR) to osimertinib is 61%. EGF816 is a covalent, irreversible, 3rd gen EGFR TKI in clinical development. In early phase data of EGF816, the ORR was 47% and disease control rate was 87% in patients with EGFR T790M mutant NSCLC. To assess clinical cross-resistance between EGF816 and osimertinib, we evaluated the clinical outcomes of patients treated with osimertinib in patients previously treated with EGF816 during the phase I/II trial. Methods: Patients with metastatic EGFR mutant lung adenocarcinoma were identified who were previously treated with EGF816 and received osimertinib after progression of disease on EGF816 (NCT02108964). All patients had documented T790M mutation prior to treatment with EGF816. The best overall response to osimertinib was determined by RECIST 1.1 criteria. Duration of clinical benefit was defined as duration of osimertinib therapy. Results: Fourteen (3 men, 11 women, median age 58 [range 33-77]) patients met eligibility criteria at our centers. The ORR to subsequent osimertinib therapy was 14% (1 CR, 1 PR, 8 SD, 4 POD). Patients continued treatment with osimertinib for a median of 9 months (95% CI 3.8-10.1, [median follow up 11 months, range 1-13 months]). 5 patients are still on osimertinib to date (one patient each 3+, 6+, 8+, 11+, and 12+ months). Conclusions: This series suggests a potentially meaningful clinical benefit for patients with sequential therapy with two different third-generation EGFR inhibitors, emphasizing the importance of understanding resistance mechanisms (genetic alteration of target, bypass signaling, pharmacology, etc.) and raising the possibility of the need for multiple third generation EGFR TKIs in clinical practice.

9039 Background: Clarke (Neurooncol 2010) reported responses with intermittent high pulse doses of erlotinib (leading to higher concentrations in CSF) given to patients with EGFR-mutant central nervous system metastases developing on standard erlotinib doses. In a phase 1 study of pulse-continuous dose erlotinib, no patient developed progression in existing or new brain or leptomeningeal metastases (Yu Ann Oncol 2016). This phase 2 trial tested pulse-continuous dose erlotinib in patients with lung cancers with EGFRmutations with brain metastases. Methods: Patients had no prior EGFR TKI or radiation to the brain and at least 1 target brain metastasis. All received initial daily "pulse" doses of erlotinib 1200 mg days 1&2 and "continuous" 50 mg doses days 3-7 (doses and schedule from the Yu Phase 1 study), weekly until progression. The co-primary endpoints were overall and brain metastasis response by RECIST 1.1. Results: We enrolled 19 patients with EGFR-mutant lung cancers: median age 61yrs (range 45-80), 74% women, 95% Karnofsky PS ≥80%, 1 leptomeningeal disease, 33% prior pemetrexed-based chemotherapy. The median size of target brain metastases was 13 mm (range 10-19 mm). 32% were on dexamethasone for cerebral edema. The partial response rate overall was 74% (95% CI 51-89%) and also 74% in brain metastases. Of 10 patients with progression, 9/10 occurred in non-brain sites (4 EGFRT790M, 1 with progression in brain as well), 1 with leptomeningeal. The median progression free survival was 10 mo (range 7-NR mo). Pulse doses were reduced in 68% (median delivered pulse dose 1050 mg days 1&2, range 600-1200 mg). Incidences of any gradeof rash and diarrhea were 84% and 63% respectively. There were no grade 4 or 5 toxicities. Conclusions: Pulse-continuous dose erlotinib alone controlled brain and leptomeningeal metastases in 89% (95% CI 67-98%) of patients with EGFR-mutant lung cancers with central nervous system spread pretreatment, with an overall response rate of 74% and progression free survival and rates of rash and diarrhea comparable to series with erlotinib 150 mg daily. Supported by Astellas, CA 129243, CA 008748. NCT01967095 Clinical trial information: NCT01967095.

11536 Background: Liquid biopsy for plasma ctDNA NGS is a rapidly evolving science. Plasma ctDNA assays are commercially available and are increasingly adopted in the community with a paucity of evidence-based guidance. We set out to study the optimal timing and utility of plasma ctDNA NGS in clinic. Methods: Pts with advanced NSCLC who were driver unknown, defined as not having prior tissue NGS or clinical concern for tumor heterogeneity that may affect treatment decisions, were eligible. Peripheral blood was collected in a Streck tube (10mL), DNA extracted, and subjected to a bias-corrected hybrid-capture 21 gene targeted NGS assay in a CLIA lab with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1% (ResolutionBio Bellevue, WA). Pts also had concurrent tissue NGS via MSK IMPACT. Clinical endpoints included detection of oncogenic drivers in plasma, ability to match pts to targeted therapy, concordance and turnaround time of plasma and tissue NGS. Results: Forty-one pts were prospectively accrued. Plasma ctDNA detected an oncogenic driver in 39% (16/41) of pts, of whom 17% (7/41) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insertionYVMA, BRAF L597Q and MET exon14. Mean turnaround time for plasma was 7 days (4-12) and 28 days (20-43) for tissue. Plasma ctDNA was detected in 56% (23/41) of pts; detection was 40% (8/20) if blood was drawn on active therapy and 71% (15/21) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.28, 95% CI 0.06 - 1.16; p = 0.06). All pts had concurrent tissue NGS; of the 10 samples resulted, there was 100% driver concordance between tissue and plasma in pts drawn off therapy. Conclusions: In pts who were driver unknown or who had clinical concern for tumor heterogeneity, plasma ctDNA NGS identified a variety of oncogenic drivers with a short turnaround time and matched them to targeted therapy. Plasma ctDNA detection was more frequent at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific, but a negative finding may still require tissue biopsy.

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]