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Purpose:Inhibition of the VEGFR-2 blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor receptor MET. Here we report results of the phase Ib/II study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET mAb emibetuzumab.Patients and Methods:A 3+3 dose escalation of emibetuzumab plus ramucirumab (phase Ib) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase II dose and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry (IHC).Results:A total of 97 patients with solid tumor [6 phase Ib, 16 gastric or gastroesophageal junction adenocarcinoma, 45 hepatocellular carcinoma (HCC), 15 renal cell carcinoma, and 15 non–small lung cancer] received emibetuzumab at 750 or 2,000 mg flat dosing plus ramucirumab at 8 mg/kg every 2 weeks. No dose-limiting toxicities were observed. Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug–drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest antitumor activity was noted in HCC with a 6.7% overall response rate, 60% disease control rate, and 5.42 months (95% confidence interval, 1.64–8.12) progression-free survival (PFS). HCC with high MET expression showed improved PFS with approximately 3-fold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression.Conclusions:Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.

Preclinical Data for Emibetuzumab and DC-101

Dose Adjustments

Progression-free Survival in Gastric Cancer population, MET +23

Exploratory Analysis of Different MET Expression Cut-offs in HCC Cohort

Summary of Serious Adverse Events by System Organ Class and Preferred Term

Table S1:Summary of baseline pathological diagnosis; Table S2:Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Capsule Formulation; Table S3: Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Tablet Formulation

Supplementary figures titles and legends are placed in this document

Trial Profile

Patient disposition

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles.Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

Purpose:We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non–small cell lung cancer (NSCLC).Patients and Methods:This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.Results:Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6–21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5–19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.Conclusions:Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.See related commentary by Garon, p. 905

Supplementary Tables 1-3

Treatment-related Adverse Events by CTCAE Grade and MedDRA System Organ Class and Preferred Term

Ramucirumab Serum Concentrations After Ramucirumab Administration

Summary of Death and Adverse Events of Special Interest

Confirmed Best Overall Central Nervous System Response

Overall survival

Purpose: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non–small cell lung cancer (NSCLC). Patients and Methods: This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. Results: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6–21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5–19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification. Conclusions: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC. See related commentary by Garon, p. 905

Background: Combination treatments of CDK4 & 6 inhibitors (CDK4 & 6i) with endocrine therapy (ET) have improved outcomes in patients with HR-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Aside from estrogen receptor positivity (ER+), predictive biomarkers of clinical benefit from CDK4 & 6i in combination with ET remain elusive. We assessed clinical outcomes by genomic alterations detected in baseline circulating tumor DNA (ctDNA) from patients treated with abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) versus placebo plus NSAI in the Phase 3 study MONARCH 3 (NCT02246621). Methods: MONARCH 3 randomized 493 postmenopausal women with HR+, HER2- ABC who had no prior systemic therapy in the advanced setting to treatment with abemaciclib plus NSAI or placebo plus NSAI. Biomarker analysis of baseline ctDNA was an exploratory objective; plasma was analyzed by the Guardant360 next-generation sequencing (NGS)-based assay to identify potential tumor-related (i.e., somatic) genomic alterations including point mutations (SNV), indels, amplifications, and fusions in over 70 cancer-related genes. Genomic alterations detected in baseline ctDNA were associated with clinical outcomes including progression-free survival (PFS) and objective response rate (ORR). Results: Baseline ctDNA results were available for 295 patients (201 abemaciclib; 94 placebo) with 83% of patients harboring one or more detectable genomic alterations. Commonly altered genes of interest (% frequency) detected in baseline ctDNA included: PIK3CA (38%); TP53 (26%); EGFR (15%); FGFR1 (12%); NF1 (12%); MYC (9%); CCND1 (9%); ESR1 (5%).Overall, patients treated with placebo plus NSAI who harbored detectable ctDNA genomic alterations had shorter median PFS compared to patients without detectable genomic alterations, as shown in the Table (14.9 months [95% CI: 11.0-23.1] vs 19.2 months [95% CI 9.4-NR]). Moreover, genomic alterations in EGFR, FGFR1, MYC, and CCND1 were associated with median PFS Conclusions: In this exploratory subgroup analysis, the presence of detectable ctDNA genomic alterations was associated with shorter PFS with placebo plus NSAI. Consistently, abemaciclib added to NSAI improved outcomes for genomically identified subgroups. In contrast to prior studies, there was no subgroup (e.g., patients harboring FGFR1 alterations) that did not derive benefit from abemaciclib, supporting the efficacy of abemaciclib, including in difficult to treat tumors. These findings are hypothesis-generating and warrant further investigations in clinical studies of CDK4 & 6i in combination with ET. TableAbemaciclib + NSAIPlacebo + NSAIEvents, n/NMedian PFS (95% CI)Events, n/NMedian PFS (95% CI)Hazard Ratio (95% CI)OVERALLITT population170 / 32828.2 (23.7 - 33.9)123 / 16514.8 (11.2 - 19.2)0.52 (0.42 - 0.66)TR population93 / 20138.7 (31.1 - NR)71 / 9416.5 (11.7 - 23.1)0.45 (0.33 - 0.61)Any Gene AlterationDetected83 / 16634.1 (27.2 - 40.0)62 / 7914.9 (11.0 - 23.1)0.47 (0.34 - 0.66)Not detected10 / 35NR (36.4 - NR)9 / 1519.2 (9.40 - NR)0.31 (0.13 - 0.78)TP53Detected29 / 5327.0 (14.1 - NR)19 / 2315.4 (5.7 - 30.4)0.53 (0.30 - 0.95)Not detected64 / 14839.9 (34.1 - NR)52 / 7117.5 (11.7 - 24.2)0.42 (0.29 - 0.60)EGFRDetected10 / 26NR (32.4 - NR)16 / 1710.9 (2.1 - 24.7)0.20 (0.09 - 0.47)Not detected83 / 17536.4 (27.7 - NR)55 / 7717.6 (14.6 - 25.5)0.52 (0.37 - 0.73)FGFR1Detected15 / 2532.8 (10.1 - NR)10 / 117.6 (1.9 - 15.4)0.37 (0.16 - 0.85)Not detected78 / 17639.9 (31.1 - NR)61 / 8319.2 (14.6 - 26.5)0.45 (0.32 - 0.63)NF1Detected10 / 2435.9 (27 - NR)8 / 1014.6 (1.6 - 33.4)0.33 (0.13 - 0.84)Not detected83 / 17738.7 (30.8 - NR)63 / 8417.5 (11.7 - 24.2)0.47 (0.33 - 0.65)MYCDetected11 / 1720.1 (5.5 - NR)9 / 106.5 (1.2 - 15.7)0.33 (0.13 - 0.86)Not detected82 / 18438.9 (32.9 - NR)62 / 8419.2 (14.6 - 26.5)0.45 (0.32 - 0.63)CCND1Detected8 / 1632.8 (5.5 - NR)10 / 107.2 (3.6 - 9.0)0.28 (0.10 - 0.77)Not detected85 / 18538.7 (31.1 - NR)61 / 8417.6 (14.6 - 25.5)0.48 (0.34 - 0.67)n = number of patients with events; N = total number of patients in the corresponding population and treatment arm; NR = not reached. TR population consists of patients in the ITT population from whom a valid baseline ctDNA result has been obtained. Citation Format: Matthew P Goetz, J. Thaddeus Beck, Mario Campone, Sara Hurvitz, Seock-Ah Im, Stephen Johnston, Antonio Llombart-Cussac, Miguel Martin, Joohyuk Sohn, Masakazu Toi, Lacey M Litchfield, Hillary T Graham, Hong Wang, Sameera R Wijayawardana, Valerie M Jansen, Angelo Di Leo. Efficacy of abemaciclib based on genomic alterations detected in baseline circulating tumor DNA from the MONARCH 3 study of abemaciclib plus nonsteroidal aromatase inhibitor [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-06.

Background: Abemaciclib is a selective inhibitor of CDK4 & 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- metastatic breast cancer (MBC) patients (pts) in combination with endocrine therapy or as monotherapy. Recent studies have demonstrated the potential for CDK4 & 6 inhibitors, including abemaciclib, to promote anti-tumor immunity. Schaer et al., (Cell Reports 2018) showed that abemaciclib monotherapy results in upregulation of antigen presentation on tumor cells and increases T-cell activation. These activities synergized with anti-PD-L1 therapy to further enhance immune activation leading to complete tumor rejection in murine tumor models (Schaer et al., Cell Reports 2018). In this exploratory analysis, we evaluated the early and late immune-modulating effects of abemaciclib in the neoadjuvant study neoMONARCH (NCT02441946). Methods: NeoMONARCH is a Phase II trial in women with stage I-IIIB HR+, HER2- BC evaluating neoadjuvant treatment with 2 weeks of abemaciclib, alone or in combination with anastrozole (abemaciclib+ANZ), or ANZ alone. All patients received 14 weeks of abemaciclib +ANZ after the first 2 weeks of treatment. Serial biopsies were collected at 3 time points: Baseline (BL) - prior to treatment, Early - after 2 weeks of therapy with abemaciclib, ANZ, or abemaciclib+ANZ, and Late – after 2 weeks of initial therapy followed by 14 weeks of abemaciclib+ANZ. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor biopsies at each time point and subjected to whole transcriptome RNA sequencing. The curated data were subjected to statistical analysis using ANOVA tests followed by pathway analysis using Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). Results: Consistent with the known activity of abemaciclib to inhibit the cell cycle, we observed at the early and late time points a significant treatment induced downregulation of genes related to mitotic spindle organization, replication stress response, G2M checkpoint, and E2F targets. Abemaciclib treatment for 2 weeks, alone or in combination with ANZ, followed by 14 weeks of combination therapy was associated with upregulation of gene expression signatures related to T-cell immune response and antigen presentation. Importantly, this phenomenon was notobserved with 2 weeks of ANZ treatment alone followed by 14 weeks of combination therapy. Conclusion: These data lend support that continuous inhibition of CDK4 & 6 signaling by abemaciclib treatment leads to prolonged cell cycle arrest resulting in tumor cell apoptosis & senescence, which then leads to an enhanced immune activation. Citation Format: Hurvitz S, Martin M, Press M, Wijayawardana S, Brahmachary M, Ebert PJ, Young S, Jansen V, Slamon D. Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-10.

Background: Combination treatments of endocrine therapy (ET) with CDK4 & 6 inhibitors have improved outcomes in patients with HR+ advanced breast cancer, both as initial therapy and after progression on ET. Abemaciclib is a selective inhibitor of CDK4 & 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- MBC patients (pts), alone or in combination with ET. However, biomarkers that predict benefit from this class of agents remain elusive. We previously reported in the phase II neoadjuvant neoMONARCH study (NCT02441946), after 2 weeks of treatment, abemaciclib, alone or in combination with anastrozole (ANZ), led to a significantly higher rate of complete cell cycle arrest (CCCA, defined as Ki67 ≤2.7%) compared to ANZ alone in early stage HR+, HER2- breast cancer (Martin et al. SABCS 2017). As an exploratory aim of this trial, we evaluated the gene expression analyses in order to determine markers of sensitivity and resistance to therapy. Methods: Serial biopsies were collected at 3 time points: Baseline (BL) - prior to treatment, Early – after 2 weeks of therapy with abemaciclib, ANZ, or abemaciclib+ANZ, and Late – after 2 weeks of initial therapy followed by 14 weeks of abemaciclib+ANZ. RNA was extracted from FFPE tumor biopsies at each timepoint and subjected to a Cell Cycle Associated Gene (CCAG) expression panel using the Modaplex® platform and whole transcriptome RNA sequencing. Ki67 was measured at each time point by immunohistochemistry (IHC). Tumors were categorized by the post-treatment Ki67 expression as either sensitive (Ki67 ≤2.7) or resistant (Ki67 ≥7.4), based upon the IMPACT and POETIC studies. Additionally, tumors intrinsically resistant/sensitive to therapy were also identified. Results: ANZ-treated tumors that did not achieve CCCA at 2 weeks (N= 8) displayed higher expression of the cell cycle associated genes FOXM1, E2F1, TOPO2A, and RRM2. The addition of abemaciclib to ANZ decreased gene expression in a majority of the tumors (N=5, 62.5%). Tumors intrinsically resistant to treatment with abemaciclib+ANZ displayed persistently elevated levels of cell cycle associated genes compared to sensitive tumors. Finally, gene expression signature of Rb loss-of-function (Rbsig) and RB1 gene expression levels were associated with sensitivity to abemaciclib. Conclusion: On-treatment Ki67 indicated treatment sensitivity and correlated with cell cycle associated gene expression in sensitive and resistant tumors. These exploratory analyses suggest that gene expression analyses may identify genomic markers for abemaciclib and ET treatment sensitivity and may help inform in which tumors to use abemaciclib. Citation Format: Hurvitz S, Martin M, Wijayawardana S, Brahmachary M, Ebert PJ, Young S, Jansen V, Slamon D. Markers of response to CDK4 & 6 inhibition from neoMONARCH: A phase II neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-08.

Purpose: Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.Patients and Methods: Patients were given prexasertib 105 mg/m2 as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.Results: Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non–small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9–4.2] for SCC of the anus, 1.6 months (90% CI, 1.4–2.8) for SCCHN, and 3.0 months (90% CI, 1.4–3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.Conclusions: Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m2 was confirmed as the recommended phase II dose. Clin Cancer Res; 24(14); 3263–72. ©2018 AACR.

BACKGROUND: Mutations (mt) in PIK3CA have been implicated in resistance to endocrine therapy (ET) in HR+ advanced breast cancer (ABC). In the MONARCH 2 study the addition of abemaciclib to fulvestrant (fulv) demonstrated a clinically meaningful and statistically significant median overall survival (OS) benefit of 9.4 months (mos) (HR 0.757, p=0.01), in addition to prolonging time to chemotherapy (TTC) (Sledge et al. JAMA Oncology 2019). We previously showed that abemaciclib plus fulv demonstrated improvement in progression-free survival (PFS) regardless of PIK3CA mt status, with a numerically larger magnitude of benefit for patients (pts) with PIK3CA mt in baseline circulating tumor DNA (ctDNA; Tolaney et al. AACR 2019). Here, we assessed the OS, TTC, and chemotherapy-free survival (CFS) in patients with and without PIK3CA mt in MONARCH 2. METHODS: MONARCH 2 (NCT02107703) was a global, randomized, double-blind phase III trial of abemaciclib plus fulv or placebo plus fulv in pre-/perimenopausal (with ovarian suppression) and postmenopausal women with ET resistant HR+, HER2- ABC. Results of PIK3CA mt status (E542K; E545K; H1047L; H1047R) from baseline ctDNA were available for 238 patients. Exploratory analyses of OS, TTC, and CFS were assessed in pts with and without PIK3CA mt using the Cox Interaction Model including treatment, PIK3CA mt status and treatment by PIK3CA interaction term. RESULTS: Abemaciclib plus fulv demonstrated a similar OS benefit for pts with PIK3CA mt (HR: 0.57; 95% CI: 0.34, 0.96) and for pts with PIK3CA wild-type (HR: 0.56; 95% CI: 0.34, 0.91) compared with placebo plus fulv. Median TTC and CFS were longer in the abemaciclib plus fulv arm compared with the placebo plus fulv arm both in pts with detectable PIK3CA mt and in pts without PIK3CA mt, as shown in Table 1. Table 1.PIK3CA mutantPIK3CA wild-typeAbemaciclib +Fulvestrant (n=58)Placebo + Fulvestrant (n=38)Hazard Ratio (95% CI)Abemaciclib + Fulvestrant (n=91)Placebo + Fulvestrant (n=51)Hazard Ratio (95% CI)Interaction p-valueOverall Survival Median (95% CI)44.5 mos (31.0, NR)33.8 mos (24.2, 41.7)0.57 (0.34, 0.96)55.5 mos (47.7, 55.5)41.7 mos (29.4, 49.7)0.56 (0.34, 0.91)0.949Time to Chemotherapy Median (95% CI)39.2 mos (24.6, NR)19.2 mos (6.7, NR)0.65 (0.37, 1.18)NR (34.3, NR)19.2 mos (12.0, 31.1)0.50 (0.31, 0.78)0.463Chemotherapy-Free Survival Median (95% CI)25.8 mos (16.0, 42.1)12.8 mos (5.2, 33.2)0.63 (0.39, 1.03)36.9 mos (20.7, NR)19.2 mos (12.0, 29.4)0.53 (0.35, 0.80)0.588CI = confidence interval; NR = not reached; mos = months CONCLUSIONS: In this exploratory analysis of MONARCH 2, abemaciclib plus fulv demonstrated benefit in OS, TTC, and CFS in patients with and without PIK3CA mutations. Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Hatem Soliman, Lacey M. Litchfield, Hong Wang, Sameera R. Wijayawardana, Valerie M. Jansen, George W. Sledge. Clinical outcomes of patients with PIK3CA mutations in circulating tumor DNA: Update from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 766.

RELAY (NCT02411448) showed a superior progression free survival benefit with RAM+ERL versus (v) PBO+ ERL (mPFS 19.4 vs 12.4mo, HR 0.59, p-value TablePts (≥2 in either treatment group) with treatment emergent alterationsaPop1bPop2bGene NameRAM+ERL (n=36)PBO+ERL (n=60)p-valuecRAM+ERL (n=98)PBO+ERL (n=129)p-valuecEGFRd16 (44)33 (55).3227 (28)47 (36).16TP538 (22)7 (12).1717 (17)16 (12).30NF15 (14)1 (2).027 (7)3 (2).08APC4 (11)1 (2).055 (5)3 (2).26MET3 (8)5 (8)1.006 (6)7 (5).82KRAS2 (6)3 (5).917 (7)3 (2).08FGFR22 (6)2 (3).603 (3)3 (2).73GNAS2 (6)0.052(2)1 (1).41BRAF1 (3)6 (10).163 (3)6 (5).54PI3KA1 (3)4 (7).391 (1)7 (5).06BRCA203 (5).094 (4)6 (5).84ERBB21 (3)3 (5).594 (4)4 (3).69AR02 (3).171 (1)2 (2).73CDK61 (3)2 (3).881 (1)2 (2).73RB11 (3)1 (2).722 (2)3 (2).88CDK41 (3)1 (2).721 (1)2 (2).73SMAD41 (3)1 (2).721 (1)2 (2).73KIT1 (3)1 (2).723 (3)1 (1).19PTEN1 (3)2 (3).882 (2)2 (2).78ARID1A1 (3)1 (2).723 (3)3 (2).73FGFR11 (3)0.162 (2)1 (1).41MAP2K11 (3)0.162 (2)0.07MAPK31 (3)0.162 (2)0.07MTOR01 (2).332 (2)1 (1).41MYC1 (3)0.162 (2)2 (2).78RET00–2 (2)0.07ROS100–2 (2)0.07STK1100–1 (1)2 (2).73Evaluable baseline NGS results were obtained for 390 out of 449 ITT patients (87%).aPts are included in more than one row if alterations arose in more than one gene.bAnalysis population 1 (Pop1, N=96) had disease progression by the 30-day post treatment discontinuation follow-up and had detectable EGFR ex19del or ex21.L858R mutation in baseline and 30 day follow-up blood samples. There is a greater confidence that alterations related to mechanisms of resistance would be detectable in this population since the patients had all progressed by 30-day follow-up and since the EGFR ex19del and ex21.L858R were detectable as shed circulating tumor DNA in the blood. Analysis population 2 (Pop2, N=227) had discontinued study treatment for any reason by the 30-day post treatment discontinuation follow-up and had any alteration detectable at baseline and at 30 day follow-up. Pop2 is a larger population (includes all Pop1 pts) and offers the opportunity to detect less common TE alterations that may not be found in the smaller Pop1. Seven (19%) RAM+ERL v 19 (32%) PBO+ERL of Pop1 and 33 (34%) v 59 (46%) of Pop2 pts had not acquired any of the evaluated alterations.cFisher's exact testdIncludes T790M; the frequencies of TE T790M in RAM+ERL v PBO+ERL for Pop1 were 42% v 50%, respectively, and for Pop2, 19% v 25% Citation Format: Edward Garon, Martin Reck, Kazuto Nishio, John Victor Heymach, Makoto Nishio, Silvia Novello, Luis Paz-Ares, Sanjay Popat, Santiago Ponce Aix, Sameera Wijayawardana, Rebecca R. Hozak, Carla Visseren-Grul, Kazuhiko Nakagawa. RELAY, ramucirumab plus erlotinib (RAM+ERL) versus placebo plus erlotinib (PBO+ERL) in previously untreated EGFR mutation-positive metastatic NSCLC: Next generation sequencing (NGS) results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT215.

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

BACKGROUND: Mutations in PIK3CA and ESR1 have been implicated in resistance to endocrine therapy in HR+ metastatic breast cancer. Herein, we assessed the clinical significance of PIK3CA and ESR1 mutations from ctDNA and FFPE samples from patients treated with abemaciclib plus fulvestrant and placebo plus fulvestrant. METHODS: Baseline plasma samples (n = 334) and FFPE tumor samples (n = 434) from 669 patients enrolled in MONARCH 2 were analyzed. Extracted DNA was analyzed by droplet digital PCR for four hotspot mutations of PIK3CA (E542K; E545K; H1047L; H1047R) and ESR1 (D538G; Y537C; Y537N; Y537S). Samples that failed DNA QC or where mutation status could not be determined were excluded from analysis. RESULTS: PIK3CA mutations were detected in 96 (40.3%) of 238 plasma samples and 133 (39.9%) of 333 FFPE samples. H1047R was the most frequent mutation followed by E545K, E542K, and H1047L. The concordance of PIK3CA mutations in ctDNA and FFPE samples was 62.8%. ESR1 mutations were detected in 190 (64.4%) of 295 plasma samples and 15 (4.4%) of 344 FFPE samples. D538G was the most frequent mutation followed by Y537C, Y537N, and Y537S. The concordance of ESR1 mutations in ctDNA and FFPE samples was 37.1%; this rate of detection of ESR1 mutations in ctDNA and FFPE samples is explained in part by the site of the biopsy (primary vs metastatic). Co-mutations in PIK3CA and ESR1 were observed in 86 (36.1%) plasma and 5 (1.5%) FFPE samples. Finally, we examined the relationship of PIK3CA and ESR1 mutation status and benefit from abemaciclib therapy as shown in Table 1. CONCLUSIONS: PIK3CA and ESR1 mutations in ctDNA but not in archived FFPE samples correlated with response to abemaciclib, confirming the potential use of ctDNA analysis. The addition of abemaciclib to fulvestrant in MONARCH 2 demonstrated improvement in PFS regardless of PIK3CA or ESR1 status; however, the magnitude of benefit was numerically greater for patients with tumors harboring PIK3CA/ESR1 mutations. Table 1.Abemaciclib + FulvestrantPlacebo + FulvestrantMutation Status (Plasma)nMedian PFS (95% CI)nMedian PFS (95% CI)Hazard Ratio (95% CI)PIK3CA wild-type9120 (14, NA)5112.7 (7.9, NA)0.68 (0.42, 1.09)PIK3CA mutant5815 (9.4, NA)385.7 (3.8, 15)0.46 (0.27, 0.78)ESR1 wild-type7216.3 (12.4, 22.8)3311.6 (7.4, 23.1)0.69 (0.41, 1.18)ESR1 mutant11821.9 (15, NA)7210.3 (5.7, 15.6)0.49 (0.33, 0.73) Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Antonio Llombart-Cussac, Hatem Soliman, Lacey M. Litchfield, Sameera Wijayawardana, Tammy Forrester, Valerie M. Jansen, George W. Sledge. Clinical significance of PIK3CA and ESR1 mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4458.

Background: Abemaciclib is a selective oral inhibitor of CDK4 and CDK6. Dosed on a continuous schedule, abemaciclib showed evidence of antitumor clinical activity in patients (pts) with metastatic BC in monotherapy or in combination with non-steroidal aromatase inhibitor (NSAI) or fulvestrant. NeoMONARCH (NCT02441946) is a Phase 2 trial in women with stage I-IIIB, HR+/HER2- BC evaluating neoadjuvant treatment with abemaciclib + anastrozole, ANZ. As previously reported, NeoMONARCH met its primary endpoint showing abemaciclib, alone or in combination with ANZ, significantly reduced Ki67 expression compared to ANZ alone after 2 weeks (wks) of treatment. Final results are presented here. Methods: 223 pts were randomized (1:1:1) and treated for 2 wks with abemaciclib (150 mg PO Q12H) + ANZ (1 mg PO QD), abemaciclib alone, or ANZ alone. Then, all pts were treated for 14 wks with the combination. Pts were treated with loperamide (2 mg PO Q12H) for 4 wks while receiving abemaciclib. Tumor biopsy was collected at baseline, Wk 2 and Wk 16. Blood samples were collected through Cycle 5 to measure abemaciclib and ANZ concentrations. Primary objective was Ki67 change from baseline to Wk 2. Secondary objectives evaluated after Wk 16 of treatment, were radiologic, pathological and clinical responses, safety, and pharmacokinetics (PK). Exploratory objectives included the mutational analysis of PIK3CA and ESR1 at baseline. Results: Table 1 shows subgroup analyses of percent change in Ki67 from baseline to Wk 2 by disease stage, baseline lymph node (LN) involvement, tumor grade, and tumor size in Ki67 evaluable (KE) population (baseline Ki67 ≥ 5%) comparing combination to ANZ alone. Data for abemaciclib arm will be shown at the meeting. 185 pts completed treatment. At the end of treatment, response rates were radiologic 46.4% (all pts), and caliper 53.6% (all pts), and pCR 3.7% (pts who completed BC surgery assessment). Ki67 end of treatment analysis in 138 pts will be presented. The most common adverse events, all pts, were diarrhea (61.4%; G3: 4.9%), constipation (43.5%; G3: 1.8%), and nausea (41.7%; G3: 2.2%). Treatment discontinuation due to AEs was low (7.6%). Results of PIK3CA and ESR1 mutational analysis, and PK will be presented. Subgroup analyses at Wk 2 of KE population CombinationANZSubgroup treatment comparaison Pts, nGM % ChangePts, nGM % ChangeGMR (95% CI)PKE population59-92.8656-62.780.19 (0.13, 0.28) Conclusions: Abemaciclib + ANZ is an effective treatment with manageable toxicities in pts with HR+/HER2- early BC. Abemaciclib-driven change in Ki67 was not associated with disease stage, baseline LN involvement, tumor grade, or tumor size. Citation Format: Martin M, Hurvitz SA, Chan D, Fernandez-Abad M, Petru E, Rostorfer R, Guarneri V, Huang C-S, Press MF, Costigan TM, Caldwell CW, Wijayawardana S, Turner PK, Barriga S, Slamon DJ. Final results of NeoMONARCH: A phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-01.

Background: Inhibition of the vascular endothelial growth factor receptor-2 (VEGFR-2) blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of MET, the hepatocyte growth factor (HGF) receptor. Preclinical data suggest that co-targeting VEGFR and MET/HGF leads to greater tumor shrinkage when compared to a VEGFR blockade alone. Here we report the safety and clinical activity observed during dose escalation and tumor-specific expansion cohorts for the combination of the anti-VEGFR-2 antibody ramucirumab (R) and emibetuzumab (E), a bivalent monoclonal anti-MET antibody that inhibits ligand-dependent and ligand-independent MET signaling (NCT02082210). Methods: Patients (pts) with advanced solid tumors, measurable disease, and a fresh pretreatment tumor biopsy were enrolled in a Phase 1b/2 study receiving either 750 or 2000 mg E in combination with 8 mg/kg R, both intravenously administered every two weeks (Q2W). Following dose escalation, pts were assigned to tumor-specific expansion cohorts including gastric/gastroesophageal junction adenocarcinoma (G/GEJ), renal cell cancer (RCC), and non-small cell lung cancer (NSCLC). The primary objective was to determine the dose range of E that can be safely given in combination with R. Additional objectives included evaluation of anti-tumor activity by RECIST v1.1, pharmacokinetic (PK) parameters, immunogenicity, and biomarkers for MET/HGF and VEGF pathways. Results: As of Sept 2016, 6 pts were treated in the dose escalation and 45 pts in the cohort expansions (n=17 G/GEJ, n=15 RCC, n=13 NSCLC) with a median of 2 prior systemic therapies (range 1-7). No dose-limiting toxicities were observed in the dose escalation, and 750 mg E and 8 mg/kg R were recommended for the tumor expansion in line with the recommended phase 2 dose in other ongoing E phase 2 studies. Common possibly related AEs of all grades included fatigue (33%), nausea (20%), and dyspnea (16%). Grade 3 or higher AEs observed in more than 1 patient were fatigue (n=3) and pulmonary embolism (n=3). Disease control rates in the cohort expansions for G/GEJ, RCC, and NSCLC pts were 53%, 47%, and 85%, respectively. Unconfirmed partial responses were observed in an ovarian and a gastric pt. The median progression-free survival was: 2.73 months (95% CI: 1.35, 4.60) in the G/GEJ cohort, 4.17 months (95% CI: 1.18, 7.39) in the RCC cohort, and 6.57 months (95% CI: 2.76, 10.61) in the NSCLC cohort. Pretreatment tumoral MET expression and other biomarker analyses are ongoing and will be presented at the meeting. Conclusions: Treatment with E at a dose of 750 or 2000 mg can be safely administered with 8 mg/kg R Q2W with minimal toxicity and shows a potential to stabilize disease in G/GEJ, RCC, and NSCLC pts. Citation Format: Johanna Bendell, Charles Fuchs, Martin Voss, Todd M. Bauer, Toni K. Choueiri, Alexander Drilon, Katharine Thorn, Sameera Wijayawardana, Brian Moser, Arantxa Uruñuela, Volker Wacheck, James J. Harding. A phase 1b/2 study of ramucirumab in combination with emibetuzumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT090. doi:10.1158/1538-7445.AM2017-CT090

CHK1 plays a critical role in DNA damage repair (DDR) pathways as well as in coordinating DNA replication. Selective CHK1/CHK2 compounds are being tested in clinical trials but predictive biomarkers of patient response are lacking. A phase 1b expansion cohort study (I4D-MC-JTJA, NCT01115790) with the CHK 1 inhibitor, prexasertib, included patients with advanced, metastatic head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA). To identify genomic biomarkers associated with single-agent drug response, pre-treatment tissues (archived or biopsy) from 71 consented patients (HNSCC=47, SCCA=24) were subjected to next-generation sequencing (NGS) using the FoundationOne gene panel. In this subset of patients, the disease control rate (DCR) (Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) based on RECIST Criteria (v 1.1)) was 60% (28/47) and 75% (18/24), respectively. We present here the observed genetic alterations corresponding to three pathways, Cell Cycle, DNA Damage Repair (DDR) and PI3K. In addition, patients’ human papillomavirus (HPV) carrier status was inferred from DNA sequencing using HPV-specific capture probes. HPV+ was 47% for HNSCC and 87% for SCCA. HPV+ and TP53 mutations were mutually exclusive across the two patient cohorts. In HNSCC patients with evaluable progression-free survival (PFS) data, greater clinical efficacy was observed in the HPV+ cohort (median PFS: 4.5 vs 1.4 months, log-rank p = 0.0008). Known or likely loss-of-function (LOF) mutations in FBXW7 and PARK2, two genes implicated in Cyclin E1 proteolysis, were noted in patients with favorable response in both tumor types. Across both HNSCC and SCCA cohorts, mutations and/or germline variants in the DDR genes BRCA1, BRCA2, MRE11A and ATR but not in Fanconi (FANC) pathway genes, were found in patients with treatment benefit. Whereas PIK3CA mutations were infrequent in the HNSCC cohort, in SCCA, mutations occurred in 5/8 (63%) patients with disease control vs 1/6 (17%) with PD. All 7 PI3KCA mutations observed in HPV+ HNSCC and SCCA patients mapped to the helical domain suggestive of Apobec-induced mutagenesis as their source of origin. The enhanced clinical benefit to prexasertib associated with HPV+ in HNSCC may reflect a prognostic effect. Alternatively, the clinical biomarker findings may support the hypothesis that oncogene-induced replication stress (RS) (i.e. arising from HPV E6/E7 and/or FBXW7 loss-dependent Cyclin E1 dysregulation) in the context of attenuated DDR (i.e. BRCA1/2, MRE11A mutations) may sensitize patients to prexasertib monotherapy. Citation Format: Ricardo Martinez, Sameera R. Wijayawardana, David Hong, Johanna Bendell, Anna Maria Russell, Richard P. Beckmann, Aimee Bence Lin. A clinical genomic biomarker study of the CHK1 inhibitor prexasertib in advanced head and neck squamous cancer and squamous cell carcinoma of the anus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1778. doi:10.1158/1538-7445.AM2017-1778

Introduction: MET is expressed in gastric cancer and associated with poor clinical outcome. LY2875358 (LY) is a humanized immunoglobin G4 (IgG4) monoclonal bivalent antibody blocking ligand-dependent and independent MET signaling. In preclinical studies, LY showed single agent anti-tumor activity for MET amplified gastric cancer in xenograft models. Based on these results, a non-randomized, multicenter, single-arm, open-label, Phase 2 study was conducted to evaluate the antitumor activity of LY in patients (pts) with MET diagnostic positive (+), advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Pts with MET diagnostic (+), advanced gastric or GEJ adenocarcinoma, who had received 2 prior chemotherapies, were administered LY 2000 mg as flat dose intravenously every 2 weeks (Q2W) on a 28 day cycle. MET diagnostic (+) tumor status was determined by immunohistochemistry (IHC). The primary objective was to evaluate the activity of LY in terms of progression-free survival (PFS) rate at 8 weeks (+ 3 days). Secondary objectives were to assess other efficacy variables (eg overall response rate, disease control rate [DCR], PFS, overall survival [OS]), toxicity and safety profile of LY, and pharmacokinetics (PK). The exploratory objectives included evaluation of pharmacodynamics, pharmacogenomics, and exploratory biomarkers. Results: Tumor samples of 65 pts were screened for MET expression by IHC and 15 pts (23.1%) with MET diagnostic (+) were enrolled in this study. Fifteen pts (5 female, 10 male) from Asia (Japan 8, Korea 7) with a median age of 63 years (range 39-74) were enrolled. PFS rate at 8 weeks was 47% (70% Confidence Interval [CI]: 33%, 59%). There was no partial response according to RECIST, while shrinkage of tumor size was observed in 3 out of 15 pts. DCR was 40.0%, with stable disease shown in 6 out of 15 pts. Median PFS was 8.3 weeks (95% CI: 4.1, 12.1) with stable disease for up to a maximum of 37.1 weeks. Median OS was 17.1 weeks (95% CI: 6.3, Not Available). A total of 12 pts (80%) experienced at least 1 LY-related treatment-emergent adverse event (TEAE). Common LY-related TEAE (all grades) included constipation and hypoalbuminemia (3 pts [20%] each). LY-related TEAEs with Grade ≥ 3 were hyponatremia and hyperuricemia (2 events in 1 patient), and hyperkalemia (1 patient). Serious adverse events were reported in 6 patients, none of which was related to LY. There was no TEAE leading to death or study treatment discontinuation. PK profiles were similar to those observed in previous studies of LY monotherapy, which were conducted in the United States, and the majority of patients were Caucasian. Exploratory biomarker analysis (IHC data) will be presented at the venue. Conclusion: LY 2000 mg Q2W showed a well-tolerated safety profile with a limited single agent activity in heavily pretreated patients with MET diagnostic (+), advanced gastric or GEJ adenocarcinoma. Citation Format: Hyun Cheol Chung, Taroh Satoh, Do-Youn Oh, Se Hoon Park, Shigenori Kadowaki, Volker Wacheck, Ayuko Yamamura, Kazunori Uenaka, Xuejing Aimee Wang, Sameera R. Wijayawardana, Toshihiko Doi. A non-randomized, open-label, single-arm, phase 2 study of LY2875358 in Asian patients with MET diagnostic positive, advanced gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C121.

Background: LY2606368 is a CHK1/2 inhibitor. In addition to its role in DNA damage response, CHK1 also phosphorylates multiple downstream targets that regulate DNA replication, chromosome alignment, spindle checkpoints, and exit from cytokinesis. Since potent inhibition of CHK1 is predicted to generate DNA damage and mitotic catastrophe, LY2606368 was evaluated as a single agent in expansion cohorts of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods: This was a phase I, multicenter, nonrandomized, open-label study in patients with advanced cancer (NCT01115790). Based on results from the dose-escalation phase, dose-expansion cohorts were comprised of patients with SCC given LY2606368 at the maximum tolerated dose (MTD) of 105 mg/m2 on day 1 of a 14-day schedule. Cohorts were defined by tumor location and by line of treatment. Patients were assessed for safety, tolerability, and preliminary efficacy. Pretreatment biopsies were obtained for pharmacogenomic analysis, including human papillomavirus (HPV) status. Aggregate results from patients with recurrent/metastatic SCCHN are presented. Results: Fifty-seven patients with recurrent/metastatic SCCHN were enrolled in the dose-expansion phase. Over 50% of patients had received ≥2 prior lines of treatment (median of 3 cycles; range: 1 to 5) in the recurrent/metastatic setting. The most frequently reported adverse event (AE) was a transient (typically 10% of patients included thrombocytopenia (44%), anemia (25%), fatigue (23%), and headache (14%). The majority of non-hematologic AEs were grade 1 or 2 (per Common Terminology Criteria) in severity. Three patients (5%) had a partial response and 25 patients (44%) had stable disease for at least 3 cycles. The duration of response ranged from 4.8-7.8+ months, and the median progression-free survival (PFS) was 1.6 months (90% confidence interval: 1.4, 2.8). Biopsy samples were evaluable from 34 patients. The median PFS by HPV status was 4.5 months in 15 patients who were HPV positive, and 1.4 months in 19 patients who were HPV negative (log-rank test, p = .0012). Conclusions: LY2606368 has an acceptable safety profile and demonstrates modest preliminary activity in a subset of patients with recurrent/metastatic SCCHN. The MTD of 105 mg/m2 is confirmed as the recommended dose for phase II testing. Citation Format: Johanna Bendell, Stefan Grant, Filip Janku, Jeffrey Infante, William N. William, Todd M. Bauer, Sarina Piha-Paul, Ricardo Martinez, Sameera Wijayawardana, Ji Lin, Lisa Golden, Aimee Bence Lin, David Hong. Checkpoint kinase (CHK) 1/2 inhibitor LY2606368 in a phase I dose-expansion study in patients with squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT240. doi:10.1158/1538-7445.AM2015-CT240