Cyclin-dependent kinase (CDK) 4/6 inhibition + ER signaling blockade is a highly effective treatment option for metastatic ER+/HER2− BC. Preclinical studies show evidence of CDK 4/6 and programmed death-1 (PD-1) blockade synergy. CheckMate 7A8, a non-comparative, phase 2 study, evaluated neoadjuvant NIVO + PALBO + ANA in patients (pts) with ER+/HER2− primary BC. Here, we report safety outcomes from the safety run-in phase.

BACKGROUND:Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.PATIENTS AND METHODS:This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.RESULTS:A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).CONCLUSION:Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits.CLINICAL TRAIL NUMBER:NCT02499770.

Background: CB-839 is an investigational first-in-class, potent, oral inhibitor of glutaminase (GLS), a mitochondrial enzyme that controls a critical step in tumor cell utilization of glutamine. TNBC is associated with high GLS expression and depends on GLS conversion of glutamine to glutamate for tumor cell survival and proliferation. Higher glutamine utilization has been observed in TNBC tumors from patients (pts) of African ancestry (AA), compared to those of European ancestry. CB-839 has demonstrated preclinical antitumor activity in both in vitro and in vivo models of TNBC and synergizes with paclitaxel (Pac) by reversing GLS-dependent mechanisms that lead to taxane resistance. In a phase 1 study, the Pac+CB-839 combination was well tolerated and demonstrated clinical activity in a cohort of heavily pretreated pts with TNBC (22% overall response rate [ORR]; 59% disease control rate [DCR] at ≥600 mg BID dose [n=37]), including those with taxane-refractory disease or of AA (Kalinsky et al. SABCS 2017). Here we present initial findings from an ongoing phase 2 study of Pac+CB-839 in pts with advanced TNBC (NCT03057600). Methods: Key eligibility criteria included advanced/metastatic TNBC with ECOG PS 0-1 and either 0 (1L) or ≥2 prior lines (3L+) of therapy for metastatic disease were eligible (N=112 pts max). Prior taxane therapy for the 3L+ cohorts was required. For the 1L cohorts, prior neo/adjuvant therapy (including taxanes) was allowed if time to recurrence was >12 months (mo). Pts were allocated to cohorts by line of therapy (1L or 3L+) and ancestry (AA or non-AA) in order to ensure sufficient enrollment to each of these subgroups. Pts received oral CB-839 (800 mg BID) in combination with intravenous Pac (80 mg/m2 on days 1, 8, 15 of each 28-day cycle). The primary endpoint was ORR. Other endpoints included overall survival, duration of response, clinical benefit rate, biomarker analyses, and safety. Results: As of the June 15, 2018 data cutoff, 44 pts have been enrolled (median age, 59 yrs; 41% AA; n=22 each in 1L or 3L+). In the 1L cohort, 64% and 36% had ECOG PS of 0 and 1, respectively. In the 3L+ cohort, 36% and 55% had ECOG PS of 0 and 1, respectively (9% unknown). Of 14 evaluable 1L pts, ORR was 43% and DCR (partial response [PR] + stable disease ≥8 weeks [SD]) was 79% (n=6 PR; n=5 SD). Of 16 evaluable 3L+ pts, ORR was 6% and DCR was 25% (n=1 PR; n=3 SD). Most common CB-839- or Pac-related treatment-emergent adverse events (TEAE) occurring in >15% included fatigue (34%), diarrhea (23%), nausea (18%), neuropathy (18%), alopecia (16%), anemia (16%), AST increased (16%), and hypophosphatemia (16%). Treatment-related grade ≥3 TEAEs occurred in 8 (18%) pts; the most common (occurring in >1 pt) were hypophosphatemia and neutrophil count decreased (n=2 each). No events of febrile neutropenia were reported. Conclusions: Early analyses of this phase 2 study show that Pac+CB-839 has clinical activity and is well tolerated in pts with advanced/metastatic TNBC. Updated data including exploratory biomarker analysis will be presented. Citation Format: Vidal G, Kalinsky K, Stringer-Reasor E, Lynce F, Cole J, Valdes-Albini F, Soliman H, Nikolinakos P, Silber A, DeMichele A, Ali H, Graham D, Giguere J, Brufsky A, Liang Y, Holland S, Fiji G, O9Keeffe B, Gogineni K. Efficacy and safety of CB-839, a small molecule inhibitor of glutaminase, in combination with paclitaxel in patients with advanced triple negative breast cancer (TNBC): Initial findings from a multicenter, open-label phase 2 study [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 P6-20-07.

Osimertinib, a third-generation EGFR inhibitor, has become the first-line therapy for patients with metastatic EGFR-mutant NSCLCs since 2018. Osimertinib is well-tolerated, therefore, it opens opportunities to be combined with other therapeutic agents to enhance the treatment outcome. In preclinical models, it has been shown that upregulated VEGF signaling mediates acquired resistance to EGFR therapies. In xenograft models, combination of anti-VEGF medications with EGFR inhibitors were significantly more effective than erlotinib or gefitinib alone. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, is approved with docetaxel in as second line treatment for NSCLCs. In clinical trial evaluations, the phase 3 RELAY trial (NCT02411448) studying ramucirumab plus erlotinib in patients with metastatic untreated EGFR-mutant NSCLC patients showed a statistically significant improvement in progression-free survival in the combination group compared to erlotinib alone. A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With strong preclinical and clinical evidence showing dual inhibition of VEGF/EGFR signaling prolongs progression-free survival for EGFR-mutant lung cancers, and demonstrated safety, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination's efficacy in treatment-naïve EGFR-mutant NSCLC. The OSI+RAM trial is a randomized phase 2 study with the primary endpoint being progression-free survival in osi+ram group as compared to osimertinib monotherapy group. The major inclusion criteria include patients with metastatic NSCLC harboring EGFR mutations (L858R/Exon 19 del). The major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. Based on the results from erlotinib bevacizumab (NEJ026) study, we expect an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65. The trial plans to enroll total of 150 patients, with 100 allocating to osi+ram arm and 50 to osimertinib monotherapy. Total of 9 study sites in the USA are planned. Hoosier Cancer Research Network will facilitate the execution of the trial. The trial protocol has received IND exemption from US FDA and has been approved by IRB at MD Anderson Cancer Center. The first subject is expected to be enrolled in May 2019. A planned interim analysis will be performed after the first 75 subjects are enrolled. NCT03909334. Section not applicable Section not applicable

Background Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

The epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The third generation irreversible EGFR inhibitor HS-10296 has been shown to be safe and effective against both EGFR TKI-sensitizing and T790M resistance mutations in preclinical studies. A Phase I, open-label, multi-center clinical trial was conducted in patients with locally advanced or distant metastatic NSCLC who have progressed following prior therapy with EGFR TKIs. The study was consisted of dose-escalation cohorts (55, 110, 220 and 260 mg) and dose-expansion cohorts (55, 110 and 220 mg) with once daily oral administration of HS-10296. In each expansion cohort, tumor biopsies were collected for central determination of EGFR T790M status. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy of HS-10296. A total of 117 patients (median age 60) received at least one dose of HS-10296 across multiple sites in China (43 patients), Taiwan (69 patients) and the United States (5 patients). Maximum tolerated dose(MTD)has not been reached in this study. The most common adverse events were grade1/2 rash, pyrexia, upper respiratory tract infection, constipation, diarrhoea and blood creatine phosphokinase elevation. Drug-related serious adverse events were anemia (0.8%), blood creatinine elevation (0.8%), anemiarhabdomyolysis (0.8%) and blood creatine phosphokinase elevation (0.8%) occurred mainly in the cohorts with higher doses at 220 mg or 260 mg, respectively. These data demonstrated favorable tolerability and safety of HS-10296 in patients enrolled. The pharmacokinetics of HS-10296 was dose proportional and the plasma half-life was 30.7∼37.5 hours. Among 82 evaluable patients (18 in escalation cohorts and 64 in expansion cohorts) with the EGFR T790M mutation, the overall objective response rate (ORR) was 52.4% (43/82; 95% CI, 41.6 to 63.3), while disease control rate (DCR) was 91.5% (75/82; 95% CI, 85.4 to 97.5). 110mg cohort showed better DCR (97.2% VS. 86.1%) than 55mg cohort. Phase II study is ongoing with the dose at 110 mg. HS-10296 has the potential to provide clinical benefit to locally advanced or distant metastatic NSCLC patients with EGFR T790M mutation who had disease progression following prior therapy with EGFR TKIs. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

Background: MONARCH 2 demonstrated that the addition of abemaciclib, dosed on a continuous schedule at 150 mg twice daily, to fulvestrant (F) significantly improved progression-free survival (PFS) and objective response rate (ORR) compared to placebo (P) plus F (PFS hazard ratio [HR], 0.553, P<.0000001; ORR in measurable disease 48.1% vs 21.3%, P<.001) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) who had progressed on endocrine therapy (ET). Here we present efficacy and safety findings from an exploratory cohort of EN pts from MONARCH 2 not included in the intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive abemaciclib or P + F (500 mg, per label). Pre/perimenopausal women received a gonadotropin-releasing hormone agonist. Pts were not allowed to have had chemotherapy in the advanced setting. Pts were stratified by metastatic site (visceral, bone only, other). The primary endpoint for this analysis was investigator-assessed PFS which was described using the Kaplan-Meier method and a Cox model. Results: Forty-four EN pts were randomized to abemaciclib + F (N = 28) or P + F (N = 16). 46% of pts presented with visceral disease, 77% with measurable disease, and 82% were postmenopausal. At the time of the analysis, 18 pts were still on treatment (13 [46.4%] in the abemaciclib + F arm and 5 [31.3%] in the P + F arm). 18 PFS events were observed (9 [32.1%] in the abemaciclib + F arm and 9 [56.3%] in the P + F arm). The median PFS had not been reached in the abemaciclib + F arm and was 23.1 months in the P + F arm (stratified HR, 0.454; 95% CI: 0.179, 1.154). The ORR in pts with measurable disease was 60.0% (5% complete response [CR]) in the abemaciclib + F arm and 57.1% (0% CR) in the P + F arm. The most common adverse events were diarrhea, nausea, fatigue, and neutropenia. Diarrhea generally occurred in the early cycles and was managed with dose adjustment and conventional anti-diarrheal medication. Conclusions: In this exploratory cohort of EN pts, the addition of abemaciclib to fulvestrant demonstrated a comparable increase in PFS and consistent safety results to those observed in the ITT population in MONARCH 2. Clinical trial identification: NCT02107703 Legal entity responsible for the study: Eli Lilly and Company Funding: Eli Lilly and Company Disclosure: P.A. Kaufman: Consulting/Advisory: Galena Biopharma, Amgen; Research Funding: Eli Lilly and Company. P. Nikolinakos: Advisory board: AstraZeneca. J.T. Beck: My institution receives research grants as part of this study. J.L. Gonzalez-Trujillo: Contract with Lilly, Bristol-Myers Squibb, Roche, Pierre Fabre, Astra for make a corporate-sponsored research. Advisory board for Bristol-Myers Squibb, MSL, Novartis. Speaker for Bristol-Myers Squibb, Novartis. Y. Lin, N. Bourayou: Employment and Stock Ownership: Eli Lilly and Company. S. Barriga: Employment Eli Lilly and Company. D. Headley: Employment and Stock Ownership: Eli Lilly and Company; Stock Ownership: AstraZeneca. A. Llombart Cussac: Honoraria: Roche, Novartis, Pfizer; Consulting/Advisory: Roche, AstraZeneca, Eli Lilly and Company; Research funding: Pfizer, Roche; Travel funds: Roche, Celgene. G.W. Sledge Jr.: Leadership, Stock: Syndax; Honoraria: Symphogen; Consulting/Advisory: Symphogen, Coherus Biosciences, Radius Health, Peregrine Pharmaceuticals, Taiho Pharmaceutical; Research Funding: Roche (Inst); Travel funds: Nektar, Radius Health, Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

Abstract Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. We report clinical activity of avelumab in a cohort of patients (pts) with locally advanced (LA) or metastatic breast cancer (MBC) refractory to or progressing after standard-of-care therapy (NCT01772004). Methods: Pts received avelumab at 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Unconfirmed best overall response was evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Biopsy or surgical specimens were collected within 90 days prior to 1st dose of avelumab for biomarker analyses. Tumor PD-L1 expression was assessed by immunohistochemistry using various cutoff criteria. Results: As of 27 Feb 2015, 168 pts (167 female, 1 male) with MBC, including ductal (56.5%), carcinoma NOS (9.5%), lobular (3.6%), or other (30.4%), were treated with avelumab and followed for a median of 10 mo (range 6-15). Median age was 55y (range 31-81), ECOG performance status was 0 (49.4%) or 1 (50.6%), and pts had received a median of 3 prior therapies for LA/M disease (range 0-10; pts must have received prior treatment with taxane and anthracycline, unless contraindicated). Pts were HER2–/ER+ or PR+ (69 [41.1%]), triple negative (TNBC = HER2–/ER–/PR–; 57 [33.9%]), HER2+ (26 [15.5%]), or had unknown biomarker status (16 [9.5%]). Median duration of treatment was 8 wks (range 2-50), and 9 pts (5.4%) remained on avelumab. Any grade treatment-related treatment-emergent AEs (TEAEs) occurred in 120 pts (71.4%); the most common (&gt;10%) were fatigue (33 [19.6%]), nausea (24 [14.3%]), and infusion-related reactions (20 [11.9%]). Treatment-related grade ≥3 TEAEs occurred in 24 pts (14.3%) and included (≥1%) fatigue, anemia, increased GGT, and autoimmune hepatitis (each 3 [1.8%]), and arthralgia (2 [1.2%]). There were 2 treatment-related deaths (acute liver failure, respiratory distress). Unconfirmed objective response rate (ORR) in the entire cohort was 5.4% (9 pts; 95% CI: 2.5, 9.9), with 1 CR and 8 PRs. Five of 9 responses were ongoing at time of cutoff. Stable disease was observed in additional 40 pts (23.8%), for an overall disease control rate of 29.2%. Evidence of tumor reduction by ≥30% was seen in 15 pts (8.9%). There were responders in all biomarker subgroups, including 5 PRs in TNBC (n=57 [8.8%; 95% CI: 2.9, 19.3]). PD-L1 expression was evaluable in 136 pts. Among all pts with PD-L1 expressing immune cells within the tumor, 33.3% (4 of 12) had PRs. In pts with TNBC who had PD-L1+ immune cells within the tumor, 44.4% (4 of 9) had PRs, compared with 2.6% (1 of 39) for TNBC and PD-L1– immune cells. Conclusions: Avelumab showed an acceptable safety profile and had clinical activity in a subset of pts with MBC. In pts with TNBC, presence of PD-L1 expressing immune cells within the tumor may be associated with clinical responses to avelumab. Further analyses of PD-L1 expression and clinical activity of avelumab in MBC are ongoing. *Proposed INN. Citation Format: Dirix LY, Takacs I, Nikolinakos P, Jerusalem G, Arkenau H-T, Hamilton EP, von Heydebreck A, Grote H-J, Chin K, Lippman ME. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-04.

7568 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. In a single-arm phase II trial (NCT00367679; VEG105290), patients received pazopanib 800 mg QD for 2–6 weeks before scheduled surgery. Tumor volume measurements were performed using high resolution CT images before and after treatment. An exploratory analysis was planned to describe the modulation of C/AFs during pazopanib treatment and identify potential predictive plasma markers. Methods: Plasma samples were collected pre- treatment and on the last day of pazopanib dosing. Levels of 52 C/AFs were measured by suspension bead multiplex assays (BioRad) or ELISA. Results were correlated with change in tumor volume. Statistical analyses included Wilcoxon tests and Pearson correlation tests. Results: 19 paired samples have been analyzed. Pazopanib treatment was associated with a significant modulation of 13 C/AFs, including a decrease in soluble VEGFR-2 (p<0.001) and increases in PlGF, IFN-α2 and HGF; chemokines/monokines: SDF1-α, CTACK, CXCL-10, CXCL-9, RANTES; and further factors: IL-12; M-CSF and TRAIL (all with p<0.05). PlGF showed the highest up-regulation during treatment with an average 15.9 fold increase, whereas changes compared to baseline for the remaining factors varied between 5 and 60%. The exploratory correlation of C/AF changes with tumor changes indicated an association with 6 factors (sVEGFR-2 (r = 0.77), VEGF (r = - 0.68), IL-16, IL-1RA, MCP-3, and IL-4; all with p<0.05). A significant correlation between baseline levels of C/AFs and tumor reduction was observed for 8 factors (PlGF, IL-2R, IL-12, IL-16, TRAIL, SCF, IL-3 and CTACK). Conclusions: Pazopanib treatment was associated with decreases in sVEGFR2 and increases in an additional 12 C/Afs, with PlGF demonstrating a particularly striking increase. The exploratory analysis identifies that baseline levels of several C/Afs may have predictive value for pazopanib treatment. Moreover a strong correlation between sVEGFR-2 changes during pazopanib treatment and tumor shrinkage was observed making this factor a potentially attractive marker of response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Pneum Rx, General Electric GlaxoSmithKline, Pneum Rx GlaxoSmithKline GlaxoSmithKline