Valentina Boni

Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children

Background Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. Methods We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression‐free survival, and safety. Results A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression‐free. The median duration of response and progression‐free survival had not been reached. At a median follow‐up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug‐related adverse events. Conclusions Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913, NCT02637687, and NCT02576431.)

Abstract A73: A Phase I first-in-human (FIH) study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870).

Background: SAR566658 (SAR) is a maytansinoid-loaded ADC (huDS6-SPDB-DM4) targeting CA6, a specific glycol-epitope of MUC-1 over-expressed in solid tumors (pancreas 26%, ovary 55%, breast 30%, bladder 60%) and rarely in normal tissues. This FIH study was designed to assess the safety, dose limiting toxicities (DLTs)/recommended dose (RD) and pharmacokinetic following SAR administration in Pts with CA6-expressing STs. Trial is funded by Sanofi. Methods: This Phase I study explored escalating intravenous doses of SAR administered as single agent every 3 weeks (q3w). An accelerated dose escalation scheme was used for the two first dose levels (DL), followed by a standard 3+3 dose escalation scheme. Results: 34 heavily pretreated Pts were enrolled including: 11M/23F, median age 58 years (range, 32-77), ECOG-PS ≤1, with a variety of advanced STs including ovary (13), pancreas (10) and breast (4). A total of 114 cycles (cy), median 2, (range,1-14) of SAR was administered across 9 DLs ranging from 10 to 240 mg/m2. DLTs were observed at the highest DL of 240 mg/m2 and included grade (Gr) 3 diarrhea at cy1 in 1 Pt and Gr3 keratitis at cy2 in 2 Pts. Anticipated toxicity was cornea, peripheral neuropathy, hematological and pulmonary. So far the number of Pts with these toxicities are: keratitis (all Gr: 11 Pts, including 2 Pts with Gr3), peripheral neuropathy (5 Pts, no Gr≥3), neutropenia (Gr3, 2 Pts), interstitial pneumonitis (1 Pt). Other than late occurrence of reversible corneal adverse events (AE) at 150 mg/m2, no dose-dependent AE was observed. Exposure to SAR (Cmax and AUC) increased with no major deviation from dose proportionality over doses of 20 to 240 mg/m2. Clearance was roughly constant over the doses with a low to moderate total variability. SAR 190 mg/m2 fulfills the criteria for RD: no DLT and manageable ocular AE versus highest DL. Clinical benefit was observed at doses ≥120 mg/m2: 1 partial response (breast), 1 PR to be confirmed (ovary), 3 stable disease (SD)>6months and 11 SDs were noted. A significant decrease in tumor marker was noted in 1 Pt. Conclusions: SAR has a favorable safety profile and encouraging antitumor activity. SAR at 190mg/m2 q3w was selected as the RD and is being confirmed in an ongoing extension cohort. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A73. Citation Format: Valentina Boni, Olivier Rixe, Drew Rasco, Carlos Gomez-Roca, Emiliano Calvo, John C. Morris, Anthony W. Tolcher, Sylvie Assadourian, Helene Guillemin, Jean-Pierre Delord. A Phase I first-in-human (FIH) study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) ([NCT01156870][1]). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A73. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01156870&atom=%2Fmolcanther%2F12%2F11_Supplement%2FA73.atom

Abstract CT050: A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors

BACKGROUND: MCLA-128 is a novel humanized full length IgG1 bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity that targets the transmembrane tyrosine kinase receptors, HER2 and HER3 present on a variety of epithelial tumor cells. In preclinical studies, MCLA-128 demonstrated potent anti-tumor activity. The primary objectives of this First-in-Human (FIH) study are to establish the MTD and Phase 2 recommended dose (RP2D) of MCLA-128 and to assess its safety, tolerability, PK, PD, and anti-tumor activity in selected patient (pt) groups. METHOD: The trial consists of 2 parts. In Part 1 (dose-escalation) patients (pts) with advanced epithelial tumors with no standard management options were enrolled with an initial accelerated 1 pt per cohort design shifting to a 3 + 3 design. The DLT evaluation period was 21 days ( = 1 cycle). MCLA-128 was administered every 3 weeks (q3w) as an intravenous infusion over 60-120 minutes. Toxicities were assessed throughout dose escalation (40 mg up to 900 mg flat dose). Part 2 consists of several expansion cohorts of pts at the RP2D (expansion phase). Here we present interim results for Part 1 of the study. RESULTS: Twenty-eight pts received MCLA-128 in 9 dose-escalation cohorts (40-160 mg in cohorts of 1 evaluable pt, 240-900 mg in cohorts of 3 to 6 evaluable pts). The most frequent drug related adverse events (AEs) observed in Part 1 were mild to moderate (G1-G2) with prompt recovery in general. AEs included infusion-related reactions (IRR), diarrhea, nausea, vomiting, fatigue, maculopapular rash, oral mucositis and G2 neutropenia in 1 pt. IRR occurred in 50% of pts with a trend for increased incidence with dose; modest and transient dose dependent cytokine release was also observed. Increasing the infusion duration to 120 min and premedication with corticosteroids was successfully implemented to mitigate IRRs and cytokine levels were no longer correlative with MCLA-128 dose levels. One drug related serious AE (SAE) has been reported: IRR G3, due to prolonged hospitalization (SUSAR). No DLTs were observed. In serum samples from 12 pts, 1 pt was positive for MCLA-128 anti-drug antibodies 36 days after starting treatment at a dose of 160 mg. A MTD was not reached in the study; PK analysis was used to support a RP2D of 750 mg q3w. Exposure to MCLA-128 increased in proportion to dose. The RP2D was calculated to maintain trough concentrations at the end of each treatment cycle significantly above the Kd of MCLA-128 as determined on HER2 amplified cell lines in vitro and above the Km in a population PK model. Preliminary signs of anti-tumor activity assessed by RECIST are encouraging. Three pts remain on study to date including 1 non-small-cell lung cancer pt who is experiencing an ongoing partial response for more than 10 months, 1 gastroesophageal junction pt and 1 colorectal cancer pt with stable disease for 5 months. In addition, 1 metastatic breast cancer pt received 5 months of MCLA-128 treatment until disease progression. CONCLUSION: MCLA-128 was well-tolerated with a favorable safety profile in pts with advanced tumors treated at doses up to 900 mg q3w. PK results and preliminary signs of anti-tumor activity support the further clinical evaluation of MCLA-128 at the RP2D of 750 mg q3w. The expansion phase of the study is ongoing at this dose level. Citation Format: Emiliano Calvo, Maria Alsina, Jan H.M. Schellens, Alwin DR Huitema, Josep Tabernero, Aurelia de Vries-Schultink, Valentina Boni, Bernard Doger, Cecile Geuijen, Robert Doornbos, Kees Bol, Martine Westendorp, Mark Throsby, Lex Bakker, Setareh Shamsili. A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT050.

Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

Metastatic breast cancer patients with coexistent HER2 mutation and amplification respond to neratinib. Neratinib for resistant metastatic breast cancer Breast cancers with amplification or mutation in the epidermal growth factor receptor (EGFR) family member HER2 are usually treated with targeted inhibitors, but resistance is common. Amplification and mutation of HER2 are generally considered mutually exclusive occurrences in treatment-naïve patients. However, Cocco et al. discovered a small proportion of treatment-naïve and, more often, previously treated patients with metastatic breast cancer in which HER2 amplification and mutation were coincident. It is not yet clear why, but these co-amplified/mutant cells were resistant to currently approved HER2-specific and HER2/EGFR-specific inhibitors but were sensitive to the new pan-EGFR inhibitor neratinib. Neratinib, which inhibits EGFR and HER2, as well as HER3 and HER4, was more effective at blocking the activity of the EGFR pathway and other receptor tyrosine kinases, common modes of resistance in HER2-driven tumors. Patients and mice bearing their tumor cells showed improved survival and even tumor regression on neratinib, suggesting that this may be a treatment option for certain breast cancer patients. Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.

Abstract LB-A10: Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations

Background: HRAS is a proto-oncogene that is mutated in head and neck, bladder, thyroid, and salivary gland tumors, among others. While discovered over 40 years ago, no specific therapies have yet been developed targeting mutant HRAS. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme requisite for HRAS activation. Over 5,000 patients (pts) have been treated with tipifarnib; although responses have been documented in several tumor indications, the mechanisms of response are still poorly understood. Tipifarnib has demonstrated robust activity in HRAS mutant patient derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and squamous non-small cell lung cancer that are resistant to standard therapies. This Phase 2 study (NCT02383927) was conducted to test the hypothesis that inhibition of mutant HRAS oncogenic activity with tipifarnib could translate to objective responses in HNSCC pts driven by the HRAS oncogene. Methods: The study was originally designed to enroll pts into 2 single-arm study cohorts: Cohort 1 (thyroid cancer) and Cohort 2 (other solid tumors), each one with a 2-stage design (11+7 evaluable pts) to determine overall response rate (ORR) as the primary objective. This design has 80% power to detect a difference between 10% and 30% ORR at one-sided significance level of 0.087. Two objective responses were needed to be observed in the first stage for each cohort to proceed to stage 2. The study is considered positive if at least 4 responses are observed in one of the 2 cohorts (N=18 each, stages 1 and 2 combined). The prespecified activity goal for the first stage of accrual in Cohort 2 was met and based on data observed in the first stage of this Cohort, ongoing enrollment to the second stage of Cohort 2 was limited to HRAS mutant HNSCC. For enrollment, pts must have an HRAS mutant, locally advanced/unresectable and/or metastatic solid tumor malignancy and RECIST v1.1 measurable disease. Tipifarnib is given at 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Response assessments are conducted every 8 weeks. Results: As of August 30, 2017, 28 pts have been enrolled. Tipifarnib was generally well tolerated with myelosuppression, gastrointestinal disturbances (nausea, vomiting and diarrhea) and fatigue constituting the most common adverse events (≥30% of pts, all grades). Twenty four pts are currently evaluable for efficacy: 10 in Cohort 1 and 14 in Cohort 2. Stage 1 enrollment continues in Cohort 1. The primary objective was met for Cohort 2 prior to completing full enrollment, with 4 confirmed responses observed out of 14 evaluable pts. Notably, of the 6 pts in Cohort 2 with HNSCC currently evaluable for efficacy, 4 (67%) achieved a confirmed partial response. Three of these pts remain on treatment in cycles 3, 5, and 19, and one subject discontinued at Cycle 21. Two (33%) pts had disease stabilization as best response (4 cycles, ongoing and 7 cycles). Importantly, 4 of these pts were refractory to prior therapies, including regimens containing immunotherapy (pembrolizumab, nivolumab) or cetuximab +/- chemotherapy. None of the 6 HNSCC patients experienced an objective partial response on their last prior therapy. Conclusions: These data suggest that HRAS mutant HNSCC pts may be refractory to standard therapies but can derive prolonged clinical benefit from tipifarnib treatment. Based on the encouraging activity of tipifarnib in pts with HNSCC with HRAS mutations, enrollment continues in this cohort. Citation Format: Alan Ho, Nicole Chau, Deborah J. Wong, Maria E. Cabanillas, Jessica Bauman, Marcia S. Brose, Keith Bible, Valentina Boni, Irene Brana, Charles Ferte, Caroline Even, Francis Burrows, Linda Kessler, Vishnu Mishra, Kelly Magnuson, Catherine Scholz, Antonio Gualberto. Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A10.

Functional PTGS2 polymorphism-based models as novel predictive markers in metastatic renal cell carcinoma patients receiving first-line sunitinib.

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management.

Predictive score of early mortality in patients with solid tumors enrolled in phase I clinical trials.

e14029Background: A usual inclusion criterion for phase I trials is life expectancy of more than 3 months. Prediction of early mortality (EM), in the first 90 days after starting treatment, is thus...

The future of oncology therapeutics

In the past decade, we have witnessed several breakthrough events that changed our clinical practice in oncology. Precision medicine is now a reality. It was built upon the availability of an unprecedented massive amount of data regarding cancer molecular biology (driven by initiatives such as the Cancer Genome Atlas, the International Cancer Genome Consortium, or the 100,000 Genome Project) [1–3], along with a progressive transition toward a digital and global practice:

Immunotherapy-based combinations: current status and perspectives

Purpose of review Since the approval of ipilimumab, different immune checkpoint inhibitors, vaccines and costimulatory agonists have been developed with success, improving patients survival in a number of different tumour types. However, immunotherapy results in durable responses but only in a fraction of patients. In order to improve this, combination of different immune agents is currently being attempted in the clinic with the potential of becoming one day the next wave of immune treatments available for our cancer patients. Recent findings Combinatory regimens may have synergistic effects by acting at different points of the cancer immune cycle, from initiation and propagation of anticancer immunity, to stimulation of neoantigen presentation and priming, promotion of trafficking of immune cells to access the tumour and, finally, cancer-cell recognition and killing. Summary In this article, the most relevant combination strategies that are currently under research are reviewed, as they are expected to become a new standard of care in the near future.

A mechanism of action study of intra-tumoral or intravenous dosing of enadenotucirev, an oncolytic adenovirus in patients with colon, lung, bladder and renal carcinoma undergoing resection of primary tumor

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