Amy V. Kapp

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. METHODS In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1-21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). FINDINGS Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5-14·1) in the ipatasertib group and 10·2 months (6·0-13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8-9·0) with ipatasertib versus 4·9 months (3·6-5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37-0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6-9·1) with ipatasertib versus 3·7 months (1·9-7·3) with placebo (stratified HR 0·59, 95% CI 0·26-1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. INTERPRETATION Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. FUNDING F Hoffmann-La Roche.

Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors

Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1–30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. Results: No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non–small cell lung cancer (n = 3). Conclusions: MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer. Clin Cancer Res; 21(11); 2462–70. ©2015 AACR.

A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.

OBJECTIVES The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer. PATIENTS AND METHODS A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. RESULTS In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). CONCLUSIONS Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.

Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck

This open‐label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual‐action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first‐line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck.

Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study

BACKGROUND Dulanermin-a non-polyhistidine-tagged soluble recombinant human apoptosis ligand 2 (Apo2L) or tumour-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-has pro-apoptotic activity in a range of cancers and synergistic preclinical activity with rituximab against lymphoma in vivo. We aimed to assess the safety, pharmacokinetics, and efficacy of dulanermin and rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma. METHODS We did an open-label phase 1b/2 randomised study. Four study centres in the USA enrolled patients into phase 1b, and 27 study centres in the USA, Italy, Australia, France, Czech Republic, New Zealand, and Poland enrolled patients into phase 2. In phase 1b, patients (age ≥18 years) with indolent B-cell non-Hodgkin lymphoma with stable disease or better lasting at least 6 months after the most recent rituximab-containing regimen were included. In phase 2, patients (age ≥18 years) with follicular lymphoma grades 1-3a were included. In phase 1b, patients received 4 mg/kg or 8 mg/kg intravenous dulanermin on days 1-5 of up to four 21-day cycles and intravenous rituximab 375 mg/m(2) weekly for up to eight doses. In phase 2, patients were randomly assigned (1:1:1) centrally by an interactive voice response system to dulanermin (8 mg/kg for a maximum of four 21-day cycles), rituximab (375 mg/m(2) weekly for up to eight doses), or both in combination, stratified by baseline follicular lymphoma International Prognostic Index (0-3 vs 4-5) and geographic site (USA vs non-USA). The primary endpoints of the phase 1b study were the safety, tolerability, and pharmacokinetics of dulanermin with rituximab. The primary endpoint of phase 2 was the proportion of patients who achieved an objective response. All patients who received any dose of study drug were included in safety analyses. Efficacy analyses were per protocol. Treatment was open label; all patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, NCT00400764. FINDINGS Between June 6, 2006, and Feb 15, 2007, 12 patients were enrolled in phase 1b, and between April 4, 2007, and April 20, 2009, 60 patients were enrolled in phase 2, of whom 59 were included in safety analyses and 58 in efficacy analyses. No dose-limiting toxic effects were noted in phase 1b. The most common grade 1-2 adverse events in phase 1b were fatigue (nine; 75%), rash (five; 42%), and chills, decreased appetite, diarrhoea, and nausea (four each; 33%). 19 grade 3 or higher adverse effects were noted in five (42%) patients, with 14 occurring in one patient. After treatment with 8 mg/kg of dulanermin, in six patients the mean serum peak concentration was 80 μg/mL, dropping below the minimum detectable concentration (2 ng/mL) within 24 h after the dose. The mean steady state peak and trough concentrations of rituximab were 461 μg/mL (SD 97.5) and 303 μg/mL (92.8), respectively. In phase 2, eight (14%) of 59 patients experienced 12 grade 3 or higher adverse events. In phase 2, objective responses were noted in 14 of 22 (63.6%, 95% CI 41.8-81.3) patients treated with rituximab only, 16 of 25 (64.0%, 43.1-81.5) treated with dulanermin and rituximab, and one of 11 (9.1%, 0.5-39.0) treated with dulanermin only. The study was terminated early, on May 5, 2010, because of an absence of efficacy in the combination group. INTERPRETATION The addition of dulanermin to rituximab in patients with indolent B-cell non-Hodgkin lymphoma was tolerable but did not lead to increased objective responses. This combination is not being developed further in non-Hodgkin lymphoma. FUNDING Genentech and Amgen.

A Phase Ib Dose‐Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS

Abstract Lessons Learned. Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents. The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. Background. KRAS‐mutant tumors possess abnormal mitogen‐activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual‐action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen‐activated protein kinase (MEK) in KRAS‐mutant tumors may provide additive benefit. Methods. Patients with KRAS‐mutant solid tumors were eligible for this phase Ib dose‐escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. Results. Twenty‐three patients were enrolled. Dose‐limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. Conclusion. Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment.

Abstract CT110: Randomized phase II study of duligotuzumab + FOLFIRI versus cetuximab + FOLFIRI in 2nd-line patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC)

Background: Duligotuzumab (MEHD, MEHD7945A) is a novel dual-action humanized IgG1 antibody that blocks EGFR and HER3 binding, inhibiting all major ligand-dependent HER complex signaling. MEHD is active in multiple tumor models, including models resistant to anti-EGFR or anti-HER3. Emerging data in CRC suggest a role for HER3 in de novo and acquired resistance to anti-EGFR therapy. Methods: This open-label, randomized Phase II study enrolled patients (pts) with KRAS exon 2 wt mCRC who progressed on/after oxaliplatin-containing chemotherapy. Pts received a combination of MEHD (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1w) + FOLFIRI (q2w) until progression or intolerable toxicity. Endpoints included progression-free survival (PFS), and objective response rate (ORR), overall survival (OS), and adverse events (AEs). Tumor samples were mandatory and underwent biomarker analysis for ERBB3, NRG1 and EGFR ligand expression by qRT-PCR, and ERBB3 by IHC. The primary efficacy analysis was conducted in patients with RAS wt tumors (no mutations detected in KRAS or NRAS exons 2, 3; exon 4 mutations pending). Results: Of 134 randomized patients, 98 were RAS ex2/3 wt (53 MEHD); median age 63 years, ECOG 0-1. As of 21Aug14, 11 pts remain active. Efficacy results (Table) show no benefit of MEHD + FOLFIRI; ORR was lower in the MEDH arm. No relationship was seen between PFS or ORR and mRNA expression for ERBB3 or NRG1, or ERB3 expression by IHC. There were fewer rash events of any grade in the MEHD arm (79% and 93%) but more diarrhea (89% and 66%). Incidence of Grade ≥ 3 AEs was similar between arms (87% and 89%); however, the frequency of SAEs was higher in the MEHD arm (55% and 48%). Cumulative dose intensity and duration of treatment with FOLFIRI were lower in the MEHD arm. Conclusions: MEHD + FOLFIRI did not improve outcomes of pts with RAS ex2/3 wt mCRC compared to cetuximab + FOLFIRI. Updated efficacy, safety and biomarker data will be presented. Citation Format: Andrew G. Hill, Michael Findlay, Matthew Burge, Christopher Jackson, Pilar Garcia Alfonso, Leslie Samuel, Vinod Ganju, Meinolf Karthaus, Alessio Amatu, Mark Jeffery, Maria DiBartolomeo, John Bridgewater, Andrew Coveler, Manuel Hidalgo, Amy V. Kapp, Roxana Sufan, Bruce McCall, Elicia Penuel, Andrea Pirzkall, Josep Tabernero. Randomized phase II study of duligotuzumab + FOLFIRI versus cetuximab + FOLFIRI in 2nd-line patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC). [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 CT110. doi:10.1158/1538-7445.AM2015-CT110

989PDPHASE 1B STUDY OF MEHD7945A (MEHD) PLUS CISPLATIN/FLUOROURACIL (CIS/5FU) OR CARBOPLATIN/PACLITAXEL (CARBO/PAC) FOR 1ST-LINE TREATMENT OF RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA OF HEAD AND NECK (RMSCCHN)

ABSTRACT Aim: MEHD, a novel dual-action humanized IgG1 antibody that blocks ligand binding to HER3 and EGFR, inhibits signaling from ligand-dependent HER dimers. MEHD is active in multiple tumor models, including models resistant to anti-EGFR or anti-HER3, and enhances activity of chemotherapeutic agents. Single-agent activity in Phase 1a included confirmed PR in 2 RMSCCHN patients (pts) who had high levels of the HER3 ligand NRG1. Methods: This open-label, multicenter, Phase 1b study with a modified 3 + 3 + 3 design assesses safety, PK and preliminary anti-tumor activity (RECIST v1.1) of MEHD plus platinum-based chemotherapy in 1st-line RMSCCHN pts. MEHD 1650 mg IV every 3 wks is combined with cis 100 mg/m2 / 5FU 1000 mg/m2/d on Days 1-4 (Arm A) or carbo (AUC 6 mg/mL·min) / pac 200 mg/m2 (Arm B) on Day 1 of 21-d cycles (up to 6), followed by MEHD maintenance until disease progression / intolerable toxicity. Mandatory tumor samples are assayed by qRT-PCR for biomarkers related to mechanism of action and SCCHN. Results: As of 28MAR14, 18 pts were treated and remain active: 6 ARM A pts have received 2-7 cycles (median 5.5) of MEHD; 13 Arm B pts have received 1-8 cycles (median 3.5). DLTs occurred in 2 pts in Arm A (1 G3 diarrhea, 1 G3 acute renal failure & G3 febrile neutropenia) and 1 pt in Arm B (G3 dehydration, anorexia). G ≥ 3 treatment-related AEs in ≥2 pts were hypokalemia (3), neutropenia (3), dehydration (3), fatigue (2), and hyponatremia (2) in Arm A and neutropenia (6), febrile neutropenia (3), and hyponatremia (2) in Arm B. Chemo dose was reduced in 9/18 pts. Preliminary MEHD PK in both arms was similar to single-agent MEHD profile. In 12 pts with on-treatment tumor assessments, best responses were 9 (75%) PR (4 confirmed) [Arm A: 4; Arm B: 5; HPV: 2 + , 5-, 2 unknown], and 3 (25%) stable disease [Arm A: 1; Arm B: 2]; after data cutoff 2 pts were reported with CR. Further biomarker data are pending. Conclusions: MEHD plus cis/5FU or carbo/pac has been reasonably well tolerated with no new safety signals. G ≥ 3 AEs were manageable and less frequent post-Cycle 1. Both combinations had promising anti-tumor activity. Updated results will be presented. Disclosure: T. Seiwert: Research funding; X. Wang, A. Kapp, S. Royer-Joo, E. Penuel, B. McCall and A. Pirzkall: Genentech employee. All other authors have declared no conflicts of interest.

Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer

Purpose: Duligotuzumab is a dual-action antibody directed against EGFR and HER3. Experimental Design: Metastatic colorectal cancer (mCRC) patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors. Results: Of 134 randomly assigned patients, 98 had RAS ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR) in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab. Conclusions: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared with cetuximab + FOLFIRI. Clin Cancer Res; 24(10); 2276–84. ©2018 AACR.

Abstract 1553: Biomarker evaluation in a randomized phase 2 study of MEHD7945A (MEHD) versus cetuximab (Cet) in ≥2 line recurrent/metastatic (R/M) squamous cell carcinomas of the head and neck (SCCHN) [MEHGAN]

Background MEHD is a novel dual-action humanized IgG1 antibody that blocks ligand binding to EGFR and HER3, inhibiting all major ligand-dependent HER complex signaling. Preclinical and Phase 1a clinical data suggested ligand-driven HER3 signaling as a promising target for therapy in a subset of patients with SCCHN. Results from the MEHGAN study showed comparable objective response rates and PFS for MEHD and Cet (Fayette et al, ESMO 2014). Here we report the results of comprehensive and comparative biomarker analyses from that study. Methods Archival and fresh (as available) tumor tissues were evaluated to characterize the biology of anti-HER therapy in SCCHN, and to identify potential predictive biomarkers for improved outcomes with MEHD compared to Cet, with particular attention to the HER3 ligand NRG1. NRG1 and ERBB3 RNA expression was measured by both ISH (data analysis are ongoing) and qRT-PCR. Additionally, extensive gene expression analyses and HPV detection were performed by qRT-PCR. Results Of 121 randomized patients in MEHGAN, 107 had archival tissues with sufficient tumor content and quality for biomarker analyses. Key findings include: 1) Most patients with CT RECIST responses on either treatment arm had higher (≥ median) tumor expression levels of NRG1 as measured by qRT-PCR 2) EGFR ligands such as amphiregulin were co-expressed with NRG1, consistent with preclinical analysis in an independent panel of SCCHN tumor samples (Genentech data on file). 3) 24 HPV (+) patients (20%) were identified, consistent with published prevalence reports. 4) Higher EGFR and HER3 ligand expression was observed in HPV (-) samples relative to HPV (+) samples and, moreover, no responses were seen in HPV (+) patients. These results are consistent with prior correlative ligand observations and may point to differential roles for HER signaling biology in HPV (-) versus HPV (+) SCCHN. Conclusions NRG1 expression did not predict enhanced responsiveness to MEHD versus Cet or, conversely, resistance to Cet. NRG1 and EGFR ligands appear to have similar expression patterns in SCCHN. Higher levels of NRG1 and EGFR ligands were associated with greater activity for both MEHD and Cet, and were consistently observed in HPV (-) SCCHN versus HPV (+) SCCHN. These data suggest distinct HER signaling biology in these 2 patient groups and warrant further evaluation to potentially inform treatment approaches in SCCHN. * We would like acknowledge and thank all of the MEHGAN study investigators and patients. Citation Format: Elicia Penuel, Amy V. Kapp, An Do, Rachel Tam, Teiko Sumiyoshi, Chaitra Marathe, Susan Sa, Franklin Peale, Mark Lackner, Scott Holden, Tanguy Seiwert, Andrea Pirzkall. Biomarker evaluation in a randomized phase 2 study of MEHD7945A (MEHD) versus cetuximab (Cet) in ≥2 line recurrent/metastatic (R/M) squamous cell carcinomas of the head and neck (SCCHN) [MEHGAN]. [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 1553. doi:10.1158/1538-7445.AM2015-1553