ORIGINAL ARTICLE

Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE)

M. Kundranda1, A. C. Gracian2,3, S. F. Zafar4, E. Meiri5, J. Bendell6, H. Algül7, F. Rivera8, E. R. Ahn9, D. Watkins10, U. Pelzer11, V. Charu12, A. Zalutskaya13, G. Kuesters13, J. M. Pipas13, S. Santillana13, V. Askoxylakis13 &A.H.Ko14*

1Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, USA; 2Medical Oncology, Centro Integral Oncologico Clara Campal and 3Departamento de Ciencias Médicas Clínicas, Universidad CEU San Pablo, Madrid, Spain; 4Hematology and Oncology, Florida Cancer Specialists, Fort Myers; 5Medical Oncology, Comprehensive Care and Research Center, Atlanta; 6GI Oncology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA; 7TUM School of Medicine, Klinikum rechts der Isar, Medizinische Klinik II, Technical University of Munich, Munich, Germany; 8Medical Oncology, Hospital Universitario Marques de Valdecilla, Santander, Spain; 9Medical Oncology, Cancer Treatment Centers of America Chicago, Zion, USA; 10Department of Medicine, Royal Marsden Hospital, Sutton, UK; 11Charité e Universitätsmedizin Berlin, Germany; 12Hematology/Oncology, Pacific Cancer Medical Center, Anaheim; 13Clinical Development, Merrimack Pharmaceuticals, Inc., Cambridge; 14Hematology/Oncology, University of California San Francisco Cancer Center, San Francisco, USA

Background: Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels. Patients and methods: CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab- paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)þ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate. Results: A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n ¼ 43; control n ¼ 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) ¼ 1.88, P ¼ 0.027]. In the high IGF-1/HRGþ subgroup (n ¼ 44), median PFS was 4.1 and 7.3 months, respectively (HR ¼ 1.39, P ¼ 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade 3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%). Conclusions: Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls. Clinical Trial Registration numbers: ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34. Key words: CARRIE, heregulin, insulin-like growth factor 1, istiratumab, metastatic pancreatic cancer, MM-141

INTRODUCTION within the decade.1,2 In patients with metastatic disease, two fl Pancreatic ductal adenocarcinoma represents one of the most chemotherapy options, FOLFIRINOX ( uorouracil, leucovorin, aggressive malignancies and is expected to become the sec- irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel, ond leading cause of cancer-related death in the United States have emerged as front-line standards of care based on data demonstrating a significant survival benefit for each of these regimens compared with single-agent gemcitabine. However, *Correspondence to: Dr Andrew H. Ko, Hematology/Oncology, University of in each of these pivotal studies the median survival of patients California San Francisco, PO Box 0981, University of California, San Francisco, þ remained less than 1 year, highlighting the ongoing need to San Francisco, CA 94143-0981, USA. Tel: 1-415-353-9888 3,4 E-mail: [email protected] (A. H. Ko). develop better therapies for this disease. Lack of effective 0923-7534/© 2019 European Society for Medical Oncology. Published by targeted agents and a paucity of validated predictive Elsevier Ltd. All rights reserved.

Volume 31 - Issue 1 - 2020 https://doi.org/10.1016/j.annonc.2019.09.004 79 Annals of Oncology M. Kundranda et al. biomarkers that can guide therapeutic decision making randomized in a 1 : 1 fashion to the experimental arm represent major limitations in the treatment of pancreatic (istiratumab plus gemcitabine and nab-paclitaxel, at afore- cancer. said doses and schedule) or to the control arm (placebo i.v. Insulin-like growth factor (IGF) signaling plays an impor- every 2 weeks plus nab-paclitaxel and gemcitabine). tant role in regulating growth and development in normal Assignment was stratified by region (United States or human tissues.5 The IGF axis comprises insulin and two Europe). Treatment started within 7 days following related ligands, IGF-1 and IGF-2, that regulate cellular pro- randomization and continued until investigator-determined cesses by interacting with specific cell-surface receptors. progressive disease (PD) based on RECIST v.1.1 or unac- The IGF-1 receptor (IGF-1R) is a heterotetrameric tyrosine ceptable toxicity. The primary endpoint was progression- kinase receptor with two extracellular ligand-binding alpha free survival (PFS), defined as the time from randomiza- subunits and two transmembrane beta subunits containing tion to the first documented radiographical progression of the kinase domain.6 Increased expression of IGF-1R and/or disease using RECIST, or death from any cause, whichever circulating levels of IGF ligands have been observed in came first. Two patient populations were used for co- various cancers, including pancreatic cancer, Ewing sar- primary PFS analysis: (i) those with high levels of free IGF- coma, breast cancer, prostate cancer, and .7 In 1 (the entire study cohort), and (ii) those with both high addition to its presence being essential for malignant levels of free IGF-1 and whose tumors showed high level of transformation, overexpression is associated with faster heregulin expression (HRGþ), as measured retrospectively disease progression and poorer prognosis.7 Furthermore, in pretreatment tumor samples by an HRG RNA-in situ hy- increased levels of IGF-1 are associated with greater risk of bridization assay (Advanced Cell Diagnostics reagents cancer development and resistance to chemotherapies.8 [Newark, California], tested and scored at Merrimack). Istiratumab (MM-141) is a fully human tetravalent bispe- HRGþ was defined as at least 10% of tumor cells showing cific antibody that binds to and co-inhibits IGF-1R and the positive staining. Secondary efficacy endpoints included epidermal growth factor family of receptor tyrosine kinases disease control rate (DCR), defined as complete response, B3 (ErbB3). Structurally, it is a homodimer containing two partial response, or stable disease lasting at least 16 weeks; sets of identical polypeptide chains: a heavy chain of an overall survival (OS); investigator-assessed objective immunoglobulin-type G1 antibody targeting IGF-1R that is response rate (ORR); duration of response, and safety engineered to present a single-chain Fv antibody fragment profile. targeting ErbB3 at the C terminus; and a light chain targeting 8 IGF-1R. The dual activity of this agent is intended to over- Patient eligibility come the limitations of monospecific anti-IGF-1R antibodies, Primary eligibility criteria included age 18 years; including inhibiting the compensatory ErbB3 signaling that confirmed metastatic adenocarcinoma of the pancreas; no occurs upon IGF-1R blockade. This multicenter, double-blind, prior surgery, chemotherapy, or investigational therapy for placebo-controlled randomized phase II trial evaluated metastatic disease; high serum levels of free IGF-1 (defined chemotherapy in combination with either istiratumab or as 0.235 ng/ml using an enzyme-linked immunosorbent placebo in patients with untreated metastatic pancreatic assay validated at a single USA-based Clinical Laboratory cancer selected for elevated free serum IGF-1 levels. Improvement Amendments-certified central laboratory); an Eastern Cooperative Oncology Group (ECOG) performance PATIENTS AND METHODS status of 0 or 1; adequate organ and bone marrow function; and measurable disease based on National Cancer Institute CARRIE was a randomized, double-blind, placebo-controlled, RECIST v.1.1.9 Free IGF-1 serum samples were shipped international, phase II study of istiratumab in combination frozen and results provided within 5 business days of with nab-paclitaxel and gemcitabine versus nab-paclitaxel receipt at the central laboratory. An archived formalin-fixed and gemcitabine alone as front-line therapy for metastatic paraffin-embedded tumor sample (tumor block or 15 un- pancreatic cancer.The study was conducted across 48 sites in stained, paraffin-dipped slides) from the primary pancreatic the United States and 24 sites in Europe. Institutional review tumor or a metastatic lesion was required for study eligi- boards and/or ethics committees approved the protocol at all bility for assessing HRG expression; if unavailable, patients sites. Study conduct followed International Conference on underwent a prospectively collected core research tumor Harmonisation Guidelines for Good Clinical Practice, biopsy. including written informed consent from all patients and rigorous data monitoring. As a safety lead-in, the first 10 patients were treated Study assessments open-label with istiratumab 2.8 g intravenously (i.v.) every 2 Tumor assessments were performed every 8 weeks weeks in combination with nab-paclitaxel 125 mg/m2 i.v. (1 week) using RECIST v.1.1 until documented PD or and gemcitabine 1000 mg/m2 i.v. administered in standard treatment termination, whichever came first. All patients dose schedule (weekly for 3 weeks followed by 1 week off). who came off treatment for reasons other than PD under- This initial group of patients was non-randomized and went serial imaging at 8-week intervals (1 week) until PD, therefore not included in the final efficacy analyses. For the initiation of another line of therapy, or death. Safety ana- randomized portion of the study, eligible patients were lyses were performed using the safety population, defined

80 https://doi.org/10.1016/j.annonc.2019.09.004 Volume 31 - Issue 1 - 2020 M. Kundranda et al. Annals of Oncology as all patients who received at least one dose of study test, stratified by United States or Europe, was used to medication. Safety assessments included physical exami- compare the ORR between the two treatment arms. The nations, electrocardiograms, adverse event (AE), and clinical study was planned to end when 30 HRGþ and 64 overall laboratory tests monitoring. Severity of AEs and laboratory events occurred or 52 weeks after the first dose of the last abnormalities were graded using the National Cancer randomized patient, whichever occurred first, or the study Institute Common Terminology Criteria for Adverse Events was terminated by the sponsor. The study was completed version 4.0. An independent data monitoring committee in June 2018. reviewed all safety information. AEs of special interest included infusion-related reactions. After patients dis- RESULTS continued study treatment, survival information and infor- Patient characteristics mation regarding ongoing cancer treatment were collected until death or study closure. Safety follow-up was done for A total of 317 patients were prescreened for the study 30 days after the last treatment dose. between May 2016 and May 2017, of whom half (n ¼ 158) were found to have high free IGF-1 levels. Of these, 88 patients were randomized to either the experimental Statistical analysis (n ¼ 43) or control (n ¼ 45) arm (Figure 1). Demographic Assessment of PFS in patients with high free IGF-1 (overall) and clinical characteristics of the study population were required a total of 64 events to detect a hazard ratio (HR) similar across treatment arms (Tables 1 and 2). Median age of 0.63, assuming 80% power in favor of the experimental was 60 in both arms. The majority of patients (w60%) had arm using a one-sided significance level at 0.15. This cor- an ECOG performance status of 1. There were slight im- responded to a median PFS of 8 months versus 5 months balances between the two arms in terms of stage at original for patients on the experimental versus control arms, diagnosis (more early stage disease, and hence more receipt respectively. Assuming an accrual duration of 12 months, of prior adjuvant therapy, in the control arm) and CA19-9 80 patients were anticipated to be needed to achieve a levels at diagnosis (more patients with non-elevated levels total of 64 PFS events over 22 months. Based on an in the experimental arm). Almost all patients had tumor anticipated high free IGF-1 prevalence rate of 50%e60% specimens available for HRG testing; in total, w60% of and an additional clinical screening failure rate of 30%e patients were ‘double-positive’ (high free IGF-1/HRGþ), 40%, it was expected that w260 patients would be with a slightly higher proportion of patients on the con- required to identify w80 IGF-1-high patients eligible for trol arm having HRGþ tumors. evaluation. The percentage of HRGþ tumors in this IGF-1- highcohortwasexpectedtobew50% (i.e. 40/80, Efficacy assuming evaluable tumor tissue from all patients). For the PFS (primary endpoint). For the entire study cohort, me- þ PFS analysis in HRG patients, 30 PFS events were dian PFS in the experimental arm was 3.6 months (95% CI required to detect an HR of 0.5 with 80% power in favor of 2.5e7.6) versus 7.3 months (95% CI 5.5e8.0) in the con- fi the experimental arm using a one-sided signi cance level trol arm. This difference was statistically significant at 0.15. This corresponds to a median PFS of 8 months (HR ¼ 1.883, P ¼ 0.0265). In the high free IGF-1/HRGþ versus 4 months, respectively, for the experimental and subgroup, median PFS also favored the control arm [4.1 þ control arms of this HRG subgroup. The co-primary PFS months (95% CI 2.4e9.2) versus 7.3 months (95% CI 4.9e endpoints for patients with high free IGF-1 levels (only) 8.0)], although this difference was not statistically signif- þ and patients with both high free IGF-1 levels and HRG icant (HR ¼ 1.390, P ¼ 0.4175; Figures 2 and 3). A similar tumors were analyzed using a stratified log-rank test. The 10 proportion of subjects on each arm received second-line Hochberg procedure to control type I error was applied therapy (62.8% on the experimental arm and 56.8% on for the analysis of the two co-primary endpoints of PFS. the control arm). The primary comparisons were based on the per-protocol population, definedasallpatientswhoreceivedatleast Secondary endpoints. For the entire study cohort, median one dose of study medication. The KaplaneMeier method OS in the experimental arm was 8.9 months (95% CI 6.8e was used to estimate median PFS for each treatment arm. 12.7) compared with 11.7 months (95% CI 8.9e13.7) in the Astratified Cox proportional hazard model was used to control arm (HR ¼ 1.358, P ¼ 0.2191). In the high free IGF- obtain an estimate of magnitude of treatment effect be- 1/HRGþ subgroup, OS was similar between the experi- tween the two arms [i.e. HR and corresponding 70% con- mental arm (9.1 months; 95% CI 3.8e14.1) and the control fidence interval (CI)]. The same methods were used for OS arm (10.8 months; 95% CI 6.3e13.0; HR ¼ 1.012, estimates. Patients who were alive or lost to follow-up at P ¼ 0.9735; Figures 2 and 3). Objective responses were the time of analysis were censored at the last known alive observed in 39.5% (17/43) of patients on the experimental date. Both ORR and DCR were summarized by frequencies arm and 51.2% (22/43) for the control arm (odds ratio and percentages, with estimates including 95% CI calcu- 0.6241; exact 95% CI 0.2430e1.6). DCRs were 46.5% and lated for each treatment arm. Patients without a post- 72.1%, respectively (odds ratio 0.3366; exact 95% CI baseline tumor assessment were considered non- 0.1240e0.9. Median duration of response was 4.8 months evaluable for response. The ManteleHaenszel chi-square (95% CI 2.1e5.7) and 5.3 months (95% CI 2.0e6.3).

Volume 31 - Issue 1 - 2020 https://doi.org/10.1016/j.annonc.2019.09.004 81 Annals of Oncology M. Kundranda et al.

Patients consented n = 325

Patients screened Withdrawn consent n = 317 n = 8

IGF-1 testing complete n = 315

Low IGF-1* High IGF-1* n = 158 n = 157

High IGF-1 randomized n = 88

Experimental group Control group High IGF-1 (n = 43) High IGF-1 (n = 45) High IGF-1 and HRG+ (n = 20) High IGF-1 and HRG+ (n = 24)

*High free IGF-1 ≥0.235 ng/ml

Figure 1. Patient disposition. HRGþ, high level of heregulin expression; IGF-1, insulin-like growth factor-1.

Safety and tolerability The frequencies of grade 3 TEAEs were similar between A total of 87 patients were included in the safety popula- treatment arms, including 38 (88.4%) patients in the tion. Median study drug exposure was three and six cycles experimental arm and 37 (84.1%) patients in control. in the experimental versus control arm, respectively. All Serious TEAE rates were also similar, including 21 (48.8%) patients experienced at least one treatment-emergent AE patients in the experimental arm and 22 (50.0%) patients in (TEAE). The most common related TEAEs of any grade the control arm. The most common TEAEs are shown in (observed in 10% of patients) in the experimental arm Table 3. were neutropenia (n ¼ 18, 41.9%), alopecia (n ¼ 17, More patients discontinued treatment as a result of low- ¼ 39.5%), diarrhea and fatigue (n ¼ 16, 37.2%, each), grade AEs in the experimental arm (n 18, 45.9%) when ¼ thrombocytopenia (n ¼ 15, 34.9%), anemia, and decreased compared with the control arm (n 11, 25.0%), including appetite (n ¼ 14, 32.6%, each). gastrointestinal, hematological, and metabolic toxicities.

Table 1. Patient demographics

Demographics Parameter Experimental arm (N [ 43) Control arm (N [ 45)a Total (N [ 88) n (%) n (%) n (%) Age Mean 61.77 60.82 61.28 Median 60.0 60.0 60.0 Min/Max 45/85 40/86 40/86 Sex Female 16 (37) 26 (58) 42 (48) Male 27 (63) 19 (42) 46 (52) ECOG performance status 0 18 (42) 19 (42) 37 (42) 1 25 (58) 26 (58) 51 (58) Geographic region United States 29 (67) 30 (67) 59 (67) Europe 14 (33) 15 (33) 29 (33) Race White 36 (84) 38 (84) 74 (84) Black 5 (12) 5 (11) 10 (11) Asian 1 (2.3) 2 (4.4) 3 (3.4) Other 1 (2.3) 0 (0) 1 (1.1) ECOG, Eastern Cooperative Oncology Group. a Forty-five patients were randomized to the control arm, but one patient was not dosed and was therefore not included in the analysis of the safety population.

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Table 2. Patient baseline disease characteristics

Disease characteristic Parameter Experimental arm (N [ 43) Control arm (N [ 45)a Total (N [ 88) n (%) n (%) n (%) Location in pancreas of original tumor Head 18 (42) 22 (49) 40 (45) Body 16 (37) 14 (31) 30 (34) Tail 17 (40) 17 (38) 34 (39) Unknown 0 (0) 1 (2.2) 1 (1.1) TNM staging: primary tumor 0 0 (0) 0 (0) 0 (0) IA 0 (0) 0 (0) 0 (0) IB 0 (0) 1 (2.2) 1 (1.1) IIA 0 (0) 2 (4.4) 2 (2.2) IIB 2 (4.7) 1 (2.2) 3 (3.3) III 1 (2.3) 2 (4.4) 3 (3.3) IV 40 (93) 39 (87) 79 (90) Baseline CA19-9 n 43 44 87 Normal 11 (26) 3 (6.8) 14 (16) <59 ULN 11 (26) 20 (45) 31 (36) 59 ULN 21 (49) 21 (48) 42 (48) Prior adjuvant therapy Yes 0 (0) 5 (11) 5 (5.7) No 43 (100) 40 (89) 83 (94) Number of metastatic sites 1 16 (37) 17 (38) 33 (38) 2 17 (40) 14 (31) 31 (35) 3 5 (12) 3 (6.7) 8 (9.1) >3 5 (12) 11 (24) 16 (18) IGF-1 level at screening (ng/ml) Mean 0.44 0.48 0.46 Median 0.43 0.43 0.43 Min/max 0.25/1.27 0.24/0.95 0.24/1.27 Intratumoral expression of HRG n 39 39 78 Positive 20 (51) 25 (64) 45 (58) Negative 19 (49) 14 (36) 33 (42) IGF, insulin-like growth factor; ULN, upper limit of normal. a Forty-five patients were randomized to the control arm, but one patient was not dosed and was therefore not included in the analysis of the safety population.

There were no serious AEs (SAEs) leading to death in the based on a prespecified interim futility analysis; moreover, in experimental arm (n ¼ 0) versus control (n ¼ 2, 4.5%). that study, dichotomization of patients based on median These two SAEs in the control arm resulting in death were baseline levels of circulating serum IGF-1 failed to show any general physical health deterioration and sepsis. AEs of treatment effect on OS or PFS.12 special interest occurred more frequently in the experi- The potential therapeutic value of inhibiting ErbB3 mental arm (n ¼ 9, 20.9%) versus control (n ¼ 0). All these (HER3), a member of the ErbB/EGFR family of signaling events were grade 1 (n ¼ 1) or grade 2 (n ¼ 8). proteins, has been studied to a lesser degree in the clinic, in the context of both anti-HER3 antibodies13,14 and pan-HER inhibitors.15,16 Upon binding to its cognate ligand heregulin DISCUSSION (HRG), ErbB3 dimerizes with other ErbB family members The mechanistic rationale for targeting the IGF axis in solid (preferentially ErbB2), resulting in activation of the PI3K/ tumors, including pancreatic cancer, derives from the AKT/mTOR pathway. Beyond its established role in pro- important role IGF/IGFR signaling is known to play in moting cancer cell growth and survival, it is also a known tumorigenesis, including activation of both the phosphoi- mediator of resistance to cancer treatment, particularly nositide 3-kinase/protein kinase B/mammalian target of epidermal growth factor receptor inhibitors.17,18 rapamycin (PI3K/AKT/mTOR) and Ras/Raf/MAPK (mitogen- Istiratumab, a bispecific antibody that binds and co- activated protein kinase) pathways that promote cell growth, inhibits both IGF-1R and ErbB3, was engineered based transformation, migration, and survival. Promising activity on the hypothesis that it degrades IGF-1R levels to a was previously observed with the addition of , an greater extent than monospecific anti-IGF-1R antibodies, anti-IGF-1R , to gemcitabine in a ran- as well as prevents compensatory upregulation of ErbB3 in domized phase II study of patients with metastatic pancreatic response to the IGF-1R blockade via simultaneous inhibi- cancer. The positive treatment effect on OS was particularly tion of ErbB3 signaling. In multiple preclinical models of pronounced in the subset of patients with higher baseline pancreatic cancer both in vitro and in vivo, istiratumab circulating factors of the IGF axis, including total IGF-1 (me- demonstrated the ability to potentiate activity of nab- dian OS of 16 months versus 6.8 months in the ganitumab- paclitaxel/gemcitabine, through inhibition of AKT phos- versus the placebo-containing arms, respectively; HR ¼ 0.25; phorylation and promotion of IGF-1R and ErbB3 degrada- 95% CI 0.09e0.67; P ¼ 0.006) and free IGF-1 (median OS of tion.8 These findings provided the rationale for the CARRIE 11 months versus 3.6 months).11 However, a subsequent study, which was designed to test the efficacy of adding phase III trial (GAMMA) of this agent in the first-line treat- this agent to gemcitabine and nab-paclitaxel in previously ment of metastatic pancreatic cancer was stopped early untreated patients with metastatic pancreatic cancer, with

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PFS

1.0 Median (95% Cl) Events (%) Censors (%) MM-141 + chemo (n = 43): 3.6 (2.5–7.6) 26 (60.5) 17 (39.5) Placebo + chemo (n = 44): 7.3 (5.5–8.0) 28 (63.6) 16 (36.4) 0.8 Stratified log-rank test P value: 0.0265 Hazard ratio (70% Cl): 1.883 (1.395–2.541) 0.6

Censored 0.4

0.2 Probability of progression-free Patient at risk 0.0 44 42 35 33 27 25 20 14 8 6 4 3 1 433931201196655110 0123456789101112 Time since randomization (months)

OS 1.0 Median (95% Cl) Events (%) Censors (%) MM-141 + chemo (n = 43): 8.9 (6.8–12.7) 33 (76.7) 10 (23.3) Placebo + chemo (n = 44): 11.7 (8.9–13.7) 32 (72.7) 12 (27.3) 0.8 Stratified log-rank test P value: 0.2191 Hazard ratio (95% Cl): 1.358 (0.832–2.215) 0.6

Censored 0.4

Probability of survival 0.2

Patient at risk 0.0 44 43 43 42 40 39 37 33 30 28 27 24 19 16 11 8 5 4 2 1 0 434241373332292623201817171376410 0123456789101112 13 14 15 16 17 18 19 20 Time since randomization (months) MM-141 + chemo Placebo + chemo

Figure 2. Progression-free survival (PFS) and overall survival (OS) in patients with high insulin-like growth factor-1 (IGF-1). CI, confidence interval. enrollment specifically limited to individuals with elevated IGF-1 levels did not suggest improved clinical outcomes circulating serum free IGF-1 levels. Quite disappointingly, with istiratumab. This trial also did not include on- or post- no improvements in any clinically relevant parameters treatment pharmacodynamic measures of on-target activity, were observed even in this biomarker-enriched cohort. and thus suboptimal inhibition of both IGF-1/IGF-1R and Thesamelackofbenefit was also true for the subset of HER3 signaling cannot be ruled out. Finally, it is possible ‘double-positive’ patients whose tumors expressed HRG. that IGF-1R blockade in our study population resulted in Indeed, somewhat surprisingly, for the primary study compensatory signaling in other pathways with pro- endpoint of PFS there appeared to be a trend toward oncogenic activity (such as insulin receptor, growth hor- poorer patient outcomes in the istiratumab-containing mone receptor, and epidermal growth factor receptor treatment arm. pathways)19 to the extent that these compensatory mech- Reasons for these negative findings remain unclear. anisms may have accelerated disease progression and Higher rates of low-grade toxicities did lead to increased contributed to the worse outcomes seen in the experi- numbers of treatment discontinuation in the experimental mental arm. arm, although this factor alone is unlikely to explain the Several valuable lessons emerge from this trial. Despite poorer results in this group. It is plausible that the threshold the negative results, CARRIE offered an important practical for free serum IGF-1 used for patient eligibility in this study demonstration of the feasibility of conducting a biomarker- was set too low; however, analyses of patients with higher selected trial in metastatic pancreatic cancer on an

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PFS

1.0 Median (95% Cl) Events (%) Censors (%) MM-141 + chemo (n = 20): 4.1 (2.4–9.2) 14 (70.0) 6 (30.0) Placebo + chemo (n = 24): 7.3 (4.9–8.0) 14 (58.3) 10 (41.7) 0.8 Stratified log-rank test P value: 0.4175 Hazard ratio (70% Cl): 1.390 (0.911–2.121) 0.6

Censored 0.4

0.2 Probability of progression-free Patient at risk 0.0 24 22 17 16 13 12 12 7 2 2 1 1 1 20 19 16 10 7 6 4 4 4 4 1 1 0 0123456 7 8 9 10 11 12 Time since randomization (months)

OS 1.0 Median (95% Cl) Events (%) Censors (%) MM-141 + chemo (n = 20): 9.1 (3.8–14.1) 15 (75.0) 5 (25.0) Placebo + chemo (n = 24): 10.8 (6.3–13.0) 18 (75.0) 6 (25.0) 0.8 Stratified log-rank test P value: 0.9735 Hazard ratio (95% Cl): 1.012 (0.503–2.036) 0.6

Censored 0.4

Probability of survival 0.2

Patient at risk 0.0 24 24 24 23 21 21 19 16 14 13 13 11 9 6 4 4 4 3 2 1 0 20202016151412111110999654210 0123456789101112 13 14 15 16 17 18 19 20 Time since randomization (months)

MM-141 + chemo Placebo + chemo

Figure 3. Progression-free survival (PFS) and overall survival (OS) in patients with high insulin-like growth factor-1 (IGF-1) and high level of heregulin expression (HRGD). CI, confidence interval. international scaledone in which the biomarker of interest setting. Previously published studies have examined represents an integral element of trial design. Indeed, for a elevated circulating levels of IGF-1 as a risk factor for disease often characterized by a rapid clinical decline, both pancreatic cancer development, with mixed results20e23; patients and physicians understandably feel an urgency to however, relatively little is known regarding the prognostic initiate treatment as soon as possible; therefore, it is information this may offer for patients after a diagnosis of imperative that any study-associated screening procedures pancreatic cancer. In the PLCO Cancer Screening Trial, 178 be completed with minimal delay. The rapid turnaround subjects who subsequently developed pancreatic cancer time for IGF-1 testing on this trial (generally 5 business had their IGF-1 levels measured at the time of trial enroll- days from laboratory receipt of sample) was critical in ment, with no significant associations observed between allowing for rapid eligibility assessment. However, we also concentration and OS following pancreatic cancer detec- acknowledge that only 56% (88 of 157) of subjects who tion. However, these measurements were obtained an tested high for IGF-1 ultimately enrolled on the trial, average of >5 years prior to the time the diagnosis of reflecting that this waiting period may have, in some in- pancreatic cancer was made.24 A nested caseecontrol study stances, been a hindrance to study participation. of 69 pancreatic cancer cases and 207 matched controls Our study results offer further insight, albeit indirect, into showed a positive, but statistically insignificant, association the prognostic implications of the IGF axis in this clinical between serum levels of IGF-1 and risk of death from

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ACKNOWLEDGEMENTS Table 3. Most common treatment-emergent adverse events Merrimack Pharmaceuticals had roles in the study design; TEAE preferred term Experimental arm Control arm (N [ 43), n (%) (N [ 44), n (%) collection, analysis, and interpretation of data; and decision to submit paper for publication. All grade Grade 3 All grade Grade 3 The corresponding author had full access to all the data Any 43 (100) 38 (88.4) 44 (100) 37 (84.1) in the study; was responsible for writing of the report; and Diarrhea 22 (51.2) 2 (4.7) 16 (36.4) 1 (2.3) fi Decreased appetite 19 (44.2) 2 (4.7) 16 (36.4) 2 (4.5) had nal responsibility for the decision to submit for Fatigue 19 (44.2) 2 (4.7) 25 (56.8) 6 (13.6) publication. Neutropenia 18 (41.9) 13 (30.2) 22 (50.0) 15 (34.1) Alopecia 17 (39.5) 0 23 (52.3) 0 FUNDING Hyperglycemia 16 (37.2) 9 (20.9) 4 (9.1) 3 (6.8) Anemia 15 (34.9) 8 (18.6) 20 (45.5) 8 (18.2) This trial was funded by Merrimack Pharmaceuticals,Inc. Headache 15 (34.9) 1 (2.3) 7 (15.9) 0 There are no grant numbers for this trial. Thrombocytopenia 15 (34.9) 7 (16.3) 13 (29.5) 3 (6.8) Nausea 14 (32.6) 1 (2.3) 24 (54.5) 1 (2.3) Epistaxis 12 (27.9) 0 5 (11.4) 0 DISCLOSURE Dehydration 11 (25.6) 2 (4.7) 6 (13.6) 0 Hypokalemia 11 (25.6) 6 (14.0) 9 (20.5) 1 (2.3) MK: Research funding (paid to institution): Celgene, Chronix, Pyrexia 11 (25.6) 0 18 (40.9) 3 (6.8) Merck. Consultant or Advisory Role: Bayer and Amgen. HA: Vomiting 11 (25.6) 3 (7.0) 14 (31.8) 1 (2.3) Speaker for Celgene and Servier; Research grant from Chugai. Asthenia 10 (23.3) 2 (4.7) 11 (25.0) 2 (4.5) Peripheral edema 10 (23.3) 1 (2.3) 17 (38.6) 1 (2.3) FR: Consultant or Advisory Role: Roche, Merck-Serono, Amgen, Platelet count decreased 10 (23.3) 3 (7.0) 3 (6.8) 0 MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier, Astra-Zeneca, Abdominal pain 9 (20.9) 1 (2.3) 18 (40.9) 6 (13.6) Bayer. Research Funding: Roche, Merck-Serono, Amgen, MSD, Constipation 9 (20.9) 0 14 (31.8) 0 fi Infusion-related reaction 9 (20.9) 0 0 0 Lilly, Celgene, Sano -Aventis, Bayer. Speaking: Roche, Merck- Peripheral neuropathy 9 (20.9) 0 13 (29.5) 1 (2.3) Serono,Amgen,MSD,BMS,Lilly,Celgene,Sanofi-Aventis, Weight decreased 9 (20.9) 1 (2.3) 5 (11.4) 0 Servier, Bayer. Grant support: Amgen. DW: AmgendFunding to TEAE, treatment-emergent adverse event. support educational conference attendance. UP: Consultant or Research grants: Bayer, BMS, Celgene, Lilly, Servier, Leo Pharma, Merck, Novartis, Pfizer, Roche, pancreatic cancer, with subjects in the highest quartile Sanofi-Aventis, Shire, B. Braun, and Halozyme. AZ, VA, GK, having an odds ratio of 2.31 (95% CI 0.70e2.64) compared 25 JMP, and SS were Merrimack employees at the time of the with those in the lowest quartile. However, this obser- study. AK: Research funding (paid to institution): Celgene, vation again speaks more to IGF-1 in terms of its possible Roche/Genentech, Merrimack, Halozyme, Merck, BMS, role in pancreatic development rather than necessarily its Astellas, AbGenomics, Apexigen. Consultant or Advisory Role: prognostic utility post-cancer diagnosis. Celgene, ARMO BioSciences, Gilead, Gritstone. ACG, SFZ, EM, Recognizing the modest sample size of our study cohort, JB, ERA, and VC have declared no conflicts of interest. patients with elevated free IGF-1 levels did not appear to have a particularly poor prognosis when comparing survival REFERENCES outcomes with those reported for patients enrolled on the (non-biomarker-selected) phase III MPACT trial of 1. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and gemcitabine/nab-paclitaxel. While acknowledging the limita- methods. Int J Cancer. 2019;144:1941e1953. tions of cross-study comparisons, survival outcomes as well 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. as additional efficacy measures (PFS and ORR) on the current 2019;69:7e34. study matched or exceeded those reported in MPACT. For 3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine comparison, it would be informative to look at survival rates for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817e1825. 4. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic in patients who failed screening for the CARRIE trial on the cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369: basis of low IGF-1 levels. However, as these patients were 1691e1703. allowed to receive any standard chemotherapy regimen (or 5. Denduluri SK, Idowu O, Wang Z, et al. Insulin-like growth factor (IGF) other experimental therapy) at the discretion of their treat- signaling in tumorigenesis and the development of cancer drug ing physician, and did not undergo any protocol-standardized resistance. Genes Dis. 2015;2:13e25. fi 6. Ullrich A, Gray A, Tam AW, et al. Insulin-like growth factor I receptor pri- follow-up, interpretation of any ndings may be limited. mary structure: comparison with insulin receptor suggests structural de- terminants that define functional specificity. EMBO J. 1986;5:2503e2512. Conclusions 7. Jin M, Buck E, Mulvihill MJ. Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current In summary, the addition of istiratumab to standard front- status and future perspectives. Oncol Rev. 2013;7:e3. line chemotherapy did not improve PFS, OS, nor any 8. Camblin AJ, Pace EA, Adams S, et al. Dual inhibition of IGF-1R and other clinically relevant parameters for patients with met- ErbB3 enhances the activity of gemcitabine and nab-paclitaxel in astatic pancreatic cancer with elevated free IGF-1 levels, preclinical models of pancreatic cancer. Clin Cancer Res. 2018;24: 2873e2885. with or without increased intratumoral HRG expression. 9. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation Further clinical development of this bispecific antibody does criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J not appear justified in this particular disease setting. Cancer. 2009;45:228e247.

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10. Hochberg Y. A sharper Bonferroni procedure for multiple tests of sig- 17. Campbell MR, Amin D, Moasser MM. HER3 comes of age: new insights nificance. Biometrika. 1988;75(4):800e802. into its functions and role in signaling, tumor biology, and cancer 11. McCaffery I, Tudor Y, Deng H, et al. Putative predictive biomarkers of therapy. Clin Cancer Res. 2010;16:1373e1383. survival in patients with metastatic pancreatic adenocarcinoma treated 18. Sergina NV, Rausch M,Wang D, et al. Escape from HER-family tyrosine kinase with gemcitabine and ganitumab, an IGF1R inhibitor. Clin Cancer Res. inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437e441. 2013;19:4282e4289. 19. Beckwith H, Yee D. Minireview: were the IGF signaling inhibitors all 12. Fuchs CS, Azevedo S, Okusaka T, et al. A phase 3 randomized, bad? Mol Endocrinol. 2015;29:1549e1557. double-blind, placebo-controlled trial of ganitumab or placebo in 20. Douglas JB, Silverman DT, Pollak MN, et al. Serum IGF-I, IGF-II, IGFBP-3, combination with gemcitabine as first-line therapy for metastatic and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. prostate, lung, colorectal, and ovarian cancer screening trial. Cancer 2015;26:921e927. Epidemiol Biomarkers Prev. 2010;19:2298e2306. 13. Meulendijks D, Jacob W, Martinez-Garcia M, et al. First-in-human 21. Gong Y, Zhang B, Liao Y, et al. Serum insulin-like growth factor axis and phase I study of , a glycoengineered humanized anti- the risk of pancreatic cancer: systematic review and meta-analysis. HER3 monoclonal antibody, in patients with metastatic or advanced Nutrients. 2017;9(4):E394. HER3-positive solid tumors. Clin Cancer Res. 2016;22:877e885. 22. Rohrmann S, Grote VA, Becker S, et al. Concentrations of IGF-I and 14. Reynolds KL, Bedard PL, Lee SH, et al. A phase I open-label dose- IGFBP-3 and pancreatic cancer risk in the European prospective inves- escalation study of the anti-HER3 monoclonal antibody LJM716 in tigation into cancer and nutrition. Br J Cancer. 2012;106:1004e1010. patients with advanced squamous cell carcinoma of the esophagus or 23. Wolpin BM, Michaud DS, Giovannucci EL, et al. Circulating insulin-like head and neck and HER2-overexpressing breast or gastric cancer. BMC growth factor axis and the risk of pancreatic cancer in four prospective Cancer. 2017;17:646. cohorts. Br J Cancer. 2007;97:98e104. 15. Adams R, Brown E, Brown L, et al. Inhibition of EGFR, HER2, and HER3 24. Toriola AT, Ziegler M, Li Y, et al. Prediagnosis circulating insulin-like signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, growth factors and pancreatic cancer survival. Ann Surg Oncol. KRAS, and NRAS (FOCUS4-D): a phase 2-3 randomised trial. Lancet 2017;24:3212e3219. Gastroenterol Hepatol. 2018;3:162e171. 25. Lin Y, Tamakoshi A, Kikuchi S, et al. Serum insulin-like growth factor-I, 16. Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients insulin-like growth factor binding protein-3, and the risk of pancreatic with HER2- and HER3-mutant cancers. Nature. 2018;554:189e194. cancer death. Int J Cancer. 2004;110:584e588.

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