Geraldine O’Sullivan Coyne

Nivolumab: Promising Survival Signal Coupled With Limited Toxicity Raises Expectations

Decades of research suggesting an association between tumors and immune tolerance have led to the development of an array of immunotherapeutic strategies to reactivate the adoptive and innate immune system against tumor antigens. Understanding of this association has led to the development of multiple immunotherapy approaches, including immune checkpoint inhibition. Emerging clinical data, such as those presented in the article by Topalian et al that accompanies this editorial, introduce the possibility that not only can these immunotherapy treatments be added to treatment regimens, but perhaps they can raise survival curves to new heights. Identified in 1976, interleukin-2 (IL-2) was the first treatment to show promise in advanced melanoma. Although positive outcomes were limited (approximately 20% response rate, with durable complete responses [CRs] of up to 8%), data were sufficient for the US Food and Drug Administration to approve the use of IL-2 in malignant melanoma in 1998. However, the substantial toxicity profile of IL-2 limited its application to select patient populations in specialized treatment centers. For the next 20 years, essentially palliative treatment options, including dacarbazine, temozolomide, and multiple combination drug regimens, resulted in reports of similar response rates, without the durable CRs seen with IL-2. Ipilimumab (Yervoy; Bristol-Myers Squibb, Princeton, NJ), an anti-CTLA-4, immunoglobulin G1 monoclonal antibody, was the first treatment to show improvement in overall survival (OS) in melanoma in randomized trials. Two separate, appropriately powered, randomized controlled trials in previously treated and untreated patients with advanced melanoma suggested a 28% to 34% decrease in mortality for patients receiving ipilimumab and a significant improvement in OS compared with the control arms. This landmark breakthrough for cancer immunotherapy led to US Food and Drug Administration approval of ipilimumab for melanoma in 2011, but also brought a novel group of adverse effects that were presumed to be secondary to host immunologic enhancement. These treatment-emergent, immune-related adverse events (irAE), which were associated with inflammation of nontarget tissues, proved to be reversible by cessation of the drug, with or without the addition of glucocorticoids. In previously treated patients receiving ipilimumab alone or with an active control (gp100 vaccine), OS was 10.1 months and 10.0 months versus 6.4 months for patients receiving the vaccine alone. In this second-line setting, an estimated 21.6% to 23.5% of patients treated with ipilimumab were alive at 24 months versus 13.7% of patients in the control group. In a subsequently reported trial, previously untreated patients had a median OS of 11.2 months versus 9.1 months when treated with ipilimumab with dacarbazine or placebo with dacarbazine, respectively. Approximately 40% of previously untreated patients who received ipilimumab-dacarbazine were still alive at 1 year, compared with 36.3% in the dacarbazine-placebo group. At 3 years, an estimated 20.8% of patients were alive in the ipilimumab-dacarbazine group versus 12.2% of patients in the dacarbazine-placebo arm. Both of these phase III ipilimumab trials had different patient populations. The study by Hodi et al included 676 patients treated with 3 mg/kg of ipilimumab in a second-line setting; 12% of patients had treated brain metastasis and 23% received previous IL-2 therapy. The trial by Robert et al included 502 previously untreated patients, excluded patients with brain metastasis, ocular melanoma, or previous adjuvant therapy, and used ipilimunab 10 mg/kg induction followed by maintenance therapy. In the article that accompanies this editorial, Topalian et al report pooled outcomes for their expansion-dose cohort of patients with melanoma treated with nivolumab, a fully human, immunoglobulin G4 antagonist monoclonal antibody targeting PD-1, an immune checkpoint. Patients had participated in the phase I trial of nivolumab in locally advanced solid malignancies, which was published in 2012. The safety and outcome data cover a maximum follow-up of 4.3 years, the longest available for patients with melanoma treated with an anti-PD-1 agent. Topalian et al included 107 patients from pooled cohorts (62% had received at least two previous therapies), and included patients with ocular melanoma or clinically stable brain metastasis. Patients receiving nivolumab were enrolled in three dose-escalation cohorts, with dose-escalation permitted within the lower-dose groups at disease progression. The authors’ analysis, which was based on findings of durable responses in this patient group, again confirmed noteworthy survival outcomes. Median OS was 16.8 months, with 1and 2-year survival rates of 62% and 43%, respectively, and an estimated median response of 2 years’ duration in patients with confirmed tumor regression (31%). Although the patient populations are different and the currently published data for nivolumab are less than for ipilimumab, the OS signal seen is encouraging. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 10 APRIL 1 2014

Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis)

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

PARP Inhibitors in Reproductive System Cancers: Current Use and Developments

The repair of DNA damage is a critical cellular process governed by multiple biochemical pathways that are often found to be defective in cancer cells. The poly(ADP-ribose) polymerase (PARP) family of proteins controls response to single-strand DNA breaks by detecting these damaged sites and recruiting the proper factors for repair. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage. While PARP inhibition may not, in itself, be sufficient to cause tumor cell death, inhibition of DNA repair with PARP inhibitors is an effective cytotoxic strategy when it is used in patients who carry other defective DNA-repair mechanisms, such as mutations in the genes BRCA 1 and 2. This discovery has supported the development of PARP inhibitors (PARPi), agents that have proven effective against various types of tumors that carry BRCA mutations. With the application of next-generation sequencing of tumors, there is increased interest in looking beyond BRCA mutations to identify genetic and epigenetic aberrations that might lead to similar defects in DNA repair, conferring susceptibility to PARP inhibition. Identification of these genetic lesions and the development of screening assays for their detection may allow for the selection of patients most likely to respond to this class of anticancer agents. This article provides an overview of clinical trial results obtained with PARPi and describes the companion diagnostic assays being established for patient selection. In addition, we review known mechanisms for resistance to PARPi and potential strategies for combining these agents with other types of therapy.

Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma

Introduction: The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib. Areas covered: The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed. Expert opinion: Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.

Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials

Since modulation of the putative target and the observed anti-tumor effects form the basis for the clinical development of a molecularly targeted therapy, early-phase clinical trials should be designed to demonstrate proof-of-mechanism in tissues of interest. In addition to establishing safety and the maximum tolerated dose, first-in-human clinical trials should be designed to demonstrate target modulation, define the proposed mechanism of action, and evaluate pharmacokinetic-pharmacodynamic relationships of a new anti-cancer agent. Assessing target modulation in paired tumor biopsies in patients with solid tumors presents multiple challenges, including procedural issues such as patient safety, ethical considerations, and logistics of sample handling and processing. In addition, the availability of qualified biomarker assay technologies, resources to conduct such studies, and real-time analysis of samples to detect inter-species differences that may affect the determination of optimal sampling time points must be taken into account. This article provides a discussion of the challenges that confront the practical application of pharmacodynamic studies in early-phase clinical trials of anti-cancer agents.

Clinical experience with ramucirumab: outcomes in breast cancer

Introduction: Monoclonal antibodies and small molecules targeting the VEGF pathway are part of the arsenal to treat malignant tumors. Antiangiogenesis therapies has been studied in breast cancer with partial success, reflected by the approval of bevacizumab in Europe but not in United States, for metastatic breast cancer (mBC). Ramucirumab is a mAb against VEGFR-2 interfering with the normal activation of this receptor by its natural ligand VEGF. Areas covered: This article will review the preclinical data available to date for ramucirumab, as well as survey the main clinical trials of antiangiogenic agents reported in breast cancer, focusing on Phase III clinical trials. It will also review the clinical trial data for ramucirumab in mBC, including the design of the Phase II trials, and report on the preliminary results of the TRIO-012 trial. This trial did not meet its primary end point in progression-free survival and has to be considered as a negative trial. Expert opinion: Despite preliminary positive data with ramucirumab in other metastatic solid tumors reported to date, the results of TRIO-012 discourage pursuing more efforts with ramucirumab in mBC unless predictive and reproducible biomarkers can be established to select those patients who are most likely to benefit from it.

MABp1 for the treatment of colorectal cancer.

ABSTRACT Introduction: Inflammation is an established process in colorectal cancer development and a hallmark of progression, and pro-inflammatory cytokines have been implicated in the morbidity and functional compromise associated with malignancy. MABp1, described as a first-in-class true human antibody against interleukin-1α, has undergone clinical trial evaluation in a number of indications, recently completing late phase clinical trial testing under Fast Track designation for cancer anorexia-cachexia syndrome in colorectal cancer patients. To date, MABp1 has been evaluated as a novel therapeutic strategy to ameliorate phenotypic factors associated with poor prognosis in colorectal cancer patients. Areas covered: In this review, the authors discuss the clinical trial data available to date for this antibody in colorectal cancer, including novel clinical trial endpoints utilized to evaluate sarcopenia and inflammation, as well as the proposed role of interleukin-1α antagonism in leading to improved patient outcomes. Expert opinion: There is a multitude of antibodies in therapeutic development in oncology, and MABp1 is a novel class of antibody which has been safely tolerated to date. Clinical studies of this agent suggest a significant improvement in lean body mass, though additional results evaluating the impact of targeting inflammation as a strategy to delay disease progression in this population are awaited.

A Phase I Study of Ganetespib and Ziv‐Aflibercept in Patients with Advanced Carcinomas and Sarcomas

Abstract Lessons Learned. The combination of the antiangiogenic agent ziv‐aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected adverse events and was not tolerable on the dosing schedule tested. Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens. Background. Although inhibition of angiogenesis is an effective strategy for cancer treatment, acquired resistance to antiangiogenic therapy is common. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates various oncogenic signaling pathways involved in acquired resistance and has been shown to play a role in angiogenesis. Combining an antiangiogenic agent with an Hsp90 inhibitor has therefore been proposed as a strategy for preventing resistance and improving antitumor activity. We conducted a single‐arm phase I study evaluating the combination of ziv‐aflibercept, an antiangiogenic drug, with the Hsp90 inhibitor ganetespib. Methods. Adult patients were eligible if they had recurrent or metastatic gastrointestinal carcinomas, nonsquamous non‐small cell lung carcinomas, urothelial carcinomas, or sarcomas that had progressed after at least one line of standard therapy. Ziv‐aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28‐day cycle. Results. Five patients were treated with the combination. Although three patients achieved stable disease, study treatment was associated with several serious and unexpected adverse events. Conclusion. The dose escalation phase of this study was not completed, but the limited data obtained suggest that this combination may be too toxic when administered on this dosing schedule.

Abstract 4678: Pilot trial of talazoparib (BMN 673), an oral PARP inhibitor, in patients with advanced solid tumors carrying deleterious BRCA mutations

Inhibition of poly (ADP-ribose) polymerase (PARP) sensitizes tumor cells to DNA damage that would normally be repaired through the base excision repair pathway. PARP inhibitors are active clinically against BRCA-deficient ovarian cancers. The PARP inhibitor talazoparib produces cytotoxicity in human cancer cell lines and animal models of tumors that harbor mutations that compromise DNA repair pathways. In this study, single agent talazoparib (1000 µg/day) was administered to patients with deleterious BRCA1 or BRCA2 mutations and advanced solid tumors in 28 day cycles. The primary objective of the trial was to examine pharmacodynamic (PD) effects of talazoparib; the secondary objective was to determine response rate in patients whose tumors carry BRCA mutations. Mandatory paired tumor biopsies were obtained pre-treatment and 3-6 hrs post-treatment on cycle 1 day 8. Optional biopsies were collected at the time of progression. One core from each time point was analyzed for PARP inhibition by a validated ELISA assay while the other core was used for IFA analysis of γH2AX. A total of 9 patients (pts) were enrolled and treated before this trial was closed due to lack of drug availability: [prostate (3), ovarian (2), breast (2), uterine sarcoma (1), pancreatic (1)]. Median age was 63 (range: 33-73 yrs); male-to-female ratio was 4:5; and the median number of prior treatments was 6 (range: 1-12). All 9 pts were evaluable for PD endpoints. One pt progressed during the first cycle of treatment; 8 pts were evaluable for clinical response. Mean time on study for evaluable pts was 8 cycles (range: 2-18); 5 of 8 (62%) pts experienced a documented partial responses [ovarian (2), prostate (2), breast (1)] lasting between 4 and 12 cycles (median: 6 cycles). Two pts had stable disease for 4 to 6 cycles, and one progressed after 2 cycles. The agent was well tolerated; the most frequent adverse events were hematologic including grade (gr) 4 anemia (1) and thrombocytopenia (1), and gr 3 anemia (2), neutropenia (1), lymphopenia (1). Decreases in PAR levels (>75%) were observed in all cycle 1 day 8 biopsy pairs, documenting a primary PD effect. Increased γH2AX expression was observed for 4/6 pts in post-dose biopsies; pre-treatment γH2AX levels, measured as %Nuclear Associated Protein (NAP), increased from a mean ± SD of 1.33 ± 1.08 to a post-treatment %NAP mean of 5.60 ± 0.78; (p=0.018), supporting a role for drug-enhanced DNA double strand breaks in the mechanism of action of talazoparib for BRCA mutant tumors. In summary, talazoparib demonstrated significant clinical activity as a single agent in patients with BRCA-deficient tumors and produced substantial reductions in tumor PAR levels in matched pre and post-treatment tumor biopsies. Citation Format: Robert S. Meehan, Alice P. Chen, Geraldine O’Sullivan Coyne, Shivaani Kummar, Jiuping Ji, Rasa Vilimas, Lamin Juwara, Robert J. Kinders, Katherine Ferry-Galow, Deborah Wilsker, Yiping Zhang, Angie B. Dull, Tony Navas, Lihua Wang, Ralph E. Parchment, James H. Doroshow. Pilot trial of talazoparib (BMN 673), an oral PARP inhibitor, in patients with advanced solid tumors carrying deleterious BRCA mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4678. doi:10.1158/1538-7445.AM2017-4678

Abstract 1316: Evaluation of immune cell subsets of cancer patients treated with a fully human IgG1 anti-PD-L1 MAb (MSB0010718C) capable of mediating ADCC of human tumor cells

Background: Several monoclonal antibodies (MAbs) with demonstrated clinical anti-cancer activities have been engineered as fully human IgG1 entities to also encompass their potential to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells. MSB0010718C is a fully human IgG1 MAb targeting the co-regulatory protein Programmed Death-Ligand 1 (PD-L1), and is thus distinct from other MAbs targeting the PD-L1/PD-1 axis currently being evaluated in clinical trials. One possibility is that an anti-PD-L1 antibody capable of inducing ADCC may negatively affect PD-L1 expressing immune cell subtypes. This work is intended to determine if there is any validity to this concern. Methods: The clinical activity of MSB0010718C, observed in several tumor types in ongoing clinical studies such as NCT01772004, has been and will be reported elsewhere. In the studies reported here, MSB0010718C is shown to mediate ADCC of several types of human tumor cell lines (e.g., breast, lung, bladder carcinomas) in vitro, with tumor cell lysis mediated mainly by human CD16+ monocytes and natural killer (NK) cells. Since some human immune cell subsets express PD-L1 on their cell surface (albeit at relatively low levels compared to many tumor cells), studies were undertaken to evaluate changes in the frequency of immune cell subsets in peripheral blood mononuclear cells (PBMC) from cancer patients pre- vs post-treatment with MSB0010718C. Immune cells evaluated were PD-L1 positive and PD-L1 negative subsets of the following: CD4+ T cells, CD8+ T cells, NK cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), natural killer T cells (NKT), plasmacytoid dendritic cells (DC), conventional DC, and B cells. Results: Forty-two post-treatment PBMC samples were evaluated as follows: pre vs 1 dose of MSB0010718C (day 15, n = 19); pre vs 3 doses of MSB0010718C (day 43, n = 14); and pre vs 9 doses of MSB0010718C (day 127, n = 9). In all cases there were no statistical differences pre- vs post-treatment in any immune cell subset, and at any time point analyzed, regardless of whether the immune subset expressed PD-L1 or not. In addition, no changes were observed in absolute lymphocyte counts at any time point analyzed. Conclusion: While immune cell subsets pre- vs post-treatment continue to be analyzed in various patient cohorts, these studies provide evidence that MSB0010718C, a fully human IgG1 MAb, capable of mediating ADCC, can be administered safely to cancer patients without altering the balance of numerous PBMC immune cell subsets. Citation Format: Lauren M. Lepone, Renee N. Donahue, Benedetto Farsaci, Italia Grenga, Benjamin Boyerinas, Caroline Jochems, Kwong-Yok Tsang, Christopher R. Heery, Ravi A. Madan, Geraldine O9Sullivan Coyne, Harpreet Singh, James L. Gulley, Jeffrey Schlom. Evaluation of immune cell subsets of cancer patients treated with a fully human IgG1 anti-PD-L1 MAb (MSB0010718C) capable of mediating ADCC of human tumor cells. [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 1316. doi:10.1158/1538-7445.AM2015-1316