Juanita Lopez

Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial

BACKGROUND Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort. METHODS Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria included measurable disease, failure of standard therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1. PD-L1 positivity was defined as expression in 1% or more of tumour cells by immunohistochemistry. Response was assessed based on investigator review using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Primary endpoints were safety and tolerability, analysed in the all-patients-as-treated population, and objective response, analysed for the full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT02054806, and is ongoing but not recruiting participants. FINDINGS As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%]). Five (20%) patients reported grade 3 treatment-related adverse events. Three (12%) patients required dose interruption because of immune-related adverse events: one (4%) of 25 each had grade 3 rhabdomyolysis and grade 2 hypothyroidism; grade 3 iridocyclitis, grade 1 erythema multiforme, and grade 3 erythema; and grade 2 infusion-related reaction. No treatment-related deaths or discontinuations occurred. Five (20%) patients had a partial response, for an objective response of 20% (95% CI 6·8-40·7), and 13 (52%) of 25 had stable disease. Responses were durable (median response duration 12·0 months [95% CI 3·7 to not reached]); two patients remained on treatment at data cutoff. INTERPRETATION Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation. FUNDING Merck.

Combine and conquer: challenges for targeted therapy combinations in early phase trials

Our increasing understanding of cancer biology has led to the development of molecularly targeted anticancer drugs. The full potential of these agents has not, however, been realised, owing to the presence of de novo (intrinsic) resistance, often resulting from compensatory signalling pathways, or the development of acquired resistance in cancer cells via clonal evolution under the selective pressures of treatment. Combinations of targeted treatments can circumvent some mechanisms of resistance to yield a clinical benefit. We explore the challenges in identifying the best drug combinations and the best combination strategies, as well as the complexities of delivering these treatments to patients. Recognizing treatment-induced toxicity and the inability to use continuous pharmacodynamically effective doses of many targeted treatments necessitates creative intermittent scheduling. Serial tumour profiling and the use of parallel co-clinical trials can contribute to understanding mechanisms of resistance, and will guide the development of adaptive clinical trial designs that can accommodate hypothesis testing, in order to realize the full potential of combination therapies.

Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1–Positive Endometrial Cancer: Results From the KEYNOTE-028 Study

Purpose The multicohort phase Ib KEYNOTE-028 (NCT02054806) study was designed to evaluate the safety and efficacy of pembrolizumab, an anti-programmed death 1 monoclonal antibody, in patients with programmed death ligand 1 (PD-L1) -positive advanced solid tumors. The results from the advanced endometrial cancer cohort are reported. Patients and Methods Female patients with locally advanced or metastatic PD-L1-positive endometrial cancer who had experienced progression after standard therapy were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until progression or unacceptable toxicity. Primary efficacy end point was objective response rate by RECIST (version 1.1). Secondary end points included safety, duration of response (DOR), progression-free survival, and overall survival. The data cutoff was February 17, 2016. Results Of 75 patients screened, 36 (48.0%) had PD-L1-positive tumors, and 24 (32.0%) were enrolled. Fifteen (62.5%) of these 24 patients had received at least two previous lines of therapy for advanced disease. Three patients (13.0%) achieved confirmed partial response (95% CI, 2.8% to 33.6%); the median DOR was not reached. Two patients were still receiving treatment and exhibiting continued response at time of data cutoff. Three additional patients (13.0%) achieved stable disease, with a median duration of 24.6 weeks. One patient who achieved partial response had a polymerase E mutation. Thirteen patients (54.2%) experienced treatment-related adverse events (AEs), with fatigue (20.8%), pruritus (16.7%), pyrexia (12.5%), and decreased appetite (12.5%) occurring in ≥ 10% of patients. Grade 3 treatment-related AEs were reported in four patients. No patient experienced a grade 4 AE, and no patient discontinued treatment because of an AE. Conclusion Pembrolizumab demonstrated a favorable safety profile and durable antitumor activity in a subgroup of patients with heavily pretreated advanced PD-L1-positive endometrial cancer.

Immuno-oncology combinations: raising the tail of the survival curve.

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Combining DNA damaging therapeutics with immunotherapy: more haste, less speed

The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I–III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.

Abstract CT010: Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations

Background: Preclinical synergy between PARP and PI3K pathway inhibition in BRCA m and sporadic cancers provided rationale for this trial. Methods: Ola 300mg BID was combined with 2 schedules of AZD BID: 4 days on 3 days off (4/7) and 2 days on 5 days off (2/7) using a novel intrapatient dose escalation design (Michalarea et al, AACR 2015). Cohort expansion of pts with gBRCA m tumors and sporadic tumors with relevant somatic mutations or BRCAness phenotype, assessed 2 regimens: (1) 300mg BID Ola + 400mg BID 4/7 AZD and (2) 300mg BID Ola + 640mg BID 2/7 AZD. Targeted next generation sequencing (NGS) of tumor and cell-free (cf)DNA from 3-weekly plasma samples with a 113 gene panel was undertaken in all pts. Results: 53 pts with advanced cancers (21 gBRCA m) were enrolled (20 in dose escalation; 33 in dose expansion), including ovarian (9/19 with BRCA m), breast (8/16 with BRCA m), prostate (3/4 with BRCA m) and bile duct (1/2 with BRCA m) cancers. Common G1-2 toxicities were nausea, fatigue, anemia, diarrhea, anorexia, mucositis and vomiting on both schedules. 1 dose limiting toxicity (DLT) of G3 rash was seen at 300mg BID Ola + 480mg BID 4/7 AZD. In 4/7 schedule (n = 23), non-DLT G3 toxicities were anemia (n = 3), diarrhea, vomiting and proteinuria (all n = 1). In 2/7 schedule (n = 30), non-DLT G3 toxicities were transaminitis, nausea, fatigue, anemia (all n = 2), rash, hyperglycemia and diarrhea (all n = 1). There were 10 RECIST complete or partial responses (CR/PR) out of 37 (15 BRCA m) evaluable pts, including gBRCA m breast (n = 4), platinum-resistant gBRCA m ovarian (n = 2), BRCA wildtype (WT) triple negative breast (n = 1), BRCA WT ovarian (n = 2) and BRCA unknown prostate (n = 1) cancer pts. A BRCA1 m prostate cancer pt has MRI and PSA responses for 21mths+. A PI3K/mTOR inhibitor resistant peritoneal mesothelioma pt had CA125 response and RECIST stable disease (SD) for 21m. Of 5 ovarian cancer pts who had prior PARP inhibitors, 1 pt had RECIST PR at 13wks+ and 2 pts had SD with tumor shrinkage (18 and 24 wks). 160 cfDNA samples from 38 pts underwent NGS (minimum coverage 500X). Driver mutations were detected and tracked from baseline in 28 (76%) pts. Concordance in mutation status between tumor and cfDNA was 100% in 24/28 (86%) pts. 70% of pts had DNA repair gene mutations, most frequently BRCA. TP53 (40%) and KRAS (25%) were the most commonly detected somatic mutations. Changes in cfDNA concentrations appeared to correlate with treatment response in 72% of pts, while tracking of mutation allele frequency in serial cfDNA samples during treatment showed potential clonal responses. Conclusion: The combination of Ola and AZD is well tolerated with multiple responses in both gBRCA and non-BRCA m tumors, and prior PARP inhibitor treated cancers. The recommended phase 2 doses are 300mg BID Ola + 400mg BID 4/7 AZD and 300mg BID Ola + 640mg BID 2/7 AZD. Citation Format: Vasiliki Michalarea, Desam Roda, Yvette Drew, Suzanne Carreira, Brent S. O’Carrigan, Heather Shaw, Rene Roux, Sanjeev Kumar, Sarah Ward, Mona Parmar, Alison Turner, Emma Hall, Sonia Serrano Fandos, Raquel Perez, Nina Tunariu, Florence Raynaud, Marie Cullberg, Andrew Foxley, Justin PO Lindemann, Martin Pass, Paul Rugman, Juanita S. Lopez, Udai Banerji, Bristi Basu, Ruth Plummer, Rebecca Kristeleit, Johann S. de Bono, Timothy A. Yap. Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations. [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 CT010.

Abstract CT323: Accelerated phase I trial of two schedules of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363 using a novel intrapatient dose escalation design in advanced cancer patients

Background: There is an urgent need for better trial designs to assess targeted drug combinations. We proposed a novel intrapatient (intrapt) dose escalation trial design to optimize drug exposures, minimize pharmacokinetic (PK) variability and reduce patient (pt) numbers needed (Yap et al, JCO 2013). In vivo synergy between PARP and PI3K pathway inhibition was seen in BRCA1-related and sporadic cancers (Juvekar et al; Ibrahim et al, Cancer Discov 2012), providing rationale for this study. Methods: Two-stage investigator initiated phase I trial: a) Intrapt dose escalation; b) Recommended phase II combination dose (RP2CD) expansion. Advanced cancer pts received escalating doses of AZD5363 (AZD) BID in 2 parallel arms (4 days on 3 days off [4/7 arm] at 320, 400, 480mg; 2 days on 5 days off [2/7 arm] at 480, 560, 640mg) with Olaparib (Ola) at 300mg BID in 3 weekly cycles. AZD was escalated after each cycle in each pt if drug related toxicities were ≤CTCAE G2. Dose limiting toxicities (DLT) were assessed during the 1st cycle of each dose level (DL). ≥6 evaluable pts were required at each DL. RECIST assessment was done every 3 cycles. Prior PARP or PI3K/AKT inhibitor use was allowed. PK and pharmacodynamics (PD) were assessed in tumor and normal tissue. Targeted +/- whole exome next generation sequencing was assessed in tumor and serial plasma DNA samples in all pts for predictive biomarkers of response. Results: Dose escalation was completed in 7.5 months (m) in 20 pts in 1 center; ≥6 evaluable pts were treated at each of the 3 DLs in both arms. Common (>15%) G1-2 toxicities were nausea, vomiting, fatigue, diarrhea and anemia. A DLT of G3 rash was seen at 480mg BID 4/7 AZD + 300mg BID Ola. Non DLT G3 anemia (n = 2), diarrhea (n = 2), fatigue (n = 1) and vomiting (n = 1) were seen in 4/7 arm; G3 hyperglycemia (n = 1), transaminitis (n = 1) and fatigue (n = 2) in 2/7 arm. No significant PK interactions were seen between Ola and AZD. Intrapt dose escalation of AZD showed dose dependent increases in PK exposures. Platelet-rich plasma PD showed significant decreases in pSer9 GSK3β post-therapy at all DLs (mean ≥55% [p Conclusion: This novel trial design led to rapid completion of dose escalation. RP2CD expansion (n = 40) is ongoing in: a) germline BRCA mut cancers; b) sporadic cancers with relevant somatic mutations. Citation Format: Vasiliki Michalarea, David Lorente, Juanita Lopez, Suzanne Carreira, Hasina Hassam, Mona Parmar, Nitharsan Sathiyayogan, Alison Turner, Emma Hall, Sonia Serrano Fandos, Satyanarayana Seeramreddi, Shaun Decordova, Karen Swales, Ruth Ruddle, Florence Raynaud, Nina Tunariu, Gerhardt Attard, L. Rhoda Molife, Udai Banerji, Ruth Plummer, Johann S. de Bono, Timothy A. Yap. Accelerated phase I trial of two schedules of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363 using a novel intrapatient dose escalation design in advanced cancer patients. [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 CT323. doi:10.1158/1538-7445.AM2015-CT323

Precision Medicine for Molecularly Targeted Agents and Immunotherapies in Early-Phase Clinical Trials

Precision medicine in oncology promises the matching of genomic, molecular, and clinical data with underlying mechanisms of a range of novel anticancer therapeutics to develop more rational and effective antitumor strategies in a timely manner. However, despite the remarkable progress made in the understanding of novel drivers of different oncogenic processes, success rates for the approval of oncology drugs remain low with substantial fiscal consequences. In this article, we focus on how recent rapid innovations in technology have brought greater clarity to the biological and clinical complexities of different cancers and advanced the development of molecularly targeted agents and immunotherapies in clinical trials. We discuss the key challenges of identifying and validating predictive biomarkers of response and resistance using both tumor and surrogate tissues, as well as the hurdles associated with intratumor heterogeneity. Finally, we outline evolving strategies employed in early-phase trial designs that incorporate omics-based technologies.

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study

Background Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier NCT02054806.

The PI3K Pathway at the Crossroads of Cancer and the Immune System: Strategies for Next Generation Immunotherapy Combinations

Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for a subset of patients with advanced cancers. Increasingly, research has identified links between the immune system and critical oncogenic growth factor pathways. The phosphoinositide 3-kinase (PI3K)-AKT-mTOR cascade is frequently hyperactivated in cancer, and plays an integral role in many cellular processes including tumour growth and survival and can underlie resistance to therapies. In this review, we first summarize two key learnings from the initial studies of inhibitors of this pathway, including the profile of immune-related adverse events such as colitis, transaminitis and pneumonitis and the increased incidence of infections with the majority of agents that target the PI3K-AKT-mTOR pathway. We then discuss recent advances in our understanding of the role of this pathway in the tumour micro-environment, and in the regulation of innate and adaptive immune responses, and propose synergistic combination strategies with PI3K-network inhibitors and cancer immunotherapy.