Kumudu Pathiraja

Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study

PURPOSE Immune checkpoint inhibition has been demonstrated to be an effective anticancer strategy. Several lines of evidence support the study of immunotherapy in triple-negative breast cancer (TNBC). We assessed the safety and antitumor activity of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab in patients with advanced TNBC. METHODS KEYNOTE-012 (ClinicalTrials.gov identifier: NCT01848834) was a multicenter, nonrandomized phase Ib trial of single-agent pembrolizumab given intravenously at 10 mg/kg every 2 weeks to patients with advanced PD-L1-positive (expression in stroma or ≥ 1% of tumor cells by immunohistochemistry) TNBC, gastric cancer, urothelial cancer, and head and neck cancer. This report focuses on the TNBC cohort. RESULTS Among 111 patients with TNBC whose tumor samples were screened for PD-L1 expression, 58.6% had PD-L1-positive tumors. Thirty-two women (median age, 50.5 years; range, 29 to 72 years) were enrolled and assessed for safety and antitumor activity. The median number of doses administered was five (range, 1 to 36 doses). Common toxicities were mild and similar to those observed in other tumor cohorts (eg, arthralgia, fatigue, myalgia, and nausea), and included five (15.6%) patients with grade ≥ 3 toxicity and one treatment-related death. Among the 27 patients who were evaluable for antitumor activity, the overall response rate was 18.5%, the median time to response was 17.9 weeks (range, 7.3 to 32.4 weeks), and the median duration of response was not yet reached (range, 15.0 to ≥ 47.3 weeks). CONCLUSION This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated, advanced TNBC. A single-agent phase II study examining a 200-mg dose given once every 3 weeks (ClinicalTrials.gov identifier: NCT02447003) is ongoing.

Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial

BACKGROUND Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. METHODS This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan. We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan. The study is registered with ClinicalTrials.gov, number NCT01848834, and is ongoing but no longer enrolling patients. FINDINGS From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled. 36 were evaluable for response by central assessment. Eight (22%, 95% CI 10-39) patients were judged to have had an overall response at central review; all responses were partial. All 39 patients were included in the safety analyses. Five (13%) patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade 3 fatigue, one case each of grade 3 pemphigoid, grade 3 hypothyroidism, and grade 3 peripheral sensory neuropathy, and one case of grade 4 pneumonitis. No treatment-related deaths occurred. INTERPRETATION In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. FUNDING Merck & Co.

Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort

Purpose Treatment with pembrolizumab, an anti–programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) –positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1–positive versus –negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC.

Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort.

LBA6008 Background: Pembrolizumab (MK-3475) is a humanized monoclonal antibody that blocks interaction of PD-1 with its ligands, PD-L1 and PD-L2, thereby promoting activity of tumor-specific effector T cells. KEYNOTE 012 (NCT01848834) had previously demonstrated clinical activity of pembrolizumab 10 mg/kg every 2 weeks in patients (pts) with recurrent/metastatic SCCHN enriched for PD-L1-positive tumors with a response rate of 20%. We now report on the larger SCCHN expansion cohort of KEYNOTE 012, irrespective of biomarker status using a 3-weekly fixed dose. METHODS Pts with advanced SCCHN irrespective of PD-L1 expression or HPV status received a fixed dose of 200 mg pembrolizumab, intravenously, every 3 weeks. Pts were evaluated every 8 weeks with radiographic imaging. The primary end point was overall response rate (ORR) per investigator assessment (RECIST 1.1). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were assessed according to CTCAE v4. PD-L1 was assessed retrospectively by immunohistochemistry. RESULTS 132 pts with recurrent/metastatic SCCHN were enrolled. Mean (SD) age was 58.9 (9.7) years; 83.3% were male; 56.8% had ≥ 2 lines of therapy for recurrent disease. 73/132 pts (55.3%) remain on treatment. Out of 132 treated pts, 99 pts were available for this preliminary efficacy analysis with a post-baseline scan or discontinued therapy prior to the scan due to clinical progression or AE. ORR (confirmed and unconfirmed) per RECIST 1.1 was 18.2% (95% CI, 11.1-27.2) with 18 partial responses and 31.3% with stable disease. Biomarker analysis is ongoing and results will be presented. Drug-related AEs of any grade occurred in 47% of all enrolled pts, and drug-related grade ≥ 3 AEs occurred in 7.6%. The most common drug-related AEs ( ≥ 5%) of any grade were fatigue (12.1%), decreased appetite (6.8%), pyrexia (6.1%), and rash (5.3%). CONCLUSIONS Pembrolizumab given at a fixed dose of 200 mg every 3 weeks was well tolerated and demonstrated a clinically meaningful ORR of 18.2% in pts with recurrent/metastatic SCCHN. CLINICAL TRIAL INFORMATION NCT01848834.

A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of the O6-Methylguanine-DNA Methyltransferase Promoter

Responses of patients with gliomas to temozolomide are determined by O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) pathways. This phase II study (NCT00423150) investigated whether MGMT promoter methylation predicts response in patients with advanced aerodigestive tract and colorectal cancers (CRC). Tumor and serum samples were screened for MGMT promoter methylation. In methylation-positive patients, 150 mg/m2 temozolomide was administered daily on a seven-day-on, seven-day-off schedule for each 28-day cycle. The primary efficacy endpoint was response rate (RR). MMR status was determined by a microsatellite instability assay. Among 740 patients screened, 86 were positive for MGMT promoter methylation and enrolled. Nineteen percent of the screened population (137/740) had confirmed tissue and/or serum MGMT promoter methylation, including 25% (57 of 229) for CRC, 36% (55 of 154) for esophageal cancer, 11% (12 of 113) for head and neck cancer, and 5% (13 of 242) for non–small cell lung carcinoma. Among patients with valid methylation results in both tissue and serum samples, concordance was 81% (339 of 419). The majority of enrolled patients (69 of 86; 80%) had microsatellite stable cancer. Overall RR was 6% (5 of 86 partial responses); all responders had microsatellite stable cancer. Temozolomide resulted in low RRs in patients enriched for MGMT methylation. MGMT methylation status varied considerably in the patient population. Although serum methylation assay is an option for promoter methylation detection, tissue assay remains the standard for methylation detection. The low RR of this cohort of patients indicates that MGMT methylation as a biomarker is not applicable to heterogeneous tumor types, and tumor-specific factors may override validated biomarkers. Mol Cancer Ther; 12(5); 809–18. ©2013 AACR.

Efficacy and safety of dinaciclib versus ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia

To the editor: Novel approaches targeting molecules involved in intracellular pathways that are crucial for the survival and proliferation of the leukemic clone have been recently approved for the treatment of chronic lymphocytic leukemia (CLL) patients. Nevertheless, CLL remains incurable outside

A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

Robatumumab (19D12; MK‐7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin‐like growth factor receptor‐1 (IGF‐1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3).

A randomized, phase II study of the anti‐insulin‐like growth factor receptor type 1 (IGF‐1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer

Overexpression of insulin‐like growth factor receptor type 1 (IGF‐1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron‐emission tomography in patients with chemotherapy‐refractory colorectal cancer treated with an anti‐insulin‐like growth factor receptor type 1 (anti‐IGF‐1R) monoclonal antibody, robatumumab. This was a randomized, open‐label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second‐line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUVmax). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUVmax (DiSUV) greater than 20% 12–14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)‐defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%–32%) had DiSUV greater than 20%. Fifty robatumumab‐treated patients were evaluable for RECIST‐defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy‐refractory colorectal cancer appeared to benefit from treatment with the IGF‐1R antagonist robatumumab.

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012

BackgroundSecond-line treatment options for advanced head and neck squamous cell carcinoma (HNSCC) are limited. The phase Ib KEYNOTE-012 study evaluated the safety and the efficacy of pembrolizumab for the treatment of HNSCC after long-term follow-up.MethodsMulti-centre, non-randomised trial included two HNSCC cohorts (initial and expansion) in which 192 patients were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks (initial cohort; N = 60) or 200 mg every 3 weeks (expansion cohort; N = 132). Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1; central imaging vendor review).ResultsMedian follow-up was 9 months (range, 0.2–32). Treatment-related adverse events (AEs) of any grade and grade 3/4 occurred in 123 (64%) and 24 (13%) patients, respectively. No deaths were attributed to treatment-related AEs. ORR was 18% (34/192; 95% CI, 13–24%). Median response duration was not reached (range, 2+ to 30+ months); 85% of responses lasted ≥6 months. Overall survival at 12 months was 38%.ConclusionsSome patients received 2 years of treatment and the responses were ongoing for more than 30 months; the durable anti-tumour activity and tolerable safety profile, observed with long-term follow-up, support the use of pembrolizumab as a treatment for recurrent/metastatic HNSCC.

Abstract P6-10-03: KEYNOTE-012: Long-lasting responses in a phase Ib study of pembrolizumab for metastatic triple-negative breast cancer (mTNBC)

Background: In the multicenter, nonrandomized phase Ib KEYNOTE-012 trial (NCT01848834), the anti–PD-1 antibody pembrolizumab demonstrated promising antitumor activity (18.5% ORR in patients [pts] with measurable disease at baseline as assessed by RECIST v1.1 and central radiology review; 6-mo PFS rate, 24%; 12-mo OS rate, 43.1%; data cutoff date, March 23, 2015) and a manageable toxicity profile as later-line of therapy for previously treated, PD-L1+ mTNBC. Here we present updated data for the mTNBC cohort of KEYNOTE-012. Methods: Key enrollment criteria were: age ≥18 yr; ER-negative, PR-negative, HER2-negative, recurrent or metastatic breast cancer; measurable disease based on RECIST v1.1; ECOG PS 0-1; any number of prior systemic treatments in the metastatic setting; and PD-L1+ tumors (expression in stroma or ≥1% of tumor cells by IHC using the 22C3 antibody). Pts received pembrolizumab 10 mg/kg Q2W for 24 mo or until disease progression or unacceptable toxicity. Clinically stable pts with initial evidence of radiographic progression could remain on pembrolizumab until progression was confirmed. Response was assessed every 8 wk by central radiology review based on RECIST v1.1. After pembrolizumab discontinuation, pts were followed every 3 mo until death or withdrawal of consent. OS was estimated using the Kaplan-Meier method. Results: Thirty two female pts were enrolled. Median age was 50.5 yr (range, 29-72); 46.9% had received ≥3 lines of therapy and 25.0% had received ≥5 lines of therapy for metastatic disease. As of the data cutoff date of April 26, 2016, median follow-up duration was 10.7 mo (range, 0.4-32.7). Median OS was 10.2 mo (95% CI, 5.3-17.5) and 12-mo OS rate was 41.1%; 25 (78.1%) pts had died. Median PFS was 1.9 mo (95% CI, 1.3-4.3) and 12-mo PFS rate was 15.0%. Of the 5 responders (including 1 complete response [CR] and 4 partial responses [PR]), 3 have had long-lasting benefit from pembrolizumab. The pt with CR discontinued study medication 11 mo after achieving CR and has remained in CR for approximately 15 mo without receiving any additional anticancer treatment. Two pts with PR discontinued pembrolizumab after completing 2 yr of treatment. The first pt has maintained response for 22.7 mo; the second pt had disease progression after 7.7 mo of response and recently restarted pembrolizumab as allowed by protocol. Median duration of response has not been reached (range, 15-58+ wk). Thirty (93.8%) pts discontinued pembrolizumab (27 [84.4%] with progressive disease and 3 [9.4%] for AEs) before reaching 2 yr of treatment. Six (18.8%) pts experienced grade 3-5 treatment-related AEs; there was 1 treatment-related death (disseminated intravascular coagulation with decreased blood fibrinogen). Conclusions: Pembrolizumab provides long-lasting responses in heavily pretreated pts with mTNBC. Further development of pembrolizumab for treatment of this poor-prognosis pt population is warranted, and a phase II study evaluating efficacy and safety of single-agent pembrolizumab as later line of treatment for mTNBC is ongoing (KEYNOTE-086, NCT02447003). Citation Format: Nanda R, Specht J, Dees C, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Ray A, Karantza V, Buisseret L. KEYNOTE-012: Long-lasting responses in a phase Ib study of pembrolizumab for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-10-03.