Phase Ib Study Of Pembrolizumab Research Articles

52P Phase Ib study of pembrolizumab and XL888 in patients with advanced colorectal cancer

52P Phase Ib study of pembrolizumab and XL888 in patients with advanced colorectal cancer

Abstract CT107: Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors

Abstract BACKGROUND: Intra-tumoral Clostridium novyi-NT (non-toxic) is an attenuated strain of C. novyi lacking alpha toxin replication within hypoxic tumor regions, causing tumor cell lysis and inflammation. Immunotherapy (IO) augments anticancer activity with intratumoral agents in prior preclinical and clinical studies. This phase 1b dose escalation study assessed safety and potential synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors. METHODS: We enrolled patients with percutaneous injectable, solid tumors to receive single intratumoral injection of C. novyi-NT administered on Day 8 across 4 dose cohorts (3 × 10^4 to 100 × 10^4 spores, 3+3 design) with pembrolizumab 200mg IV Q3weekly starting on Day 0 up to 24 months. Primary objectives: Safety, tolerability and maximum tolerated dose (MTD) of combination. Secondary objectives: anti-tumor activity of combination in the injected tumor lesion and overall response by iRECIST 1.1. RESULTS: At data cutoff on October 24, 2022, 16 patients were enrolled and evaluable for toxicity and efficacy. It was well tolerated across all cohorts without dose limiting toxicities with median number of 5 cycles administered (1-34). 10 patients (63%) experienced progression; 1 withdrew consent; 1 completed therapy; 1 came off trial due to toxicity (immune related dermatitis) and 3 patients remain on trial. Median age was 62.5 years (40-71) while all patients (100%) had performance status of 1. 8 (50%) received prior IO and 7 (44%) had > 4 lines of prior therapies. Confirmed overall objective response rate (ORR) was 25% in 4 patients [non-keratinizing undifferentiated nasopharyngeal squamous carcinoma (NPC), human papilloma virus positive squamous cell carcinoma of base of tongue, vulvar melanoma and chordoma] with 3 partial responses (PR) and 1 complete response (CR). Among responders, median duration of response was 8.18 months and 1/4 (25%) had prior IO. NPC patient completed 24 months on trial to completion with best response at PR (-87%) while vulvar melanoma patient remains on trial with best response at CR (-100%). Median injected tumor size was 2.65cm (1-11) with confirmed ORR in injected lesions at 19% with 2 PRs and 1 CR. Most prevalent grade 1 and 2 adverse events were injection site reaction (25%), pyrexia (19%), pruritus (13%), leukopenia (13%) and anemia (13%). No grade 3 or 4 treatment related adverse events noted. Signs and symptoms of C. novyi-NT germination (infection) including fever, injection site pain, erythema, swelling, tenderness, and in some cases, ulceration, spontaneous drainage, tissue sloughing, bleeding, and malodor were observed in 5 patients. CONCLUSIONS: Intratumoral C. novyi-NT with pembrolizumab demonstrates clinical activity with favorable tolerability in patients regardless of tumor histology. This study is ongoing to define the recommended phase 2 dose (NCT03435952). Citation Format: Blessie Elizabeth Nelson, Filip Janku, Siqing Fu, Ecaterina I. Dumbrava, David S. Hong, Daniel Karp, Aung Naing, Jordi Rodon, Apostolia Tsimberidou, Rodabe N. Amaria, Anthony Conley, Senthil Damodaran, Kanwal P. Raghav, Brent L. Kreider, David Tung, Mary Varterasian, Khashayarsha Khazaie, Sarina Piha-Paul. Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT107.

Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer

BackgroundPreclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.MethodsThis was a single-arm...

A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL.

e16195 Background: Trans-arterial chemoembolization (TACE) is the gold-standard for intermediate stage HCC. We hypothesised the ischemic and cytotoxic effect of TACE to boost anti-cancer immunity and to synergise with the anti PD-1 pembrolizumab (pembro). We designed a phase Ib study to test the safety and preliminary efficacy of pembro after TACE in intermediate HCC. Methods: PETAL study will enroll up to 32 patients with intermediate HCC to receive pembro 200 mg every 3 weeks for up to 1 year or until disease progression or unacceptable toxicity. The first safety-run-in phase includes 6 patients: if no dose limiting toxicities (DLTs) emerge over a 21-day window after first pembro, the others are enrolled in the expansion phase. Pembro is given within 30 days after 1 or 2 TACEs. The first phase includes 1 patient scoring Child-Pugh (CP)-B7 and the remaining have to be CP-A. Safety is the primary endpoint and is measured as the incidence of treatment-related adverse events (TRAEs), graded according to NCI CTCAEv4. Efficacy is the secondary endpoint and is evaluated as progression free survival (PFS) from first TACE, according to mRECIST criteria. Survival is estimated using Kaplan-Meier method. All the patients who have received at least one dose of pembro are evaluable for safety. Results: At the time of data cut-off, on the 14th of January 2022, 14 patients had received at least one dose of pembro. The median age was 72 (IQR: 63.3-74.6), 79% were male, 71% were cirrhotic, 29% had viral hepatis and 43% ECOG PS 1. One patient had Child-Pugh (CP) class B7 and 13 had A. The median number of nodules was 1.5 (IQR:1-2.8), and 4.1 cm (IQR: 3.7-4.5) the median diameter. Overall, 5 patients received 2 TACEs and 9 had 1. Patients received a median of 4.5 cycles (IQR: 2.3-6.5) of pembro. No DLTs emerged in the first phase. Treatment-related adverse events (TRAE) of any grade (G) were reported in 86% of participants, 21% of participants experienced G3 TRAEs, and there were no G4 or G5 TRAEs. Specific skin-related toxicity was the most frequently reported (35%) TRAE. No patients had treatment-related liver toxicity. Causes of treatment discontinuation were PD (n=7), TRAEs (n=1), clinical deterioration in the CP B patient (n=1), COVID pandemic (n=2) and withdrawal of consent (n=1); at the time of data cut-off, mPFS from first TACE was 10.8 months (95%CI: 6.63-14.97). Conclusions: Adjuvant pembro following TACE is manageable and tolerable with signs of activity. These results prompt the investigation in larger trials. Clinical trial information: NCT03397654. [Table: see text]

NSABP FC-10: Phase IB study of pembrolizumab in combination with premetrexed + oaliplatin in patients (pts) with chemo-refractory metastatic colorectal cancer (mCRC).

TPS262 Background: The majority of mCRC pts are microsatellite stable (MSS), have poor intratumoral CD8+ T cell infiltration, and no clinical response to immunotherapy checkpoint inhibitors. Preclinical studies suggest that chemotherapy may synergize with anti-PD-1. In non-small cell lung cancer (NSCLC), the combination of pembrolizumab (PemB), pemetrexed (PemT), + carboplatin demonstrated synergistic activity. This study will combine PemB with PemT, then that combination + oxaliplatin (Ox). The rationale for addition of Ox to PemT is that enhanced immunogenic cell death may induce CD8+ T cell infiltration into CRC tumors and model the mechanism of cytotoxicity seen in NSCLC. Thus, the combination of PemB+ PemT + Ox may induce synergistic antitumor immune activity. Methods: This multi-center phase Ib trial is actively enrolling pts with incurable mCRC with prior treatment for mCRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and if RAS wild-type, anti-EGFR therapy. Measurable disease by imaging (RECIST 1.1) is required. Standard ineligibility includes active infections, systemic steroid use, or other conditions contraindicating immunotherapy. Cohort 1 will receive PemB + PemT; Cohort 2 will receive PemB + PemT + dose-escalated Ox. Imaging will be performed every 6 wks. The primary aim of Cohort 1: to evaluate for safety and efficacy using doses of PemB and PemT that have been studied in NSCLC. The primary aim of Cohort 2: to evaluate the safety, tolerability, and efficacy of PemB in combination with PemT + Ox. The RP2D of the 3-drug combination will be at the MTD taking into account toxicity profiles of study therapy agents. Secondary aims: to evaluate the clinical benefit rate of the doublet and triplet combinations in pts with chemo-refractory MSS mCRC and to estimate progression-free survival and overall survival in pts with MSS mCRC treated with these combinations. The cohorts will be analyzed separately with descriptive intent only. Maximum enrollment is 33 pts. Support: Merck; Lilly; NSABP Foundation, Inc. Clinical trial information: NCT03626922.

750P - A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL

BackgroundThe efficacy of TACE is secondary to its dual ischaemic and cytotoxic effect, which promotes immunogenic tumor cell death. TACE may prime adaptive immunity and facilitate pembrolizumab (pembro; anti-PD1) in promoting tumour immune rejection and improve outcome in HCC. We designed this phase Ib study to evaluate safety, preliminary activity of TACE+pembrolizumab and explore mechanisms of efficacy. MethodsUp to 32 patients (pts) with intermediate-stage HCC were planned to receive up to 2 rounds of conventional TACE followed by pembro 200mg q3w 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety with dose-limiting toxicities emerging from the combination being evaluated over a 21-days window from commencement of pembro. Secondary endpoints included PFS rates q12w. We explored tumour and host determinants of response in tissue, blood and stool samples to confirm the bioactivity of the combination. ResultsIn cohort 1 (n=6) patients were all of BCLC-B stage, 83% males, 16% HCV-positive, 50% ECOG PS 0, median age 62 years. Child-Pugh (CP) was A in 5 and B7 in 1pt. Median tumour size was 4cm, and median number of lesions was 2. All-grade adverse events potentially related to treatment (tx) occurred in 50% of pts including diarrhoea (n=1, G3), skin rash (n=2, G2), infusion reaction (n=1, G2) and adrenal insufficiency (n=1, G2). Pembro yielded no synergistic toxicity with TACE and no DLTs were reported. At data cut-off, tx was ongoing for 3 pts with a median duration of tx of 2.8 months. Of the 4 radiologically evaluable patients, 3 had stable disease on pembro, 1 had progressive disease. Cause of withdrawal included disease progression/death (n=2) and worsening liver failure in the CP B7pt, non tx-related (n=1). Updated data from an expanded pt cohort will be shown and efficacy data will be correlated with T-cell responses to recognized tumor-associated antigens, tumour-infiltrating lymphocyte profiling and stool bacterial metagenomics. ConclusionsThe TACE+pembro combination had a tolerable safety profile with no evidence of synergistic toxicity. Alongside emerging efficacy data, this encourages the clinical development of the combination in CP A pts. Clinical trial identificationNCT03397654. Legal entity responsible for the studyImperial College London. FundingMerck Sharp & Dohme. DisclosureD.J. Pinato: Research grant / Funding (self), Funder of the clinical study presented: MSD; Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): ViiV Healthcare; Honoraria (self), Travel / Accommodation / Expenses: Bayer. All other authors have declared no conflicts of interest.

Phase Ib study of pembrolizumab and trebananib (angiopoietin-2 inhibitor [Ang-2]): Preliminary analysis of the colorectal cancer (CRC) cohort.

e14160 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling and in hypoxic microenvironments. Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing monocyte activation. Our group demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival (OS) in patients treated with PD-1 blockade. Methods: We initiated a phase 1b trial to evaluate the safety, efficacy, and immunological effect of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody, in solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the preliminary data in the fully enrolled CRC expansion cohort. Results: The study enrolled a total of 18 microsatellite stable (MSS) heavily pretreated CRC patients. There were no DLTs and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib (3 in dose escalation, 12 in dose expansion) plus pembrolizumab. Nine patients (60%) were female and the median age was 51 years (43-63). The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria (each reported in 40% of the patients). One grade 3 transaminitis and one grade 4 pneumonitis related to pembrolizumab were reported. As of the date of data retrieval, 11 patients were off treatment and four were continuing with a median follow-up of 6.1 months. The response rate was 7% (1 partial response for 14 months) and the disease control rate was 33% (4 stable disease with CEA trending down). Median time to progression and OS were 2.8 (90% CI: 1.5 to 4.9 months) and 11.4 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in heavily pretreated MSS CRC. Paired biopsies and blood were collected for planned correlative immune analyses which will be presented at the meeting. Clinical trial information: NCT03239145.

A phase Ib study of pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver metastatic MSS colorectal cancer (CRC): A postoperative safety analysis.

e15047 Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intra-tumoral and intra-lymphatic antigen release and a rapid influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence rate at 1 year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: 10 patients (median age 61.5 [range 39-69]) have been enrolled and completed the intended neoadjuvant therapy, operative management and at least 4 adjuvant cycles of Pem. All patients had received prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all patients. Mean gross tumor size targeted was 19.1cc (2.3-80.4). Any-grade post-operative AEs (>20%) attributable to Pem include diarrhea (30%), hyperbilirubinemia (20%%), and leukopenia (20%). Post-operative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity in the post-operative setting. Clinical trial information: NCT02837263.

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151)

BackgroundPembrolizumab shows robust antitumor activity and favorable safety in metastatic melanoma. KEYNOTE-151 evaluated pembrolizumab in Chinese patients, who have more aggressive melanoma subtypes than other populations. MethodsChinese patients aged ≥18years with advanced melanoma previously treated with one line of therapy received pembrolizumab 2 mg/kg every 3 weeks for 35 cycles or until confirmed disease progression, intolerable toxicity, or study withdrawal. Primary end points were objective response rate (ORR) per RECIST v1.1 by blinded independent central review and safety. Key secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). ResultsMedian age was 52 years (N=103); 37.9% had acral and 14.6% had mucosal melanoma. Median follow-up was 7.9months at data cutoff (December 27, 2017). ORR was 16.7% (95% CI, 10.0–25.3%) (1 complete, 16 partial responses). Disease control rate was 38.2%. ORR was 15.8% for acral, 13.3% for mucosal melanoma. Median DOR was 8.4months; 65.6% of patients had response duration ≥6months. Median PFS was 2.8months (95% CI, 2.7–3.5months); 6-month rate was 20.4%. Median OS was 12.1months (95% CI, 9.6months–not reached); 6-month rate, 75.7%; 12-month rate, 50.6%. Treatment-related AEs (TRAEs) occurred in 87 (84.5%) patients; 9 (8.7%) experienced grade 3/4 TRAE and 2 (1.9%) discontinued because of TRAE; none died. Two deaths occurred that were unrelated to treatment. ConclusionsPembrolizumab was well tolerated and provided clinically meaningful antitumor activity as second-line therapy in Chinese patients with advanced melanoma.

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus)

Background:Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy.Methods:Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted.Results:Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.Conclusions:Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.

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

Abstract 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.

Phase IB study of pembrolizumab in combination with chemoradiotherapy (CRT) for locally-advanced squamous cell carcinoma of the head and neck (LA-SCCHN).

TPS6107Background: The host immune response is critical for the clearance of SCCHN during CRT. Recent translational research has demonstrated that the programmed death receptor 1 (PD-1) and its lig...

Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma: Big Ten Cancer Research Consortium BTCRC-GU14-003.

559 Background: Renal cell carcinoma (RCC) tumor vasculature is abnormal and does not provide nutritive blood flow, which results in regions of hypoxia. This hypoxia contributes to the immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma. In addition, tumor angiogenesis enhances activity of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that suppress innate anti-cancer immunity. It has been demonstrated in preclinical models that antiangiogenic therapy decreased the number of MDSCs and changed polarization of TAMs from an immunosuppressive (M2-like) to an immunostimulatory (M1-like) phenotype. We hypothesized that therapy with bevacizumab will normalize the tumor vasculature, promote M1-like phenotype of TAMs, and thus potentiate the immunotherapeutic activity of pembrolizumab. As a prerequisite to testing this hypothesis, the objective of this study was to establish the safe dose of bevacizumab when used in combination with pembrolizumab. Methods: Our subject population included males and females (age > 18 y) with metastatic clear cell RCC after failure of at least one systemic therapy. In this Phase Ib dose escalation study, pembrolizumab (200 mg fixed dose every 3 weeks) was given in combination with bevacizumab (either at 10 mg/kg or 15 mg/kg every 3 weeks). The primary endpoint was to establish the maximum safe dose. Results: 12 subjects have been enrolled: 10 males (ages 33-68 y, mean: 52.7, median: 54.5) and 2 females (ages 61 and 62 y). To date 3 patients have received 1 cycle; 2 patients have received 2, 3, and 4 cycles each; and there are single patients who have received 5, 6, and 7 cycles each. No dose-limiting toxicity or serious adverse events related to the study drug have been reported. There were no grade 3 or 4 drug-related toxicities noted, and the most common grade 1 and 2 toxicities were diarrhea, fatigue, fever, hypertension, nausea, rash, and rigors. Conclusions: The 200 mg fixed dose of pembrolizumab and 15 mg/kg dose of bevacizumab, both given every 3 weeks, was determined to be safe and recommended for a multicenter Phase 2 study that is ongoing. Clinical trial information: NCT02348008.

14P - KEYNOTE-012: A phase Ib study of pembrolizumab (MK-3475) in patients (pts) with metastatic triple-negative breast cancer (mTNBC)

14P - KEYNOTE-012: A phase Ib study of pembrolizumab (MK-3475) in patients (pts) with metastatic triple-negative breast cancer (mTNBC)

Abstract S1-09: A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer

Abstract Introduction: The PD-1 receptor-ligand pathway can be used by tumors to evade immune surveillance, thereby allowing neoplastic growth. Pembrolizumab is a highly selective, humanized IgG4/kappa isotype mAb designed to block PD-1 interaction with its ligands PD-L1 and PD-L2, thereby reactivating the immune system to eradicate tumors. Methods: This is a multi-center, non-randomized trial of single agent MK-3475 treatment given intravenously at 10 mg/kg every 2 weeks, in patients with recurrent/metastatic triple-negative (ER, PR, and HER2 negative) breast cancer (TNBC). PD-L1 expression in tumor or stroma was required for study entry. PD-L1 status was determined by immunohistochemical analysis of patient’s tumor tissues using the Merck proprietary 22C3 antibody. Primary objectives of this study were to determine the safety, tolerability, and anti-tumor activity of MK-3475 in patients with PD-L1 positive, advanced TNBC. Secondary objectives included assessments of progression-free survival, overall survival, and response duration. Adverse events (AEs) reported in any patient receiving at least 1 dose of study treatment were monitored and graded using NCI CTCAE v. 4.0. Radiographic imaging was obtained every 8 weeks and evaluated by both investigator and an independent radiologist to assess clinical responses as defined by RECIST 1.1. This study (Clinicaltrials.gov: NCT01848834) is being conducted in conformance with Good Clinical Practices. Results: A total of 32 female patients with a median age of 50.5 years (range 29 – 72 years) with PD-L1 positive, recurrent/metastatic TNBC were enrolled in the study. Most of these patients had received and progressed on multiple lines of therapy for advanced disease. A preliminary analysis of data collected as of 23May2014 indicates that 5 patients (15.6%) experienced at least one drug-related serious adverse event (SAE); each of 4 patients experienced one of the following: Grade 3 anemia, headache, aseptic meningitis or pyrexia, and a fifth patient experienced disseminated intravascular coagulation (DIC) with thrombocytopenia and decreased blood fibrinogen. The patient who experienced DIC died. Preliminary analysis of data collected from investigators as of 23May2014 indicates that no patient had a complete response, 16.1% of patients had a partial response, 9.7% had stable disease, and 64.5% had progressive disease. As of 23May2014, all but one of the responders, in addition to three patients with stable disease, remain on treatment. Conclusion: This is the first report of clinical activity of an immune checkpoint inhibitor in TNBC. The preliminary results from this study suggest that single agent MK-3475 is a well-tolerated and effective treatment with significant therapeutic activity in a subset of heavily pre-treated patients with recurrent/metastatic triple-negative breast cancer. Citation Format: Rita Nanda, Laura Q Chow, E Claire Dees, Raanan Berger, Shilpa Gupta, Ravit Geva, Lajos Pusztai, Marisa Dolled-Filhart, Kenneth Emancipator, Edward J Gonzalez, Jennifer Houp, Kumudu Pathiraja, Vassiliki Karantza, Robert Iannone, Christine K Gause, Johnathan D Cheng, Laurence Buisseret. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-09.

A Phase Ib Study of Pembrolizumab (Pembro; Mk-3475) in Patients (Pts) with Human Papiilloma Virus (Hpv)-Positive and Negative Head and Neck Cancer (Hnc)

ABSTRACT Aim: Background: The highly selective, anti-PD-1 humanized monoclonal antibody pembro has shown antitumor activity in several solid tumors, including HNC. We present updated safety, tolerability, and antitumor activity of pembro for recurrent/metastatic HNC (Clinicaltrials.gov: NCT01848834). Methods: During screening, PD-L1 expression in archival or newly obtained tumor samples was assessed using a prototype immunohistochemistry assay; PD-L1 expression in stroma or ≥1% of tumor cells was required for study entry. Pembro 10 mg/kg was given every 2 wk until complete response, progression, unacceptable toxicity, physician decision, or consent withdrawal. Adverse events (AEs) were recorded throughout the study. Response was assessed every 8 wk. Primary end point was overall response rate (ORR) per RECIST v1.1. Results: Out of 104 HNC pts screened, 81 (78%) were PD-L1-positive, 61 enrolled, and 60 received ≥1 pembro dose: 23 HPV+, 37 HPV-. After a median follow-up of 10.2 mo, 15 pts (25%) remain on pembro. ORR (confirmed + unconfirmed) per RECIST v1.1 by investigator review was 20%, and response duration ranged from 8+ to 41+ weeks (median not reached). 9 of 11 responders had a smaller target lesion burden (ie, sum below the median) at baseline. ORR was similar in HPV+ and HPV- pts, whereas PFS and OS were longer in HPV+ pts (Table). PD-L1 expression was positively correlated with ORR (P = 0.018) and PFS (P = 0.024). ORR was 50% in the 12 pts with high PD-L1 expression. Drug-related AEs of any grade occurred in 58% of pts (grade ≥3 in 17%). The most common drug-related AEs were fatigue (18%), pruritus (10%), and nausea (8%). There were no drug-related deaths. Conclusions: Pembro is safe and tolerable and shows antitumor activity in both HPV+ and HPV- advanced HNC. These findings support further development of pembro in advanced HNC. Overall N = 61* HPV+ n = 23* HPV– n = 38* ORR, n (%) 11 (20) 4 (20) 7 (19) Median PFS (95% CI), wk 9.3 (8.0-20.1) 17.2 (8.0-41.7) 8.1 (7.9-15.6) Median OS (95% CI), mo 12.6 (8.2-12.6) NR (9.6-NR) 9.5 (3.9-12.6) *ORR and PFS were evaluated in the 56 pts (20 HPV+, 36 HPV-) who received ≥1 pembro dose and had measurable disease per RECIST v1.1 by investigator review. Disclosure: L.Q. Chow: Advisory Board Member for Bristol Myers Squibb, Novartis, Celgene; Research funding from Bristol Myers Squibb, Novartis, AstraZeneca/Medimmune, Genentech/Roche, VentiRx, Pfizer, Lily/Imclone; B. Burtness: Advisory board membership for VentiRx and Novartis; Research funding from Merck, Genentech, Boehringer Ingelheim, and Pfizer; E.J. Gonzalez, J.K. Lunceford, C. Gause and J.D. Cheng: Employee of and stock ownership in Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; J. Pulini, J. Johnson, M. Dolled-Filhart, K. Emancipator and K. Pathiraja: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; T. Seiwert: Advisory board membership for Novartis and Onyx/Bayer; Research funding from Boehringer Ingelheim and Genentech; Honoraria from Merck. All other authors have declared no conflicts of interest.