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Background. The efficacy of robotic-assisted gait training (RAGT) should be considered versatilely; among which, gait assessment is one of the most important measures; observational gait assessment is the most commonly used method in clinical practice, but it has certain limitations due to the deviation of subjectivity; instrumental assessments such as three-dimensional gait analysis (3DGA) and surface electromyography (sEMG) can be used to obtain gait data and muscle activation during walking in stroke patients with hemiplegia, so as to better evaluate the rehabilitation effect of RAGT. Objective. This single-blind randomized controlled trial is aimed at analyzing the impact of RAGT on the 3DGA parameters and muscle activation in patients with subacute stroke and evaluating the clinical effect of improving walking function of RAGT. Methods. This randomized controlled trial evaluated the improvement of 4-week RAGT on patients with subacute stroke by 3DGA and surface electromyography (sEMG), combined with clinical scales: experimental group ( n = 18 , 20 sessions of RAGT) or control group ( n = 16 , 20 sessions of conventional gait training). Gait performance was evaluated by the 3DGA, and clinical evaluations based on Fugl-Meyer assessment for lower extremity (FMA-LE), functional ambulation category (FAC), and 6-minute walk test (6MWT) were used. Of these patients, 30 patients underwent sEMG measurement synchronized with 3DGA; the cocontraction index in swing phase of the knee and ankle of the affected side was calculated. Results. After 4 weeks of intervention, intragroup comparison showed that walking speed, temporal symmetry, bilateral stride length, range of motion (ROM) of the bilateral hip, flexion angle of the affected knee, ROM of the affected ankle, FMA-LE, FAC, and 6MWT in the experimental group were significantly improved ( p < 0.05 ), and in the control group, significant improvements were observed in walking speed, temporal symmetry, stride length of the affected side, ROM of the affected hip, FMA-LE, FAC, and 6MWT ( p < 0.05 ). Intergroup comparison showed that the experimental group significantly outperformed the control group in walking speed, temporal symmetry of the spatiotemporal parameters, ROM of the affected hip and peak flexion of the knee in the kinematic parameters, and the FMA-LE and FAC in the clinical scale ( p < 0.05 ). In patients evaluated by sEMG, the experimental group showed a noticeable improvement in the cocontraction index of the knee ( p = 0.042 ), while no significant improvement was observed in the control group ( p = 0.196 ), and the experimental group was better than the control group ( p = 0.020 ). No noticeable changes were observed in the cocontraction index of the ankle in both groups ( p > 0.05 ). Conclusions. Compared with conventional gait training, RAGT successfully improved part of the spatiotemporal parameters of patients and optimized the motion of the affected lower limb joints and muscle activation patterns during walking, which is crucial for further rehabilitation of walking ability in patients with subacute stroke. This trial is registered with ChiCTR2200066402.

Treatment-Related Adverse Events Occurring in {greater than or equal to}1 Patient Treated With Pembrolizumab plus Ipilimumab

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.

Electrocatalysts with atomically dispersed metal moieties are of importance in enhancing electrocatalysis for a specific reaction including oxygen reduction. However, it is still challenging to modulate the coordination structure of metal atoms with heteroatoms on carbon supports. Herein, an innovative and facile bridging strategy to regulate the coordination structure of cobalt with nitrogen atoms on reduced graphene oxide (rGO) sheets was developed by the interfacial complexation of amino-rich folic acid with cobalt ions on graphene oxide sheets and the subsequent thermal treatment. Typically, the actual coordination interaction between cobalt and nitrogen species was revealed by using X-ray absorption spectroscopy (XAS), exhibiting the Co-N4 coordination structure well-dispersed on reduced graphene oxide. Such unique structure enables the efficient oxygen reduction and evolution reactions via the favorable adsorption and desorption of intermediates. With the enhanced bifunctional electrocatalytic activities, the fabricated Zn-air battery exhibited the excellent performance with large power density of 319.8 mW cm−2 and good long-term stability (over 300 h). This work establishes the synthesis strategy for bridging metal atom with heteroatom on graphene sheets to enhance the bifunctional electrocatalysis toward Zn-air batteries.

Fe–Cu diatomic nanoclusters with a unique bridge structure are proposed as a new type of active site for the oxygen reduction reaction.

The porous carbon embedded with hollow cobalt oxide nanoparticles was prepared via a spray-drying method followed by carbonization, which endows rechargeable zinc–air batteries with the improved bifunctional catalytic activity.

In this work, ultra-small Fe particles (Fe-UPs) anchored on carbon aerogel (CA) (Fe-UP/CA catalysts) are successfully prepared by the optimal pyrolysis of hollow composite particles of zeolitic imidazolate framework-8 (ZIF) coated with coordination complexes of tannic acid (TA) and Fe precursors. Within these Fe-UPs, each Fe–N4 moiety is separated by one O atom while each Fe atom is coordinated with four N atoms and one O atom. The as-prepared Fe-UPs composed of the Fe–N4–O–Fe–N4 moiety (FeFe–O–Fe-UPs) are proposed as a new type of active species for the first time, to the best of our knowledge. Moreover, different types of active species (such as Fe single atoms, FeFe–O–Fe-UPs, and Fe nanoparticles) in the CA can be controlled by rationally adjusting the Fe-to-TA molar ratios. More importantly, FeFe–O–Fe-UPs in Fe-UP/CA catalysts are realized at an Fe-to-TA molar ratio of 2.2. With the merits of both Fe-single atom and traditional Fe-NPs, the as-prepared FeFe–O–Fe-UP/CA catalysts are able to regulate properly the adsorption of reactants and the desorption of intermediates and products due to their increasing size and the presence of the multi-metal-atom structure. Accordingly, the as-prepared FeFe–O–Fe-UP/CA catalysts towards the oxygen reduction reaction (ORR) exhibit a higher half-wave potential (0.93 V vs. 0.89 V of Pt/C), a higher onset potential (1.08 V vs. 1.0 V of Pt/C), a higher kinetic current density (14.2 mA cm−2 at 0.9 V) and better long-term stability in alkaline media. Additionally, Zn-air batteries assembled with such electrocatalysts also exhibit a higher power density of 140.1 mW cm−2 and a larger specific capacity of 781.7 mA h g−1, which are better than those of the state-of-the-art the commercial Pt/C catalyst.

Carbon-based catalysts are widely regarded as one of the most promising materials for energy storage and conversion technologies due to their high electrical conductivity as well as tunable micro- and nanostructures. Developing efficient, low-cost, and durable bifunctional carbon-based electrocatalysts remains challenging. In this review, the recent advances in the field of carbon-based oxygen reduction reaction/oxygen evolution reaction electrocatalysts for Zn–air batteries are briefly reviewed, focusing on the fabrication strategies of carbon-based electrocatalysts. Finally, the present challenges and perspectives in developing advanced bifunctional carbon-based electrocatalysts are outlined.

Exploration of cost-effective and highly durable carbon-based multifunctional electrocatalysts for energy conversion and storage devices (e.g., metal-air batteries) is of critical significance. Herein, we present a unique worm-like structure of hierarchically porous nitrogen-doped graphene (N-rGO) embedded with cobalt nitride (Co5.47N) nanoparticles (named as Co5.47N@N-rGO) by tannic acid assisted nitridation method for Zn-air batteries and overall water splitting. Benefiting from the unique worm-like structure to expose more active sites and the synergy advantages of a close contact between Co5.47N nanoparticles and the N-rGO sheets, the Co5.47N@N-rGO exhibits efficient bifunctional catalytic activities toward oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Notably, Zn-air batteries assembled with Co5.47N@N-rGO-750 show a power density of 120.7 mWcm−2 and excellent cycling stabilities for 330 h in an aqueous electrolyte. More interestingly, when assembled into a flexible solid-state rechargeable Zn-air battery, the Co5.47N@N-rGO-750 displays a specific capacity of 610 mAh gzn−1 and good cycling stability over 40 h. Moreover, the integrated device for water splitting powered by Zn-air batteries is also fabricated by using the Co5.47N@N-rGO-750 electrocatalyst, exhibiting a good gas generation rate. This work offers a new strategy to design and synthesize efficient multifunctional carbon-based electrocatalysts applied in electrochemical devices.

In this work, three-dimensional N, S co-doped carbon with high density Fe-single atom-nanoclusters of homogeneous dispersion (N, S co-doped CPANI–TA–Fe Fe-SA-NC catalysts) is successfully prepared by the optimal pyrolysis of freeze-dried polyaniline (PANI) hydrogels containing homogeneously distributed Fe precursors due to the controlled chelation between tannic acid (TA) and ferric ions and the interaction between Fe precursors and PANI for the first time, to the best of our knowledge. More importantly, active species (such as Fe single atoms, Fe-SA-NCs and Fe NPs) in the 3D N, S co-doped carbon materials can be controlled by judiciously adjusting the Fe-to-TA molar ratios. High density Fe-SA-NCs as active species (up to 5.6 wt%) in the N, S co-doped carbon are realized by controlling the Fe-to-TA molar ratio at 10. In addition, these Fe-SA-NCs are composed of isolated Fe-SAs, which are separated by the coordination with four N atoms and two O atoms. The resulting N, S co-doped CPANI–TA–Fe Fe-SA-NC catalysts for the oxygen reduction reaction (ORR) exhibit a higher half-wave potential (0.923 V vs. 0.88 V of Pt/C), a higher onset potential (1.09 V vs. 0.99 V of Pt/C), a higher kinetic-limiting current density (12 mA cm−2 at 0.9 V) and better long-term stability in alkaline media. Their ORR activity in acidic media is comparable to those recently reported in the literature. Additionally, the suitability and durability of N, S co-doped CPANI–TA–Fe Fe-SA-NC catalysts as the air electrode of a zinc–air battery were investigated. The fabricated Zn–air batteries exhibited a higher power density of 136.4 mW cm−2 and a higher specific capacity of 795.1 mA h g−1, which are better than those of the state-of-the-art commercial Pt/C catalyst. Our synthetic strategy can be extended to prepare other metal nanocluster-based porous carbon materials as electrocatalysts in electrochemical energy devices, as TA can be chelated with diverse metal ions.

We propose time-varying coefficient model selection and estimation based on the spline approach, which is capable of capturing time-dependent covariate effects. The new penalty function utilizes local-region information for varying-coefficient estimation, in contrast to the traditional model selection approach focusing on the entire region. The proposed method is extremely useful when the signals associated with relevant predictors are time-dependent, and detecting relevant covariate effects in the local region is more scientifically relevant than those of the entire region. Our simulation studies indicate that the proposed model selection incorporating local features outperforms the global feature model selection approaches. The proposed method is also illustrated through a longitudinal growth and health study from National Heart, Lung, and Blood Institute.

Flexible and rechargeable zinc–air batteries with high energy density and stable output voltage are promising energy sources for wearable electronics and implantable medical devices. The development of efficient bi-functional catalysts with low-cost and environmentally friendly properties has become the focus of research on rechargeable zinc–air batteries. Herein, we present the in situ growth of manganese oxide (MnOx) on carbon cloth (MnOx-CC) by incorporating a simple chemical bath deposition method with the phase transformation of MnOx driven by thermal treatment for improving the bifunctional catalytic activities for the ORR and OER. With bifunctional catalytic activities, the carbon cloth supported MnOx electrode without an additional nonconductive binder has been used to assemble an all-solid-state rechargeable zinc–air battery. The solid-state battery shows a high open circuit voltage (1.47 V), superior round-trip efficiency (62.4% after 120 cycles), long cycling life (45 h over an operating voltage of 1.2 V), and high capacity (728 mA h g−1), which is superior to those of the Pt/C and RuO2 based battery. The battery also demonstrated excellent mechanical flexibility and cycling stability without obvious performance degradation. The present work provides an efficient approach to prepare advanced bifunctional electrocatalysts for the fabrication of all-solid-state zinc–air batteries, which would meet the demand for flexible and wearable devices.

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.

In this work, Fe-Ni alloy nanoclusters (Fe-Ni ANCs) anchored on N, S co-doped carbon aerogel (Fe-Ni ANC@NSCA catalysts) are successfully prepared by the optimal pyrolysis of polyaniline (PANI) aerogels derived from the freeze-drying of PANI hydrogel obtained by the polymerization of aniline monomers in the co-presence of tannic acid (TA), Fe3+ , and Ni2+ ions. In addition, the optimal molar ratio of the TA, Fe3+ , and Ni2+ ions for synthesis of Fe-Ni ANC@NSCA catalysts are 1:2:5, which can guarantee the formation of carbon aerogel composed of quasi-2D porous carbon sheets and the formation of high-density Fe-Ni ANCs with an ultrasmall size between 2 to 2.8 nm. These Fe-Ni ANCs consisting of N4 -Fe-O-Ni-N4 moiety are proposed as a new type of active species for the first time, to the best of the authors' knowledge. Thanks to their unique features, the Fe-Ni ANC@NSCA catalysts show excellent performance in oxygen reduction reaction with a half-wave potential (E1/2 ) of 0.891 V and oxygen evolution reaction (260 mV @ 10 mA cm-2 ) in alkaline media as bifunctional catalysts, which are better than the state-of-the-art commercial Pt/C catalysts and RuO2 catalysts. Moreover, Zn-air battery assembled with the Fe-Ni ANC@NSCA catalysts also shows a remarkable performance and exceptionally high stability over 500 h at 5 mA cm-2 .

Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti–programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

© 2017 Elsevier Ltd Background Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. Methods In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. Findings Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8–18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3–4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3–4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53–69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60–75), and estimated 1 year overall survival was 89% (95% CI 83–93). Interpretation Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. Funding Merck & Co, Inc.

9545 Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAFV600mutant, and 13% received ≥1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61% (95% CI, 53%-69%); the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685.

510 Background: The CTLA-4 antibody ipi and the PD-1 antibody pembro have demonstrated efficacy in pts with advanced malignancies. While these immune checkpoint inhibitors have shown robust activity as monotherapy, combination therapy may further improve outcomes. KEYNOTE-029 (NCT02089685) is a phase 1/2 study designed to assess the safety and efficacy of pembro + ipi or pegylated interferon alfa-2b (IFN-α) in pts with advanced melanoma or RCC. Here we report data from the phase 1 portion of the study in pts with RCC treated with pembro + ipi. Methods: Pts ≥18 years with advanced/unresectable or metastatic clear cell RCC who received ≥1 prior therapy for metastatic disease, had ≥1 measurable lesion per RECIST v1.1, and ECOG PS 0-1 were enrolled. Pts received pembro 2 mg/kg Q3W + low-dose ipi (1 mg/kg Q3W for 4 doses) until disease progression, unacceptable toxicity, investigator/patient decision, or 2 years of pembro treatment. AEs were monitored throughout treatment and for 30 days thereafter and graded per NCI CTCAE v4.0. Primary end point was safety; primary efficacy end point was ORR assessed per RECIST v1.1 by independent central imaging vendor review. Results: As of the March 17, 2016, data cutoff, 10 pts with RCC received pembro + low-dose ipi. 60% were male, 70% were white, median age was 61 years (range, 48-70 years), 40% received 2 prior lines of therapy, and 40% received prior immunotherapy. With a median follow-up of 17.4 months (0.9-23.5 months), 70% of pts experienced treatment-related AEs (TRAEs) of any grade, most commonly fatigue (30%); and 50% experienced grade 3/4 TRAEs, most commonly increased lipase (20%). 50% of pts discontinued pembro because of TRAEs, most commonly increased lipase (40%). There were no treatment-related deaths. ORR was 20% (2 partial responses); median duration of response was not reached (14.1+-17.1 months+). An additional 3 pts had stable disease; disease control rate was 50%. Conclusions: The combination of pembro + low-dose ipi for 4 doses, followed by pembro monotherapy, demonstrates a manageable toxicity profile and preliminary antitumor activity in pts with advanced RCC. Clinical trial information: NCT02089685.

6011Background: Current treatment options for patients (pts) with recurrent/metastatic (R/M) HNSCC who progress on platinum and cetuximab have very limited efficacy. Pembrolizumab, an anti–PD-1 ant...

3013Background: Pembro (anti–PD-1), ipi (anti–CTLA-4), and PEG-IFN (cytokine) are approved as monotherapy for treating melanoma. KEYNOTE-029 (NCT02089685) is a first-in-human, phase 1 study that in...

9506Background: Pembro (MK-3475), an anti–PD-1 antibody that prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, is approved in several countries for treating advanced melanoma. In KEYNOTE-...