Blogs

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• Avelumab + axitinib improves PFS and ORR as first-line treatment of patients with advanced renal cell carcinoma (RCC): JAVELIN Renal 101 (LBA6_PR, Presidential Symposium)
• Atezolizumab plus bevacizumab improves PFS in AngiogenesisLow and T-effectorHigh gene signature subsets and sunitinib improved PFS in AngiogenesisHigh subset of patients with untreated metastatic renal cell carcinoma (mRCC): IMmotion151 (LBA31)
• Pembrolizumab indicates antitumor activity in patients with high-risk, non-muscle invasive bladder cancer (NMIBC) unresponsive to BCG: KEYNOTE-057 (8640)
• Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg provides longer PFS and OS than nivolumab monotherapy in patients with platinum-pretreated metastatic urothelial carcinoma (mUC): expansion from CheckMate 032 (LBA32)
• Atezolizumab plus nab-paclitaxel improves OS and PFS in patients with previously untreated metastatic triple-negative breast cancer (mTNBC): IMpassion130 (LBA1_PR, Presidential Symposium)
• Immunotherapy strategies for luminal breast cancer: promising response rates with ‘immune induction’ followed by nivolumab: TONIC (Special Symposium)
• The addition of atezolizumab to carboplatin + nab-paclitaxel improved PFS and OS in patients with advanced non-squamous NSCLC: IMpower130 (LBA53)
• First-line Pembrolizumab provides a clinically relevant benefit to patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): KEYNOTE-048 (LBA8_PR, Presidential Symposium)
• A sustained clinical benefit and long-term survival with nivolumab plus ipilimumab combination therapy in advanced melanoma: 4-year update from CheckMate 067 (LBA44)
• The addition of Pembrolizumab to Dabrafenib and Trametinib as first-line therapy indicates sufficient efficacy in patients with BRAF-Mutant Advanced Melanoma: KEYNOTE-022 (12440)
• Neo-Adjuvant ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) combination therapy is less toxic and preserves the high response rate in patients with resectable stage III melanoma: OpACIN-neo (LBA42)
• An intravenously delivered oncolytic virus, Coxsackievirus A21 (CVA21), in combination with pembrolizumab is well tolerated and indicated encouraging clinical signals in advanced NSCLC and bladder cancer patients: KEYNOTE-200 (LBA40)
• Driving immunotherapy efficacy through modulation of the tumor microenvironment (TME): tumor infiltrating lymphocytes, STING & β-catenin pathways, Batf3 DCs, commensal microbiota (Keynote Lecture)

Avelumab + axitinib improves PFS and ORR as first-line treatment of patients with advanced renal cell carcinoma (RCC): JAVELIN Renal 101 (LBA6_PR, Presidential Symposium)

Robert Motzer, MD (Memorial Sloan Kettering Cancer Center, New York, NY, USA) presented results from the multinational, randomized, open-label, parallel-arm Phase III JAVELIN Renal 101 trial (NCT02684006), evaluating the anti-tumor activity and safety of avelumab in combination with axitinib and of sunitinib monotherapy in first-line treatment of patients with advanced RCC. Axitinib is a highly potent VEGFR TKI and Sunitinib is receptor tyrosine kinase inhibitor, both approved for the treatment of advanced RCC. A total of 886 patients, including 560 patients with PD-L1+ tumors, were randomized 1:1 to receive avelumab (10 mg/kg IV, Q2W) + axitinib (5 mg PO, BID) per 6-week cycle or sunitinib (50 mg PO, QD, 4 weeks on, 2 weeks off). In the PD-L1+ group, median PFS was 13.8 months (95% CI: 11.1- NE) in patients treated with avelumab + axitinib and 7.2 months (95% CI: 5.7-9.7) with sunitinib (HR 0.61 [95% CI: 0.475-0.790, p < 0.0001]). In overall population, median PFS was 13.8 months (95% CI: 11.1- NE) in patients treated with avelumab + axitinib and 8.4 months (95% CI: 6.9-11.1) with sunitinib (HR 0.69 [95% CI: 0.563-0.840, p < 0.0001]).  ORR in the PD-L1+ group was 55% (95% CI: 49.0-61.2) and 26% (95% CI: 20.6-30.9) in avelumab + axitinib and sunitinib cohorts, respectively. In overall population, ORR was 51% (95% CI: 46.6-56.1) in the avelumab + axitinib group and 26% (95% CI: 21.7-30.0) in the sunitinib cohort. Grade 3/4 treatment-related AEs were observed 55% of patients treated with avelumab + axitinib or sunitinib. The study continues to follow-up for OS. These results with improved PFS and ORR support avelumab + axitinib as a new first-line standard of care for patients with advanced RCC.

Atezolizumab plus bevacizumab improves PFS in AngiogenesisLow and T-effectorHigh gene signature subsets and sunitinib improved PFS in AngiogenesisHigh subset of patients with untreated metastatic renal cell carcinoma (mRCC): IMmotion151 (LBA31)

Brian I. Rini, MD (Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA) described data from the open-label, randomized, Phase III IMmotion151 study (NCT02420821), investigating the efficacy and safety of atezolizumab plus bevacizumab vs sunitinib (receptor tyrosine kinase inhibitor) in patients with inoperable, locally advanced, or mRCC. A total of 915 eligible patients were randomized 1:1 to receive atezolizumab (atezo) plus bevacizumab (bev) (1,200 mg IV, Q3W + 15 mg/kg IV, Q3W, respectively) or sunitinib (50 mg PO, QD). PFS was 11.2 months (atezo + bev) and 7.7 months (sunitinib) in PD-L1+ cohorts (HR 0.74 [95% CI: 0.57-0.96, p = 0.02]) and 11.2 months (atezo + bev) and 8.4 months (sunitinib) in ITT population (HR 0.83 [95% CI: 0.70-0.97]). Comparing the subsets classified by an Angiogenesis gene signature, PFS was 8.94 months (atezo + bev) and 5.95 months (sunitinib) in the AngiogenesisLow subset (HR 0.68 [95% CI: 0.52-0.88]), 12.45 months (atezo + bev) and 10.12 months (sunitinib) in the AngiogenesisHigh subset (HR 0.95 [95% CI: 0.76-1.19]). For sunitinib vs atezo + bev, PFS was 10.12 months (AngiogenesisHigh) and 5.95 months (AngiogenesisLow) in sunitinib population (HR 0.59 [95% CI: 0.47-0.75]) and 12.45 months (AngiogenesisHigh) and 8.94 months (AngiogenesisLow) in the atezo + bev cohort (HR 0.86 [95% CI: 0.67-1.1]). Analysis of the association of T-effector gene signature demonstrated the improvement of PFS by atezo + bev compared to sunitinib in T-effectorHigh subset: 12.45 months (atezo + bev) months and 8.34 months (sunitinib) (HR 0.76 [95% CI: 0.59-0.99]). These data of tumor molecular signatures associated with clinical outcomes using VEGF inhibition and first-line immunotherapy suggest future strategies of biomarker use to enable personalized therapy for mRCC patients.

Pembrolizumab indicates antitumor activity in patients with high-risk, non-muscle invasive bladder cancer (NMIBC) unresponsive to BCG: KEYNOTE-057 (8640)

Ronald de Wit, MD, PhD (Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands) presented results from the Phase II, single-arm KEYNOTE-057 study (NCT02625961), assessing the efficacy and safety of pembrolizumab in patients with high risk NMIBC unresponsive to BCG therapy and who are considered ineligible for or unwilling to undergo radical cystectomy. Eligible patients (including CIS alone or combination of CIS and papillary disease, cohort A) received pembrolizumab (n = 103, 200 mg IV, Q3W) for up to 24 months. At the time of data cutoff on July 18, 2018, CR rate at month 3 was 38.8% (n = 40, [95% CI: 29.4-48.9]). Median time to CR was 12.4 weeks (95% CI: 10.4-19.3). Median duration of response for patients who achieved CR at month 3 is not reached, 80% of patients in this groups had a CR duration of ≥ 6 months. Although 10 (25.0%) patients experienced recurrent NMIBC after CR, no patient developed muscle invasive or metastatic disease. Treatment-related AEs occurred in 65 patients (63.1%), Grade 3-5 in 13 patients (12.6%), and most common (≥ 5%) were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). These interim data support the Phase III KEYNOTE-676 to further examine pembrolizumab in combination with BCG in patients with high-risk NMIBC that is persistent or recurrent following BCG induction.

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg provides longer PFS and OS than nivolumab monotherapy in patients with platinum-pretreated metastatic urothelial carcinoma (mUC): expansion from CheckMate 032 (LBA32)

Jonathan E. Rosenberg, MD (Memorial Sloan Kettering Cancer Center, New York, NY, USA) presented the extended follow-up data from the multicenter, open-label, Phase 1/2 CheckMate 032 study (NCT01928394), assessing the safety and efficacy of nivolumab as a single agent or in combination with ipilimumab in patients with advanced or metastatic solid tumors, including platinum-pretreated mUC. A total of 274 eligible patients were randomized 1:1:1 to receive nivolumab 3 mg/kg monotherapy (Nivo3; IV Q2W, n = 78), nivolumab 3 mg/kg + ipilimumab 1 mg/kg (Nivo3+Ipi1; IV Q3W for 4 cycles, n = 104), or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (Nivo1+Ipi3; IV Q3W for 4 cycles, n = 92). ORR was 25.6% (95% CI: 16.4-36.8), 26.9% (95% CI: 18.7-36.5), and 38.0% (95% CI: 28.1-48.8), respectively. Median PFS was 2.8 (95% CI: 1.5-5.3), 2.6 (95% CI: 1.4-3.9), and 4.9 (95% CI: 2.7-6.6). Median OS was 9.9 (95% CI: 7.3-21.1) in the Nivo3 group, 7.4 (95% CI: 5.6-11.0) in Nivo3+Ipi1, and 15.3 (95% CI: 10.1-27.6) in Nivo1+Ipi3. OS rate at month 12 was 47%, 38.0%, and 57%, respectively. In the low PD-L1 status (< 1%) subgroup, ORR was 25.6% (95% CI: 13.5-41.2) in Nivo3, 25.0% (95% CI: 14.4-38.4) in Nivo3+Ipi1, and 23.8 (95% CI: 12.1-39.5) in Nivo1+Ipi3. In contrast, in the high PD-L1 expression (≥ 1%) subgroup, ORR was 26.9% (95% CI: 11.6-47.8) in Nivo3, 35.5% (95% CI: 19.2-54.6) in Nivo3+Ipi1, and 58.1 (95% CI: 39.1-75.5) in Nivo1+Ipi3. Grade 3/4 treatment-related AEs were identified in 27% of patients received Nivo3, 31% with Nivo3+Ipi1, and 39% with Nivo1+Ipi3. Overall, a trend toward higher ORR and longer median PFS and OS was observed in the Nivo1+Ipi3 cohort in this PD-L1 unselected patient population. These data support the ongoing Phase III trial of Nivo1+Ipi3 vs chemotherapy in previously untreated mUC (CheckMate 901; NCT03036098).

Atezolizumab plus nab-paclitaxel improves OS and PFS in patients with previously untreated metastatic triple-negative breast cancer (mTNBC): IMpassion130 (LBA1_PR, Presidential Symposium)

Peter Schmid, MD, FRCP, PhD (Barts Cancer Institute, Queen Mary University of London, London, UK) presented data from the global, randomized, double-blind, Phase III IMpassion130 study (NCT02425891), evaluating the efficacy, safety, and pharmacokinetics of atezolizumab administered with nab-paclitaxel compared with placebo with nab-paclitaxel in treatment-naïve patients with locally advanced or mTNBC.  In all, 902 patients were randomized 1:1 to receive atezolizumab + nab-paclitaxel (n = 451, 840 mg IV, Day 1 and 15, Q4W) or placebo nab-paclitaxel (n = 451). At data cutoff on 17 Apr 2018, primary PFS in ITT population was 7.2 months and 5.5 months in the atezolizumab and placebo groups, respectively (HR 0.80 [95% CI: 0.69-0.92, p = 0.0025]): 1-year PFS rate was 24% (95% CI: 20-28) and 18% (95% CI: 14-21). In PD-L1+ population (positive ≥ 1%), PFS was 7.5 months and 5.0 months in the atezolizumab and placebo groups, respectively (HR 0.62 [95% CI: 0.49-0.78, p = 0.0001]): 1-year PFS rate was 29% (95% CI: 22-36) and 16% (95% CI: 11-22). Interim OS in ITT population was 21.3 months and 17.6 months in the atezolizumab and placebo cohorts, respectively (HR 0.84 [95% CI: 0.69-1.02, p = 0.0840]): 2-year OS rate was 42% (95% CI: 34-50) and 40% (95% CI: 33-46). In PD-L1+ population, OS was 25.0 months and 15.5 months in the atezolizumab and placebo groups, respectively (HR 0.62 [95% CI: 0.45-0.86]): 2-year OS rate was 54% (95% CI: 42-65) and 37% (95% CI: 26-47). Treatment-related AEs (Grade 3-5) were more common with atezolizumab compared with placebo (41% vs 30%). These data suggest that atezolizumab plus nab-paclitaxel was well tolerated with a clinical benefit and has potential to be a new standard of care for the first-line immunotherapy of mTNBC patients.

[ The link to co-publication - https://www.nejm.org/doi/full/10.1056/NEJMoa1809615 ]

Immunotherapy strategies for luminal breast cancer: promising response rates with ‘immune induction’ followed by nivolumab: TONIC (Special Symposium)

Marleen Kok, MD, PhD (Netherlands Cancer Institute, Amsterdam, Netherlands) described immunotherapy strategies to modulate antitumor immune response. There are breast cancer subtypes, triple negative breast cancer (TNBC; HER2-, ER-, PR-), HER2- (ER+, PR+), and HER2+. For the TNBC subtype, no targeted treatments are available. Lymphocytic infiltration patters in the breast cancer subtypes are evaluated for immunomodulatory capacity and immunotherapy development: ‘hot’ tumor vs ‘cold tumor’. In ‘hot’ tumor, different types of immune cells are infiltrated, e.g. macrophages, NK cells, TH17 cells, TH1 cells in addition to many T cells. Dr. Kok hypothesized that turning a ‘cold’ tumor into a ‘hot’ tumor is a key to effective immunotherapy treatment.

Then, she presented results from the adaptive Phase II randomized trial of nivolumab after induction treatment in TNBC: TONIC (NCT02499367). This ongoing study assesses whether the induction with irradiation or chemotherapy modulates cancer immune response, leading to the improvement of anti-PD1 (nivolumab) efficacy in pre-induced patients. In this study, four types of an induction treatment followed by nivolumab were tested; each type of induction to target the specific antitumor immune response: 1) irradiation to activate STING/type I IFN, priming T cells, 2) cyclophosphamide to deplete Tregs, 3) cisplatin to upregulate MHC-I, stimulate T cell function, and 4) doxorubicin to increase in type I IFN, immunogenic cell death.   

ORR was 17% with no induction control (n = 12), 8% in radiotherapy and cyclophosphamide induction groups (n = 12 each), 23% in cisplatin (n = 13), and 35% in doxorubicin (n = 17). In addition, after cisplatin or doxorubicin induction, ‘hot’ tumor gene signatures were upregulated. Dr. Kok concluded by discussing the future immuno-oncology (I-O) development, small signal finding combination studies in cooperating translational research: targeted/I-O, chemo/I-O, I-O/I-O and re-thinking of classical breast cancer sub-classification to signature-based.

The addition of atezolizumab to carboplatin + nab-paclitaxel improved PFS and OS in patients with advanced non-squamous NSCLC: IMpower130 (LBA53)

Federico Cappuzzo, MD, PhD (Dipartimento di OncologiaMedica, AziendaUnitàSanitaria Locale dellaRomagna, Ravenna, Italy) presented data from the randomized, open-label, multicenter, Phase III IMpower130 study (NCT02367781), investigating the safety and efficacy of atezolizumab in combination with carboplatin + nab-paclitaxel compared with carboplatin + nab-paclitaxel alone in chemotherapy-naive patients with Stage IV non-squamous NSCLC. A total of 723 patients (679 ITT-WT) were randomized 2:1 to receive atezolizumab + chemotherapy (n = 451, 1,200 mg IV, Q3W) or chemotherapy alone (n = 228) for 4 or 6 21-day cycles. Median PFS in total population (EGFR-WT/ALK-negative) was 7 months (95% CI: 6.2-7.3) in the atezolizumab + chemotherapy group and 5.5 months (95% CI: 4.4-5.9) in the chemotherapy group (HR 0.64 [95% CI: 0.54-0.77, p < 0.0001]). PFS rate was 56.1% and 42.5% at 6 months; 29.1% and 14.1% at 12 months, respectively. Median OS was 18.6 months (95% CI: 16.0-21.2) in the atezolizumab + chemotherapy group and 13.9 months (95% CI: 12.0-18.7) in the chemotherapy group (HR 0.79 [95% CI: 0.64-0.98, p < 0.033]). OS rate was 63.1% and 55.5% at 1 year; 39.6% and 30.0% at 2 years. Analysis of baseline PD-L1 status indicated that the addition of atezolizumab improved PFS across status; PD-L1-high (HR 0.51 [95% CI: 0.34-0.77]), PD-L1-low (HR 0.61 [95% CI: 0.43-0.85], and PD-L1-negative (HR 0.72 [95% CI: 0.56-0.91]). Treatment-related AEs (Grade 3-5) were identified in 74.9% of patients received atezolizumab + chemotherapy and 60.7% with chemotherapy alone. These results with improved PFS and OS support atezolizumab plus chemotherapy as a treatment option for patients with advanced non-squamous NSCLC, regardless of PD-L1 status.

First-line Pembrolizumab provides a clinically relevant benefit to patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): KEYNOTE-048 (LBA8_PR, Presidential Symposium)

Jean-Pascal Machiels, MD, PhD (Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium) presented data from the open-label, randomized, Phase III KEYNOTE-048 study (NCT02358031), investigating the potential of pembrolizumab or pembrolizumab in combination with chemotherapy prolongs PSF and OS compared to standard treatment of R/M HNSCC patients. A total of 882 patients were randomized to receive pembrolizumab (n = 301, 200 mg IV, Q3W) up to 24 months, pembrolizumab + Platinum + 5-FU (n = 281), or Cetuximab + Platinum + 5FU (n = 300). Cutoff date for this final PFS/interim OS analysis was Jun 13, 2018 (minimum follow-up, ~17 months). Median OS of pembrolizumab and Cetuximab + Platinum + 5FU was 14.9 and 10.7 months, respectively, in the PD-L1 combined positive score (CPS) ≥ 20 subgroup (n = 255, HR 0.61 [95% CI: 0.45-0.83, p = 0.0007]) and 12.3 and 10.3 months in the CPS ≥ 1 subgroup (n = 512, HR 0.78 [95% CI 0.64-0.96, p = 0.0086]). Comparative analysis between the pembrolizumab + Platinum + 5-FU and Cetuximab + Platinum + 5FU indicated that OS was 13.0 and 10.7 months (HR 0.77 [95% CI: 0.63-0.93, p = 0.0034]) and PFS was similar (HR 0.92) in total population. For first-line R/M HNSCC, pembrolizumab monotherapy improved OS in the PD-L1 CPS ≥ 20 group and Pembrolizumab + Platinum + 5-FU improved OS in the total population over Cetuximab + Platinum + 5FU. These data support pembrolizumab and pembrolizumab + platinum + 5-FU as new first-line standards of care for R/M HNSCC. The study continues to the final OS analysis.

A sustained clinical benefit and long-term survival with nivolumab plus ipilimumab combination therapy in advanced melanoma: 4-year update from CheckMate 067 (LBA44)

Stephen Hodi, MD (Dana-Farber Cancer Institute, Boston, MA, USA) presented the latest results from the randomized, double-blind, Phase III CheckMate 067 study (NCT01844505), investigating the efficacy of nivolumab or nivolumab in combination with ipilimumab on PFS and OS compare to ipilimumab alone in patients with previously untreated unresectable or metastatic melanoma. In all, 945 patients were randomized 1:1:1 to receive Nivo 1mg/kg + Ipi 3mg/kg (Q3W, 4 doses) followed by Nivo 3 mg/kg (Q2W, n = 314), Nivo 3mg/kg (Q2W) + Ipi-matched placebo (n = 316), or Ipi 3mg/kg (Q3W, 4 doses) + Nivo-mached placebo (n = 315). Median PFS was 11.5 months in the Nivo + Ipi group (HR 0.42 [95% CI: 0.35-0.51] vs Ipi alone), 6.9 months in Nivo alone (HR 0.53 [95% CI: 0.44-0.64] vs Ipi alone), and 2.9 months in Ipi alone. Median OS was not reached (NR) in the Nivo + Ipi group (HR 0.54 [95% CI: 0.44-0.67] vs Ipi alone), 36.9 months in Nivo alone (HR 0.65 [95% CI: 0.53-0.79] vs Ipi alone), and 19.9 months in Ipi alone. Among patients alive at 4 years, 71% (113/159), 50% (69/138), and 39% (32/82) of patients in the Nivo+Ipi, Nivo, and Ipi groups, respectively, were treatment free. A clinical benefit of Nivo + ipi and Nivo alone was observed across clinically relevant subgroups, such as BRAF mutation status and PD-L1 expression. Grade 3/4 treatment-related AEs were identified in 59.1%, 22.4%, and 27.7% of patients in the Nivo+Ipi, Nivo, and Ipi groups, respectively. These 4-year results indicate a durable, sustained clinical benefit of first-line Nivo + Ipi or Nivo alone treatment in patients with advanced melanoma, which may reduce the need for subsequent.

The addition of Pembrolizumab to Dabrafenib and Trametinib as first-line therapy indicates sufficient efficacy in patients with BRAF-Mutant Advanced Melanoma: KEYNOTE-022 (12440)

Paolo Antonio Ascierto , MD (Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy) described results from the randomized, double-blind, Phase I/II KEYNOTE-022 trial (NCT02130466, part 3), assessing the safety, tolerability, and efficacy of pembrolizumab in combination with trametinib (MEK inhibitor) and dabrafenib (BRAF inhibitor) in patients with treatment-naive BRAFV600E/K-mutant stage III/IV melanoma. In each arm, 60 patients were assigned to pembrolizumab (2 mg/kg, Q3W) + Dabrafenib (150 mg BID) + Trametinib (2 mg QD) or pembrolizumab-matched placebo. Median PFS was 16.0 months (95% CI: 8.6-21.5) in the pembrolizumab cohort and 10.3 months (95% CI: 7.0-15.6) with placebo (HR 0.66 [95% CI: 0.44-1.07, p = 0.04287]): PFS rate was 59% and 45% at 12 months. Best ORR was 63.3% and 71.7%; CR rate was 18.3% and 13.3% in the pembrolizumab and placebo groups, respectively. Median DOR was 18.7 months (1.9+ to 22.1) vs 12.5 (2.1-19.5+). Median OS was NR (95% CI: 19.6-NR, n = 19) in the pembrolizumab group and 23.4 months (95% CI: 17.8-NR, n = 24) in placebo (HR 0.76 [95% CI: 0.41-1.39, p = 0.18467]); OS rate at 12 months was 80% and 73%. Grade 3-5 treatment-related AEs occurred in 57% vs 27% of patients the pembrolizumab and placebo groups, respectively. Pembrolizumab + Dabrafenib + Trametinib, compare to pembrolizumab-matched placebo, showed promising efficacy and manageable tolerability in patients with advanced BRAFV600E/K-mutant melanoma. These data assist a Phase III studies to validate a role of PD-1 inhibitors as part of triplet therapy with BRAF and MEK inhibitors.

Neo-Adjuvant ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) combination therapy is less toxic and preserves the high response rate in patients with resectable stage III melanoma: OpACIN-neo (LBA42)

Christian U. Blank, MD, PhD (Netherlands Cancer Institute, Amsterdam, Netherlands) detailed results from the multicenter, open-label three-arm Phase II OpACIN-neo trial (NCT02977052), assessing the optimal neo-adjuvant combination scheme of ipilimumab (Ipi) and nivolumab (Nivo) in patients with resectable stage III melanoma. In all, 86 patients were randomized 1:1:1 to receive arm A: 2x Ipi 3mg/kg + Nivo 1mg/kg (Q3W, n = 30), arm B: 2x Ipi 1mg/kg + Nivo 3mg/kg (Q3W, n = 30), or arm C: 2x Ipi 3mg/kg (Q2W) followed immediately by 2x Nivo 3mg/kg (Q2W, n = 26) prior to surgery. Median follow-up was 8.3 months as of Sep 28, 2018. Grade ≥ 3 immune-related AEs occurred in 40%, 20%, and 50% of patient arms A, B, and C, respectively. Radiologic response rate was 60%, 60%, and 42%, partial pathologic response was 80% (47% pCR), 77% (57% pCR), and 65% (23% pCR). None of the patients with a pathologic response have relapsed (98.4% relapse-free survival), while 9/21 patients (42.9%) with no pathologic response have relapsed. IFN-gamma signature was high in relapse-free patients. This study suggests that neoadjuvant combination therapy of Ipi 1 mg/kg + Nivo 3mg/kg is less toxic and preserves the high response rate, supporting this schedule a promising candidate to be tested in resectable stage III melanoma patients in a Phase III study.

An intravenously delivered oncolytic virus, Coxsackievirus A21 (CVA21), in combination with pembrolizumab is well tolerated and indicated encouraging clinical signals in advanced NSCLC and bladder cancer patients: KEYNOTE-200 (LBA40)

Charles M. Rudin, MD, PhD (Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA) described results from the open-label, dose-finding and signal-seeking Phase Ib KEYNOTE-200 trial (NCT02043665), examining the safety and efficacy of IV CVA21 alone and in combination with pembrolizumab in patients with late stage solid tumors, including NSCLC and bladder cancer. CVA21 is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. In the expansion cohort, 78 pts were given IV CVA21 + pembrolizumab, with IV CVA21 dose 1x109 TCID50 on study days 1, 3, 5, 8, 29 and Q3W for 6 additional infusions. Pembrolizumab was given at 200 mg IV Q3W from Day 8 for up to 2 years. In evaluable immune checkpoint inhibitor (ICI) naïve NSCLC patients, best ORR (irRECIST) was 23% (7/31, 2CR+5PR) and 33% (7/21) in patients harboring no EGFR or ALK mutations; median OS was 9.5 months and N/A, respectively. In ICI naïve bladder cancer population, ORR was 31% (8/26, 3CR+5PR) and median OS was 11.2 months. Preliminary IHC staining data of paired biopsies from ICI naïve patients with negative/low baseline PD-L1 revealed a notable increase in PD-L1+ tumor cells at Day 15 of 62% (8/13) following treatment with CVA21 and pembrolizumab. Prolonged SD was the best ORR observed in patients previously treated with ICI (n=17). These data indicate systemic CVA21 with pembrolizumab is well tolerated and has demonstrated encouraging clinical signals of activity in these cohorts.

Driving immunotherapy efficacy through modulation of the tumor microenvironment (TME): tumor infiltrating lymphocytes, STING & β-catenin pathways, Batf3 DCs, commensal microbiota (Keynote Lecture)

Thomas F. Gajewski, MD, PhD (University of Chicago Comprehensive Cancer Center, Chicago, IL, USA) discussed the TME and how we can manipulate it to increase the efficacy of immunotherapy. First, he described that T cell-inflamed TME serves as an approximate predictive biomarker for response to anti-PD-1-based immunotherapies. Immune-inhibitory Tregs, PD-L1, and IDO are associated with a CD8+ T cell infiltrate and anti-PD1 activity in multiple cancers is associated with T cell-inflamed TME signature at baseline. Tumor infiltrating lymphocytes (TIL) co-expressing LAG-3 and 4-1BB are actively proliferating in situ but dysfunctional TIL actively undergo apoptosis. In these proliferating/apoptosing TIL, DNA damage response was detected by DNA and protein expression analyses. Dr. Gajewski suggests that a deeper mechanistic understanding of TIL apoptosis could lead to new therapeutic strategies.

Next, he hypothesized that many instances of primary resistance are mediated by inadequate generation of a T cell-inflamed TME, leading to a question how we can covert non-T cell-inflamed tumors to T cell-inflamed to expand antitumor activity. Innate immune sensing of tumors through the STING pathway in host APCs leads to spontaneous T cell priming, and STING agonist promotes T cell infiltration and tumor control in β-catenin-expressing GEM model. Currently, Phase I trials are ongoing to access intra-tumoral STING agonists, alone and combined with anti-PD-1. Thus, non-T cell-inflamed tumors might be amenable to de novo immune priming with STING agonists.

In non-T cell inflamed melanomas (T cell/chemokine signature absent), 48% percent of patients showed evidence of active β-catenin signaling. Tumor cell-intrinsic β-catenin activation fails to recruit Batf3 DCs, preventing host antitumor immune response. Batf3 DCs have at least 3 roles in CD8+ T cell immunity: 1) CD8+ T cell cross-priming, 2) recruitment of effector CD8+ T cells, and 3) reactivation of CD8+ T cells upon PD-1/PD-L1 blockade; thus, Batf3-lineage DCs are necessary for anti-PD-L1 efficacy at effector phase. Dr. Gajewski team has identified that > 22 types of cancers showing inverse correlation between β-catenin protein and immune gene signature (manuscript submitted) and his team is currently screening new β-catenin pathway inhibitors.

He then concluded by describing multi-factorial mechanisms that affect TME: 1) somatic differences, 2) germline genetic differences, and 3) environmental differences, such as the involvement of commensal microbiota to shape systemic immunity and TME as well as the correlation between microbiota and responses of anti-PD-1/PD-L1 therapy. Multidimensional “omics” analyses are identifying individualized molecular correlates of response vs resistance in patients, including commensal microbiota and germline genetic variants.

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