Faculty Bibliography

Background/UNASSIGNED:-positive non-small cell lung cancer. We describe patient-reported outcomes (PROs) from the NP28761 study. Patients and methods/UNASSIGNED:PROs and health-related quality of life (HRQoL) benefits were assessed using two self-administered questionnaires (the European Organisation for Research and Treatment of Cancer 30-Item Quality of Life Questionnaire-Core (EORTC QLQ-C30), and the 13-item EORTC QLQ-lung cancer-specific module) at enrolment and every 6 weeks until week 66, disease progression or death. Results/UNASSIGNED:Clinically meaningful mean improvements (≥10 point change from baseline) were observed in 10 domains, including global health status (GHS), role and social functioning, fatigue, pain, dyspnoea, and appetite loss. A clinically meaningful improvement was observed in GHS from the first assessment (6 weeks) until week 60. Alectinib demonstrated a rapid effect, with a median time to symptom improvement, using the composite endpoint of cough, dyspnoea and pain in the chest, of 1.4 months (6.1 weeks) (95% CI 1.4 to 1.6) and a median time to symptom deterioration of 5.1 months (22.1 weeks) (95% CI 2.8 to 6.8). Patients with CNS metastases at baseline experienced comparable HRQoL over the duration of the study as patients without CNS metastases. Exploratory analysis showed that the occurrence of an objective response may be associated with a better HRQoL. Conclusions/UNASSIGNED:Patients treated with alectinib in this phase II study achieved clinically meaningful improvements in HRQoL and symptoms and had delayed time to symptom deterioration.

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Background Entinostat is an oral, class I selective histone deacetylase (HDAC) inhibitor that has been shown in pre-clinical models to enhance anti- PD-1 activity through inhibition of immune suppressor cells in the tumor microenvironment. ENCORE 601 is a Phase 1b/2 study evaluating safety and efficacy of ENT plus PEMBRO in NSCLC, melanoma and colorectal cancer patients. We previously reported the results of Phase 1b, which identified ENT 5 mg PO weekly plus PEMBRO 200 mg IV every 3 weeks as the dose to be further explored. Methods Efficacy of ENT 5 mg PO weekly plus PEMBRO 200 mg IV q3wks is being assessed in a Simon 2-stage Phase 2 study involving two cohorts of patients with advanced NSCLC: anti-PD-(L)1-naive (Cohort 1), and progressed on anti-PD-(L)1 (Cohort 2). The primary endpoint is objective response rate. Based on investigator feedback to incorporate Phase 1b patients dosed at entinostat 5 mg into the Stage 2 go/no go assessment, revised criteria for advancement were >=4 responses observed out of 17 evaluable patients in Cohort 1 and >=3 out of 31 in Cohort 2. Tumor biopsies and blood samples for immune correlates were taken pre- and post-treatment. Results Enrollment has been completed for Stage 1 of both cohorts. In Cohort 1, 4 of 17 (24%, 95% CI: 7-50) evaluable patients achieved a partial response (PR; 2 confirmed, 2 unconfirmed). In Cohort 2, 3 of 31 (10%, 95% CI: 2-26) evaluable patients achieved a PR (2 confirmed, 1 unconfirmed). As of the data cutoff, the longest duration of response was 24 weeks (and ongoing). Baseline PD-L1 expression for responders was <1% (1 patient), 1-49% (2 patients) and not available (1 patient) for Cohort 1, and <1% (2 patients) and not available (1 patient) for Cohort 2. 31% of patients experienced a Grade 3/4 event deemed related to study drug. The most common of these events included hypophosphatemia and neutropenia in Cohort 1, and fatigue, anemia, and pneumonitis in Cohort 2. 13% of patients discontinued therapy due to an adverse event. Circulating myeloid derived suppressor cells were reduced in both cohorts at Cycle2/Day1 compared to pretreatment. Gene expression analysis of tumor biopsies and association with responses is in progress. Conclusions ENT plus PEMBRO demonstrates anti-tumor activity and acceptable safety in patients with NSCLC who are both naive to and have progressed on prior PD-(L)1 blockade. Based on the responses seen, Cohort 2 has advanced to Stage 2 and is currently enrolling

Background: Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42-1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36-1.31). We present results from the May 31, 2017 data cutoff. Method: Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS >=1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m² Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025). Result: 123 patients were randomized. Median follow-up was 18.7 months (range, 0.8- 29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%-41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33-0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5-NR) months versus 8.9 (6.2-11.8) months. The HR for OS was 0.59 (95% CI, 0.34-1.05; P=0.0344). Median (95% CI) OS was not reached (22.8-NR) months for pembrolizumab + PC and 20.9 (14.9-NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3-5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm. Conclusion: Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months)

INTRODUCTION: Alectinib demonstrated clinical efficacy and an acceptable safety profile in two phase II studies (NP28761 and NP28673). Here we report pooled efficacy and safety data after 15 and 18 months' longer follow-up than the respective primary analyses. MATERIALS AND METHODS: Enrolled patients had ALK-positive NSCLC and had progressed on, or were intolerant to, crizotinib. Patients received oral alectinib 600 mg twice daily. The primary endpoint in both studies was objective response rate (ORR) assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Secondary endpoints included disease control rate (DCR); duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety. RESULTS: The pooled dataset included 225 patients (n=138 NP28673; n=87 NP28761). The response-evaluable (RE) population included 189 patients (84%; n=122 NP28673; n=67 NP28761). In the RE population, ORR by IRC was 51.3% (95% confidence interval [CI], 44.0-58.6; all partial responses), DCR was 78.8% (95% CI, 72.3-84.4), and median DOR was 14.9 months (95% CI, 11.1-20.4) after 58% of events. Median PFS by IRC was 8.3 months (95% CI, 7.0-11.3) and median OS was 26.0 months (95% CI, 21.4-not estimable). Grade >/=3 adverse events (AEs) occurred in 40% of patients, 6% withdrew treatment due to AEs and 33% had AEs leading to dose interruptions/modification. CONCLUSION: This pooled data analysis confirmed the robust systemic efficacy of alectinib in ALK-positive NSCLC with a durable response rate. Alectinib also had an acceptable safety profile with a longer duration of follow-up.

BACKGROUND: Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria. METHODS: Both studies enrolled patients aged >/=18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee. RESULTS: Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7-68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate). CONCLUSION: Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune checkpoint blockade targeting the programed death (PD)-1 receptor, often with palliative radiation therapy. Outcome data are limited in this population. MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy at four centers. RESULTS: We identified 137 patients who received radiation and PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and 121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received radiation following the start of PD-1 blockade, 25 continued to receive PD-1 inhibition for a median of 179days and survived for a median of 238 additional days. Median survival following first course of radiation for brain metastases was 634days. Melanoma patients received brain directed radiation relatively less frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS: Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.