JITC Digest May 2022

JITC Editor Picks

Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial

Charu Aggarwal, Amy Prawira, Scott Antonia, Osama Rahma, Anthony Tolcher, Roger B Cohen, Yanyan Lou, Ralph Hauke, Nicholas Vogelzang, Dan P Zandberg, Arash Rezazadeh Kalebasty, Victoria Atkinson, Alex A Adjei, Mahesh Seetharam, Ariel Birnbaum, Andrew Weickhardt, Vinod Ganju, Anthony M Joshua, Rosetta Cavallo, Linda Peng, Xiaoyu Zhang, Sanjeev Kaul, Jan Baughman, Ezio Bonvini, Paul A Moore, Stacie M Goldberg, Fernanda I Arnaldez, Robert L Ferris, Nehal J Lakhani
Journal for ImmunoTherapy of Cancer 2022;10:e004424 (12 April 2022)
Research

Summary:

B7-H3 (CD276) is an immune checkpoint that inhibits T cell activation and cytokine production with broad surface expression on many malignant neoplasms and minimal expression on normal tissues. In a phase I/II trial, Charu Aggarwal and colleagues report meaningful antitumor activity with combination anti-B7-H3 and pembrolizumab in patients with a variety of solid tumors. Treatment with combination pembrolizumab and enoblituzumab (a B7-H3-specific monoclonal antibody Fc-optimized for enhanced antibody-dependent cell mediated cytotoxicity) led to an overall response rate (ORR) of 33.3% in 21 patients with head and neck squamous cell carcinoma (HNSCC) who were anti-PD-1-naïve. No responses were observed for 24 patients with HNSCC who had prior anti-PD-(L)1, yet 47% (n = 9) had disease stabilization with a median duration of disease control of 3.55 months. Similar trends were seen in patients with non-small cell lung cancer—the ORR in 16 anti-PD-(L)1-naïve patients was 35.7% and among 21 evaluable patients with prior anti-PD-(L)1 there were 2 who had partial responses and 11 with stable disease with a median duration of response of 3.45 months. Benefit was independent of PD-L1 expression. Limited responses were seen in cohorts of patients with melanoma and urothelial cancer who had previously received anti-PD-(L)1. The safety profile was acceptable, with the majority of adverse events being grade 1 and 2. One treatment-related death due to pneumonitis occurred. The results support further evaluation of safety and efficacy for the combination of pembrolizumab and enoblituzumab in anti-PD-(L)1-naïve tumors.

Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial

Research

Summary:

Consolidation therapy with the anti-PD-L1 durvalumab after chemoradiation is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), but response rates are less than 30% and robust biomarkers to predict clinical benefit are lacking. Hypothesizing that subvisual features of pre-treatment NSCLC tumors on CT imaging may correspond to physiologic characteristics that increase likelihood of recurrence, Khalid Jazieh and colleagues developed a radiomic risk score to predict progression free survival (PFS) and overall survival (OS) after durvalumab consolidation. In training and validation sets that each included 59 patients with unresectable stage III NSCLC who received durvalumab consolidation, low pre-treatment radiographic risk scores were associated with significantly improved PFS and OS. High radiomic risk score was also associated with worse PFS and OS in a separate cohort of 15 patients that received chemoradiotherapy alone. High radiographic risk score was associated with worse PFS regardless of tumor PD-L1 expression status. For OS, however, a low radiographic risk score only corresponded with improved survival outcomes in the patients with tumor PD-L1 expression less than 50%. Decision curve analysis demonstrated that an integrated radiomic risk score and clinical model had the highest net benefit in identifying patients who should receive consolidation durvalumab. With further validation, CT image-derived radiomic biomarkers may provide a minimally invasive decision support tool for consideration of risks versus benefits of immunotherapy.

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC

Research

Summary:

Tumors with high levels of aneuploidy are known to be poorly immune-infiltrated. While overall tumor mutation burden has been well-characterized as a predictor of response to PD-1 blockade in some settings, the effects of gains or losses of specific genomic loci or regions on immunotherapy response are incompletely understood. Using “shallow” whole-genome sequencing in samples from non-small cell lung cancer (NSCLC) tumors, Joan Frigola and colleagues demonstrate an association between somatic copy number alterations and progression-free survival (PFS) with checkpoint blockade. Across samples from 77 patients with NSCLC who received checkpoint inhibitor therapy in the first, second, or subsequent line of therapy, somatic copy number alterations affected an average of 45% of the genome. The overall number of somatic copy number alterations was not statistically significantly associated with PFS, however, the fraction of the genome altered was inversely correlated with survival. Notably, the burden of copy number alterations affecting less than 50% of a chromosome arm was not associated with PFS benefit—the biomarker with the best predictive value was the fraction of the genome altered by events affecting more than 50% of a single chromosome arm combined with those affecting both chromosome arms and encompassing at least 50% of the entire chromosome. The association between the fraction of the genome-altered score and PFS with checkpoint blockade remained significant across smoking status, histology, primary or metastatic site, and patient sex, although the effect size was greater for female patients. In the patient samples as well as analysis of The Cancer Genome Atlas, higher fractions of the genome altered by somatic copy number variations were associated with decreased immune cell infiltration by gene expression profiling signatures.

Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials

Summary:

Hyperprogression, an apparent acceleration of tumor growth after treatment with anti-PD-(L)1 checkpoint blockade has been reported in single-arm retrospective studies, but it remains unclear whether a sudden acceleration in tumor growth on treatment represents an atypical response to immunotherapy or the natural course of disease. In the first analysis of its kind using randomized trial data, Yoon-Koo Kang and colleagues find no evidence for hyperprogression in patients receiving nivolumab monotherapy or nivolumab plus ipilimumab. Because serial pre-treatment scans were not available to calculate tumor growth rate, hyperprogression was defined based on percentage change from baseline in target lesion sum of the longest diameters across multiple cut-offs. A total of 358 patients from ATTRACTION-2 (243 received nivolumab and 115 placebo) and 531 patients from CheckMate 415 (177 received nivolumab monotherapy, 179 nivolumab plus ipilimumab, and 175 placebo) had baseline and first post-treatment scans available for analysis. In both CheckMate 415 and ATTRACTION-2, the numbers of patients who had sum of target lesion diameter increases of greater than 50% or 20% were lower in the immunotherapy arms compared to the placebo arms. The small numbers of patients who had tumor growth greater than 100% were similar across placebo and immunotherapy arms for both trials. Greater than 20% increase in tumor size from baseline was significantly associated with worse overall survival in both trials. No obvious association between MDM2/MDM4 amplification and hyperprogression was identified in either study population, but the number of tumors harboring alterations was small. The findings suggest that rare cases of rapid growth on treatment may be attributable to intrinsic tumor biology as opposed to an unknown mechanism induced by checkpoint blockade.  

Other Recent JITC Articles

view other articles from this issue

JITC 10th Anniversary