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BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPR(bx), ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate–high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPR(bx) associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054–0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPR(bx), indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

SUMMARY: We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFNγ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFNγ in vitro exposure leads to a conserved transcriptome response unless cells have IFNγ receptor alterations. This conserved IFNγ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFNγ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy. ETOC BLURB: Analyzing the transcriptome of biopsies of patients during immune checkpoint blockade therapy, Grasso et al. show that the increase of T cell infiltration and the downstream IFNγ signaling drive clinical responses.

Background The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. Objective We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). Methods The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. Results A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. Limitations The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. Conclusions The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.

Aim: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, is active and tolerable in pts with advanced MEL (Topalian et al. NEJM 366:2443, 2012). We report long-term clinical activity, response duration off-therapy, tumor PD-1 ligand (PD-L1) expression associated with survival endpoints, and 3-yr overall survival (OS) for the MEL pts in this phase 1 trial. Methods: Previously treated pts with advanced MEL and no prior ipilimumab therapy received nivolumab 0.1, 0.3, 1, 3 or 10 mg/kg IV Q2W for ≤96 wks and were evaluated for OS and progression-free survival (PFS). Tumor cell surface expression of PD-L1 was retrospectively assessed in archival pretreatment specimens by a Dako immunohistochemistry assay, with PD-L1+ defined as ≥5% tumor cells expressing this marker. Results: From 2008–2012, 107 MEL pts initiated treatment with nivolumab: 25% had ≥3 prior therapies. One-, 2- and 3-yr OS rates were 63%, 48% and 41%, respectively. For the 33/107 (31%) pts with objective responses (OR; RECIST), median response duration was 22.9 months. Twenty-four OR pts stopped nivolumab for reasons other than disease progression; 11 (46%) maintained responses for ≥24 wks off drug (range: 24, 56+ wks). Four (4%) additional pts had unconventional “immune-related” responses; overall survival for these pts was 21.1, 28.6 + , 43.1+ and 48.0+ months as of September 2013. In a subset of 41/107 pts with available tumor samples, median OS for pts with PD-L1+ (n = 18) and PD-L1– (n = 23) tumors was not reached and 12.5 months, respectively; median PFS was 9.1 and 1.9 months, respectively. Safety has been previously reported (Topalian et al. J Clin Oncol 32:1020, 2014). Conclusions: In pts with advanced MEL, nivolumab demonstrated notable 2- and 3-yr OS rates, durable responses with several persisting following discontinuation of therapy, and an acceptable safety profile. Additional analyses will be presented on the correlation between key pt characteristics and response to nivolumab. Ongoing phase 3 trials are further evaluating nivolumab for MEL pts and will also explore the role of PD-L1 as a potential predictive biomarker for nivolumab activity. Disclosure: D.F. McDermott: Consultant advisor, BMS advisory board; Research Funding BMS; M. Sznol: Paid consultant and scientific advisory board-Bristol-Myers Squibb, Genentech/Roche, MedImunne, Amgen, Nektar, Symphogen, Merus, Amphivena, NeoStem, Anaeropharma, BeiGene, Kyowa-Kirin, Immune Design, Lion Biotechnologies, Seattle Genetics; R. Carvajal: Consultant- Aura Biosciences; S.L. Topalian: Consultant-BMS(uncompensated), Jounce Therapeutics (comp.), Sanofi (comp.); Stock options: Compugen, Amplimmune, NexImmune, Jounce Therapuetics; Research funding BMS; Other remuneration-BMS and Amplimmune Inc., patent royalties through Johns Hopkins Univ; M.B. Atkins: Consultant advisor, honoraria- BMS; J.D. Powderly: Employment-Biologics Human Application Lab; Consultant advisor-BMS, Genetech, Amplimmune, Merck; Honoraria-BMS; Research Funding-BMS, Genetech, Amplimmune, Merck, AstraZeneca; Other Rumuneration-BMS Speakers Bureau and Advisory Boards; W.H. Sharfman: Consultant advisor, honoraria-MerckM; D.C. Smith: Research funding-BMS; J.M. Taube: Consultant advisor, research funding-BMS; R.A. Anders: Research Funding BMS; C. Horak: BMS-employee, stock; G. Kollia: BMS-employee, stock; J.A. Sosman: Consultant advisor-BMS; Honoraria-Glaxo Smith Kline, Amgen; Research funding-BMS, Novartis, Glaxo Smith Kline; F.S. Hodi: Consultant advisor BMS-uncompensated. All other authors have declared no conflicts of interest.