Programmed Cell Death Ligand 1 Status Research Articles

139TiP - Phase 2, Open-Label, International, Non-Comparative Study of MEDI4736 in Patients with Locally Advanced or Metastatic, Pd-L1 +, Stage 3B–4 Nsclc Who Have Received ≥2 Prior Systemic Treatment Regimens (ATLANTIC)

Background: The inhibitory programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway plays a major role in controlling T-cell activation. Many cancers appear to exploit this pathway to evade antitumour responses. Encouraging clinical activity against several tumour types has been seen for anti-PD-L1 mAbs. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80, and is associated with a low frequency of anti-drug antibodies. Evidence of clinical activity for MEDI4736 in NSCLC has been seen in a Phase 1 study, with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). An accelerated clinical development programme for MEDI4736 in NSCLC is underway. Here we describe the ATLANTIC (NCT02087423) study that is assessing the efficacy and safety of MEDI4736 in patients (pts) with locally advanced or metastatic NSCLC. Trial design: In this Phase 2, open-label, international, non-comparative study, the efficacy and safety of MEDI4736 (10 mg/kg IV every 2 weeks for up to 12 months) is being assessed in pts with PD-L1+ locally advanced or metastatic NSCLC (Stage 3B–4). Pts were initially included regardless of PD-L1 status, but once a diagnostic became available, this was amended to PD-L1+ tumours only. Eligible pts must have a WHO Performance Status of 0 or 1, and received ≥2 prior systemic treatment regimens, including 1 platinum-based chemotherapy. Around 188 PD-L1+ pts (Cohort 1: ∼50% epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] positive; Cohort 2: ∼50% EGFR and ALK-negative), will be treated at ∼100 sites across North America, Asia, and Europe. In Cohort 1, prior therapy must include the appropriate tyrosine kinase inhibitor. The primary outcome measure is ORR according to RECIST v1.1 based on independent central review. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, progression-free survival, overall survival, and deep sustained response), safety (CTCAE v4.03), tolerability, PK, and immunogenicity. Recruitment is ongoing. Clinical trial identification: NCT02087423 (March 4, 2014); EudraCT 2013-005427-16 (June 24, 2014) Disclosure: M.C. Garassino: Member of AstraZeneca Advisory Board. J.F. Vansteenkiste: Research funding at University Hospitals KU Leuven: AstraZeneca, Amgen. Advisory functions: GlaxoSmithKline, Merck-Serono, Novartis, BMS, Merck. Speaker bureau: Eli-Lilly, Boehringer-Ingelheim. M. Ballas: Employee of AstraZeneca and owns stock/stock options in AstraZeneca Owns stock in Bristol Myers Squibb. D. Jayawardene and P.K. Stockman: Employee of AstraZeneca and own stock/stock options in AstraZeneca. J.D. Powderly: Speaker Bureaus: BMS, Dendreon, Genentech. Research Funding: BMS, Genentech/Roche, AstraZeneca/MedImmune, Merck/EMD Serono, Amplimmune, CellDex, ABBVie, Lilly/Imclone, InCyte and MacroGenics Stock Ownership: BioCytics (Founder) N. Rizvi: Advisory Board/consulting: Merck, Genentech, Roche, Medimmune, Astrazeneca, Novartis, Astellas, BMS Research grant: BMS. All other authors have declared no conflicts of interest.

The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs

Recent clinical trials have shown that immune-checkpoint blockade yields remarkable response in a subset of non-small cell lung cancer (NSCLC) patients. However, few studies directly focus on the association between epidermal growth factor receptor (EGFR) mutational status and programmed cell death-ligand 1 (PD-L1) expression. We examined whether PD-L1 is related to clinicopathologic factors and prognosis in patients with advanced NSCLC treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). One-hundred and seventy patients with advanced NSCLC were explored. Paraffin-embedded tumour sections were stained with PD-L1 antibody. EGFR mutation was examined by fluorescent quantitative polymerase chain reaction (PCR). The correlations between PD-L1 expression and EGFR status and survival parameters were analyzed. The overall frequency of PD-L1 over-expression was 65.9% (112/170). In lung adenocarcinoma, PD-L1 tended to be associated with mutant EGFR (PD-L1 overexpression in mutant and wild-type EGFR, 64/89 (71.9%) vs. 32/56 (57.1%), respectively; p=0.067). Subgroup analyses showed that high PD-L1 expression was associated with significantly shorter overall survival (OS) in EGFR wild-type patients (p=0.029) but not in EGFR mutant patients (p=0.932) treated with EGFR-TKIs. Even more, for EGFR mutant patients, higher expression of PD-L1 might only signal better outcome with TKIs. High PD-L1 expression was likely to be associated with the presence of EGFR mutation in advanced lung adenocarcinoma. For EGFR wild-type patients, the PD-L1 over expression can be considered as a poor prognostic indicator of OS.

Abstract A80: Acral melanoma in the Hawaiian Islands: Exploring immunologic PDL-1 signature in the minority population

Abstract Background: While acral melanoma (AM) is the least common subtype amongst the principal histologic variants of cutaneous melanoma (CM), darker-skinned individuals such as Asians, Pacific Islanders, and African Americans are more frequently affected. Asian/Pacific Islanders with AM in particular, exhibit the worst survival amongst all ethnic groups. Recent studies have profiled the importance of programmed cell death ligand 1 (PDL-1) in the therapeutic armamentarium for melanoma. However, the pathologic features and immunologic characteristics of AM evaluating PDL-1 in the minority population have not been thoroughly analyzed. Methods: IRB approval was obtained for this retrospective analysis. From 2004 to 2011, 17 Asian/Pacific Islander patients histologically confirmed to have invasive AM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, ulceration, tumor infiltration lymphocyte (TIL) status, and mitoses per mm squared were compiled. Immunohistochemistry was performed targeting the PDL-1 (CD274) antigen on primary tumor cells in formalin-fixed paraffin-embedded archived biospecimens. PDL-1 expression was graded on a scale from 0 (absent) to 2 (high). Results: Our findings demonstrated that PDL-1 expression was low in this series (3/17; 17.6%). All AM patients had a non-brisk TIL response. A significant proportion of our entire cohort (8/17; 47.1%) exhibited thick primary lesions (>4.0 mm) with a high propensity for ulceration (8/17; 47.1%). Demographics of the Asian/Pacific Islander cohort included mean age of 63.8 years (range 40-86) and male gender (9/17; 53 %). Tumor location primarily involved the foot (11/17; 64.7%); median Breslow thickness was 3.98 mm (range 0.96-11.0), and mean mitoses per mm squared was 3.9 (range 0-10). Conclusion: Asian/Pacific Islanders with AM were found to have a low frequency of PDL-1 expression. The lack of a brisk lymphocytic host response in AM may provide insight into its mechanism of tumorigenesis. This is the first study to our knowledge that has examined the immunologic signature of TIL and PDL-1 status in a multi-ethnic population of AM patients. This is compelling data that may be applied to patient selection in future trials utilizing immunotherapy. Citation Format: Shane Y. Morita. Acral melanoma in the Hawaiian Islands: Exploring immunologic PDL-1 signature in the minority population. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A80. doi:10.1158/1538-7755.DISP13-A80