Giaccone, Giuseppe

11085 Background: The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) jointly initiated an effort to establish evidence-based recommendations for the molecular analysis of lung cancers required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Methods: Three co-chairs without relevant conflicts of interest were selected, one from each of the sponsoring societies: CAP (P.T.C.), IASLC (M.L.), and AMP (N.I.L.). Writing and advisory panels were formed from additional experts from these societies. Unbiased literature searches were performed to capture articles up to February 2012, yielding 1,533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for relevance. Evidence was formally graded for each of the recommendations first formulated by the co-chairs and panel members at a public meeting. Each guideline section was assigned to at least two panelists. Successive drafts were circulated for comments to the writing panel, the advisory panel, the public (online posting), and the three professional societies. Results: We generated 37 guideline items addressing 14 areas of EGFR and ALK testing. The major, evidence-based recommendations are to test for EGFR mutations and ALK fusions in all patients with advanced stage adenocarcinoma, regardless of sex, race, or smoking history, and to prioritize EGFR and ALK testing over other molecular predictive tests. Recommendations and expert consensus opinions were generated for all other key aspects of EGFR and ALK testing in lung cancer related to oncology and pathology practice and technical issues in molecular testing. Conclusions: As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards and thereby improving patient outcomes.

1030 Background: Previous studies have shown that 44-71% of trastuzumab (T)-treated pts develop HER2-specific immunity (Clin Cancer Res 2007, 13:5133; Cancer Res 2016, 76:3702; Breast Cancer Res 2018, 20:52). M is an Fc-engineered mAb that shares similar HER2 binding and antiproliferative activity as T. The Fc region of M has been engineered for increased affinity to the activating FcγRIIIA (CD16A) and lower binding to the inhibitory FcγRIIB (CD32B), attributes that may enhance the mAb’s immune function, such as antigen presentation. Methods: HER2+ cancer pts who progressed on prior therapy received M (0.1-6 mg/kg QW for 3 of every 4 weeks [N = 34]; or 10-18 mg/kg Q3W [N = 32]) in phase 1 trial NCT01148849. PBMC and plasma were collected pre-dose and 50 days post-dose for 46 pts and > 4 years for 3 pts on long-term treatment. Response to HER2 or control antigens (Ag) was assessed by IFNγ ELISpot and antibody (Ab) ELISA. In 14 pts, T-cell antigen receptor (TCR) repertoire was assessed by immunosequencing. Results: Following M treatment, mean frequencies of IFNγ-producing T cells specific for intra- or extracellular fragments of HER2 increased by 2.5 to 6-fold (p < 0.0027, paired t test). Most (95%) of subjects responded to ≥2 of 6 (median = 5) HER2 Ag. Mean HER2-specific Ab concentration increased by 19-54% (p < 0.0001), with all subjects responding to ≥2 (median = 5) of the 6 Ag. A small 1.6-fold increase in IFNγ response to control CMV/EBV/Flu (but not tetanus or cyclin D1) peptides was observed; no increase in Ab response to control Ag was noted. Subsets of HER2-specific T-cell and Ab responses persisted during long-term treatment. Median TCR clonality increased by 54% (p = 0.003), with an average of 125 unique clones expanding, while overall TCR diversity remained unchanged (p = 0.19). Conclusions: Treatment of HER2+ cancer with M was associated with enhanced HER2-specific T-cell and Ab responses together with increased TCR clonality, indicative of a more focused T-cell repertoire. The high frequency of HER2-specific immunity in M-treated patients ( > 95%) is consistent with its enhanced Fc region contributing to linkage of innate and adaptive immune responses.