Introduction Many patients with oncogene driven non-small cell lung cancer treated with TKIs experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to CNS and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively. Materials and Methods Patients with metastatic ALK+ NSCLC treated with crizotinib (n=38) and EGFR-MT NSCLC treated with erlotinib (n=27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression free survival (PFS1) and site of first progression were recorded. A subset of patients with either non-leptomeningeal CNS and/or ≤4 sites of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same TKI. The subsequent median progression free survival from the time of first progression (PFS2) and pattern of progression were recorded. Results PFS1 in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. 25 of 51 (49%) patients who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, 1 with surgery, and continuation of the same targeted therapy. Post LAT, 19/25 patients progressed again, with median PFS2 of 6.2 months Discussion Oncogene addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with >6 months of additional disease control.

Purpose A preliminary analysis demonstrated that local ablative therapy (LAT) can provide short-term control of extra-CNS (eCNS) lesion progression in tyrosine-kinase addicted non-small cell lung cancer (NSCLC) patients. However, little is known about the long-term efficacy and safety of single and multiple courses of radiotherapy when used to treat these sites of progressive disease. This study analyzes the durability and toxicity of radiotherapeutic LAT applied to eCNS disease progression in ALK+ NSCLC patients. Materials and Methods ALK+ NSCLC patients receiving crizotinib manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results 33 of 38 patients progressed on crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1–3 courses of LAT with radiotherapy. The 6 and 12 month actuarial local lesion control rates (LC) with radiotherapy was 100 and 86%, respectively. The 12 month LC with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% vs. 60% (p = 0.01). No acute or late grade >2 radiotherapy-related toxicities were observed. Median overall time on crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 and 10.1 months, respectively. Patients remaining on crizotinib for >12 months vs ≤12 months had a 2 year OS of 72% vs 12%, respectively (p < 0.0001). Conclusions LAT safely and durably eradicated sites of individual lesion progression in ALK+ NSCLC patients receiving crizotinib. A dose-response relationship for LC was observed. The suppression of OPD on crizotinib by LAT allowed an extended duration of exposure to crizotinib, which was associated with longer OS.

BackgroundMerkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC.Case presentationWe report a case of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody.ConclusionImmunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents.

The incidence of cutaneous melanoma is on the rise worldwide despite increasing awareness and vigilance towards prevention by the lay public and health professionals. Melanoma is easily curable by surgical excision when detected early, but it is nearly incurable when discovered in its later stages owing to resistance to treatment. Unfortunately, treatment options traditionally used in melanoma have not shown a survival benefit. However, as the understanding of tumor biology and metastatic growth evolves, new therapeutic options for metastatic melanoma have shown impressive survival benefit. The blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) by use of the monoclonal antibody, ipilimumab (Yervoy™, Bristol-Myers Squibb), produces favorable antitumor immune system responses and was recently approved by the US FDA for use in patients with advanced melanoma. In addition, targeting components of the MAPK pathway have also demonstrated survival advantage in patients with BRAF-mutated melanoma and vemurafenib (Zelboraf™, Plexxikon/Roche) was approved by the FDA in August 2011 for the first-line treatment of both metastatic and unresectable melanomas for patients whose tumors have V600E mutations in the BRAF gene.

7526 Background: This study aimed to investigate the benefits of local treatment of limited disease progression and continuation of crizotinib (C) or EGFR-TKI in patients with ALK+ or EGFR-Mt metastatic NSCLC, respectively. Methods: Patients with advanced ALK+ NSCLC treated with C (n=38) and EGFR-Mt NSCLC treated with EGFR TKIs (erlotinib or gefitinib) (n=27) were identified. Patients were evaluated for initial response, site of first progression (CNS or extra CNS (eCNS)) and median progression free survival (PFS1). A subset of patients with limited sites of progression (oligoprogressive disease) suitable for local therapy received either radiation or surgery to these sites and continued on the same TKI. The subsequent pattern of progression and median progression free survival from the time of first progression (PFS2) were recorded. Results: In 38 ALK+ patients, PFS1=9.0 months on C. In 27 EGFR-Mt patients, PFS1=13.8 months on EGFR-TKI. CNS was the first site of progression in 13/28 (46%) of ALK+ patients and 5/23 (22%) EGFR-Mt patients. 25 of 51 patients who progressed (49%) were deemed suitable for local therapy (15 ALK+, 10 EGFR-Mt; 24 with radiotherapy (Body: 3 XRT, 9 SBRT; CNS: 7 WBRT, 5 SRS), 1 with surgery (adrenalectomy)) and continuation of the same targeted therapy. 19/25 patients progressed post local therapy, median PFS2 = 6.2 months. In patients who progressed at PFS1 only in the CNS, there was a trend to longer PFS2 than patients who progressed at PFS1 in eCNS (7.1 months vs 4.0 months, p=0.26). 60% who progressed only in the CNS at PFS1, progressed eCNS at PFS2 (n=10). Conclusions: Progression of oncogene addicted NSCLC on relevant targeted therapies is often suitable for local therapy (oligoprogressive disease). Continuation of the targeted therapy following local therapy is associated with >6 months of additional disease control. [Table: see text]