Carmelia Maria Noia Barreto

Immune checkpoint inhibitors for advanced non-small cell lung cancer: emerging sequencing for new treatment targets

Lung cancer is the leading cause of cancer-related deaths in the world. Immune checkpoint inhibitors (ICI) stimulate cytotoxic lymphocyte activity against tumour cells. These agents are available for the treatment of non-small cell lung cancer (NSCLC) after failure of platinum-based therapy. One recent study has demonstrated that ICI monotherapy was superior to platinum-based chemotherapy for first-line treatment. Nevertheless, this benefit was only for a minority of the population (30%) whose tumour programmed death receptor ligand-1 (PD-L1) expression was above 50%. Therefore, several strategies are under investigation. One option for patients with PD-L1 expression lower than 50% may be the combination of ICI with platinum-based chemotherapy or with ICIs against different targets. However, all of these combinations are at an early stage of investigation and may be very expensive or toxic, producing several harmful adverse events.

Small Intestine Cancer

Primary small intestine cancers are not frequent, accounting for <1 % of all adult neoplasms. Various histologic types are associated with small intestine cancer. The most common used to be adenocarcinoma; however, carcinoid tumors are showing an improved incidence and are the most common histologic type in some series. Adenocarcinomas are more frequent in the duodenum, while carcinoid tumors are more common in the ileum. Other histologic types are lymphomas and sarcomas. The symptoms are vague and non-specific. Less of an index of suspicious can cause a late the diagnosis. The stage at diagnosis is the most important prognostic factor. Radiologic and endoscopic exams can be performed to achieve a specimen sample and to stage the disease. Early tumors can be treated properly with surgical resection. Adjuvant treatment for adenocarcinoma has not been studied in large trials, but it is indicated in extrapolating colon data. The treatment for advanced adenocarcinoma of the small intestine has only been studied in a few large cohorts. Treatment for other histologic types is discussed in a separated chapter.

P2.45: An Estimate of the Economic Impact of Treatment of NSCLC With Immunotherapy Relative to PD-L1 Expression in Brazil: Track: Immunotherapy

Pedro Aguiar Jr., Ramon De Mello, Hakaru Tadokoro, Barbara Gutierres, Carmelia Barreto, Hani Babiker, Gilberto Lopes Clinical Oncology, Universidade Federal de São Paulo, São Paulo/BRAZIL, Universidade do Algarve, Faro/ PORTUGAL, Universidade Federal de São Paulo, São Paulo/BRAZIL, Universidade Paulista, São Paulo/BRAZIL, Honor Health, Scottsdale/AZ/UNITED STATES OF AMERICA, Oncoclinicas do Brasil, São Paulo/BRAZIL

O.03: Cost Effectiveness of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Relative to PD-L1 Expression

Background: NSCLC is genomically complex with several guideline-recommended genomic targets. Nextgeneration sequencing (NGS) of circulating tumor DNA (ctDNA) enables non-invasive detection of these targets but liquid biopsy studies to date are modestly sized. Method: A highly accurate, deep-coverage (15,000x) ctDNA plasma NGS test targeting 54-70 genes (Guardant360) was used to genotype 5,206 advanced-stage NSCLC patients (6/2014 e 4/2016); 85% of samples were ordered at clinical progression and 15% at baseline when tissue was of insufficient quantity (QNS) for recommended genotyping. Frequencies of somatic ctDNA alterations per gene were compared to those previously described in tissue sequencing compendia (e.g., TCGA). Accuracy of ctDNA sequencing (PPV) was assessed by comparing available tissue testing to ctDNA results in 229 consecutive patients. Clinical utility (identifying treatment-impacting alterations) was examined in 362 consecutive NSCLC patients (6/ 2014-6/2015) with tissue testing data available and in the 85% of ctDNA samples ordered at clinical progression. Results: Somatic ctDNA alterations were detected in 86% of cases; EGFR mutations in 25%, KRAS mutations in 17% and other uncommon-to-rare alterations at lesser frequencies. Alteration patterns among driver oncogenes were highly consistent with those from TCGA (Pearson r1⁄40.92, 0.99, and 0.99 for EGFR, KRAS, and fusion breakpoint location). PPV of ctDNA-detected variants in 229 samples with matched tissue testing reports was 100% forEGFR, 98% for EGFR, 96% for ALK, RET, or ROS1 fusions, and 100% for KRAS mutations. As expected, PPV was lower (27%) for EGFR in ctDNA, indicating later acquisition of this resistance mutation, not present at initial tissue biopsy. In 63% (229/362) of consecutive NSCLC cases, tissue was QNS or under-genotyped (UG). In these QNS/UG cases, alterations not previously identified (EGFR, ALK, RET, BRAF,MET, KRAS) were found via ctDNA in 24% (51/229). Among 1,111 EGFRmutant NSCLC cases, resistance mutations were identified at progression at frequencies consistent with published literature: EGFR 47%, METamp 5%, ERBB2 amp 5%, FGFR3 fusions 0.4%, ALK/other fusions 1%, BRAF mutations 1.8%, PTEN inactivation 2.5%, NF1 inactivation 3%, RB1 inactivation 3%, KRAS mutations 1.9%). Conclusion: This series represents the largest NSCLC ctDNA study to date. Genotypic patterns of driver mutations in this large clinical ctDNA cohort were consistent with TCGA. However, TCGA is earlier stage and thus lacks secondary resistance mutations such as EGFR prevalent in ctDNA. CtDNA NGS identified new targetable alterations at progression and also when tissue biopsy was QNS/UG. Studies employing ctDNA in serial testing for evolution of resistance alterations are ongoing.

Treatment of Metastatic Renal Cell Carcinoma: Latest Evidence and Ongoing Challenges

Recently, the development of antiangiogenic drugs has changed the therapy for metastatic renal cell carcinoma (RCC). As a result, the survival of individuals with advanced RCC has more than doubled. The median overall survival improved from 12 months during the cytokines era to near 30 months with antiangiogenic drugs. In this decade, the advent of immune checkpoint inhibitors showed enthusiastic results and is the new standard of care for patients with metastatic RCC previously treated with antiangiogenic drugs. The combination of immune checkpoint inhibitors plus antiangiogenic drugs may have a synergistic activity. As a result, current studies investigate the combination for treatment-naïve patients. This may potentially change clinical practice. In this article, we will highlight new therapeutic options available and agents or combinations that are being investigated for metastatic RCC.

P2.44: An Update of a Pooled Analysis of Nivolumab for the Treatment of Advanced NSCLC and the Role of PD-L1 as a BIOMARKER: Track: Immunotherapy.

Results: Enrollment in KEYNOTE-042 is ongoing, and participating countries in Latin America include Argentina, Brazil, Chile, Columbia, Guatemala, Mexico, and Peru. Conclusion: To date, KEYNOTE-042 has enrolled patients from 28 countries in Africa, Asia, Europe, North America, and South America, and enrollment will continue until w1240 patients are allocated.

Metabolic Disturbance in Cancer Patients

Patients with cancer are at risk for metabolic disorders. The pathophysiologies include organic dysfunction due to systemic dissemination, dysfunction due to anticancer treatment, paraneoplastic metabolic changes due to tumor proliferation mechanisms, and metabolites production. The main metabolic emergencies in cancer patients are the tumor lysis syndrome, hypercalcemia, hyponatremia, and adrenal insufficiency.