Onkologie 15. November 2016
SCLC: genomic alterations pave the way to targeted approaches
Rapid growth and early development of metastatic disease are characteristic of small-cell lung cancer (SCLC), which constitutes approximately 15 % of all lung cancer cases . In limited-stage disease, a cure is possible with chemoradiotherapy. However, 68 % of patients present with extensive-stage SCLC (ES-SCLC). Although high initial responses to platinum-based chemotherapy and radiotherapy are observed, recurrence of chemo-refractory disease takes place as a rule.
At present, the lack of effective therapies for relapsed SCLC is one of the greatest unmet needs in the management of lung cancer patients. Nearly all SCLC cases are attributable to cigarette smoking, which has implications for the mutational landscape of these cases, and thus for the potential use of certain treatments.
Genomic profiling of SCLC patients
Ali et al. reviewed 883 patients with SCLC using a comprehensive genomic profiling approach . Importantly, all types of genomic alterations were identified (i.e., base-pair substitutions, insertions/deletions, copy number alterations, rearrangements). This study is the largest to date that describes the genomic profiles of SCLC patients through the course of their clinical care.
These patients included the unique index case of a never-smoker whose tumour harboured JAZF1-MYCL1 without amplification of MYCL1. This patient experienced durable complete remission over 18 months when treated with the investigational aurora A kinase inhibitor alisertib (MLN8237), and durable partial response to nivolumab. The biological implication of this is that JAZF1-MYCL1 might ectopically stabilise functional MYCL1 expression, thus hyper-activating the downstream target aurora kinase, as well as hyper-inhibiting the downstream target PD-L1. MYCL1 amplifications might represent a less dramatic elevation of downstream activity, but they still confer sensitivity to aurora kinase inhibitors and PD-1 inhibitors. Therefore, some patients, and particularly those harbouring MYCL1 amplifications, might benefit from the combination of an aurora kinase inhibitor and an immunotherapeutic drug.
The tumour mutational burden (TMB) in SCLC was calculated at 9.9 mutations/ megabase. In comparison, the TMB for melanoma is 12.6 mutations/ megabase, while it is lower in other tumours. Assuming that the TMB correlates with the efficacy of PD-1/PD-L1 inhibitors, the distribution of the TMB in SCLC suggests a similar response to immunotherapy as seen in NSCLC.
Aurora A kinase inhibition plus paclitaxel
Aurora A kinase (AAK) is a key regulator of mitosis. It can be overexpressed or amplified in a range of solid tumours and haematological malignancies. Inhibition of AAK leads to disrupted mitosis and cell death, which makes AAK a potential target for anti-cancer therapies. AAK inhibitors appear to be effective in SCLC cell lines, and especially in those with amplification and/or high expression of Myc [3, 4], which is a main driving oncogene in many cancers. Myc amplification of overexpression occurs in 18 % to 31 % of SCLCs, and is more common in chemo-refractory disease .
Activity in c-Myc–expressing tumours
For PFS in the ITT population, which was defined as the primary endpoint, the analysis revealed a significant advantage of the alisertib combination (3.32 vs. 2.17 months; HR, 0.71; p = 0.038). Patients with resistant or refractory relapses also experienced significant PFS benefit (2.86 vs. 1.64 months; HR, 0.659; p = 0.037). For OS, DCR and ORR, the results hinted at favourable outcomes with the alisertib combination, although the differences did not reach significance.
Figure 1: Effect on PFS of addition of alisertib to paclitaxel, according to c-Myc protein expression
Preliminary results with atezolizumab
The humanised monoclonal anti–PDL1 antibody atezolizumab has demonstrated promising clinical activity and a tolerable safety profile in a number of NSCLC clinical trials. As SCLC shows a high frequency of somatic mutations, these tumours might be amenable to treatment with PD-1/PD-L1 inhibitors. Sequist et al. presented the results obtained for an ES-SCLC cohort that was part of a larger phase Ia clinical trial investigating atezolizumab in locally advanced or metastatic solid tumours . The first five patients were PD-L1–selected; after that, the enrolment continued regardless of PD-L1 expression status. Seventeen patients were evaluated in the safety and efficacy analyses.
Figure 2: Confirmed responses to atezolizumab in patients with ES-SCLC (according to irRC)
Other novel agents
Chu et al. presented encouraging data on the monoclonal antibody BMS-986012 that targets fucosyl-GM1, which is a chemically defined monosialoganglioside that shows limited expression in normal tissues, but is highly expressed on the surface of tumour cells in SCLC . BMS-986012 was developed as a first-in-class fully human immunoglobulin G1 monoclonal antibody. The anti-tumour activity of this agent is based on antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis.
In contrast, negative trial results were obtained with roniciclib, an oral, highly potent, small-molecule inhibitor of cyclin-dependent kinases . A phase II, randomised, double-blind, placebo-controlled study conducted in patients with ES-SCLC compared cisplatin/ etoposide with carboplatin/ etoposide as first-line therapy in combination with roniciclib or placebo. No improvements were observed for the addition of roniciclib with regard to PFS, OS, ORR and time to progression. Moreover, the combination was not well tolerated, as patients who received roniciclib showed higher incidence of clinically important AEs and fatal AEs than those in the control group. The study was terminated following primary completion.
1 Alvarado-Luna G, Morales-Espinosa D, Treatment for small cell lung cancer, where are we now? -a review. Trans Lung Cancer Res 2016; 5: 26-38
© 2016 Springer-Verlag GmbH, Impressum
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