Federico Cappuzzo

Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure

Since their discovery aurora kinases have been identified as a potential target in anticancer therapy and currently many aurora‐selective small molecule kinase inhibitors are in development. Aurora kinases play an essential role as key mitotic regulators and are frequently overexpressed in prostate cancer. In vivo data in the transgenic mouse prostate carcinoma model revealed tumour regressions of >80% in three out of 16 animals and disease stabilizations in 10 out of 16 animals treated with danusertib. Two phase I dose escalation studies with danusertib in patients with advanced solid tumours were performed, which established two doses and schedules for phase II studies. However, the preliminary data of the available phase II studies with danusertib in solid tumours showed limited activity. Danusertib may yield more activity in the treatment of leukaemias than in solid tumours. Danusertib is generally well tolerated with neutropenia as the main dose limiting toxicity. This phase II study determined the efficacy and toxicity of danusertib administered intravenously over two different dosing schedules in patients with metastatic castration‐resistant prostate cancer (CRPC) with progressive disease after docetaxel‐based treatment. Danusertib showed in vivo antitumour activity in prostate cancer models and clinically relevant disease stabilizations were observed in several patients with solid tumours in phase I studies. However, our study revealed that monotherapy with danusertib, although well tolerated, showed only limited activity in the treatment of patients with CRPC. In view of the new advances in the treatment of patients with CRPC and the negative result of our study it is unlikely that danusertib will be further explored for the treatment of patients with CRPC. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization to select subsets of patients with CRPC who may benefit from treatment with danusertib.

Predictive biomarkers of immunotherapy for non-small cell lung cancer: Results from an Experts Panel Meeting of the Italian Association of Thoracic Oncology

Unleashing the potential of immune system to fight cancer has become one of the main promising treatment modalities for advanced non-small cell lung cancer (NSCLC). The knowledge of numerous factors that come into play in the cancer-immunity cycle provide a wide range of potential therapeutic targets, including monoclonal antibodies that inhibits the programmed death-1 (PD-1) checkpoint pathway. Over the last two years, nivolumab, pembrolizumab and atezolizumab received approval for treatment of pretreated advanced NSCLC, and more recently, immunotherapy with pembrolizumab is the new standard of care as first-line in patients with high levels of programmed death-ligand 1 (PD-L1) expression. Selection of patients is mandatory and PD-L1 is the only biomarker currently available in clinical practice. However, PD-L1 staining is an imperfect marker, whose negativity does not exclude a response to immunotherapy, as well as the roughly half of patients are not-responders despite high tumor PD-L1 levels. The right cut-off, the differences among various immune checkpoint inhibitors and among various antibody clones, and a not trivial activity reported even in PD-L1 negative tumors are questions still open. New biomarkers beyond to PD-L1 assays as well as new strategies, including combination of immune checkpoint inhibitors are under investigation.

Gemcitabine in non-small cell lung cancer

Gemcitabine is considered to be one of the most active drugs in the treatment of non-small cell lung cancer (NSCLC). When used as a single agent, gemcitabine yielded response rates consistently > 20%, with a uniformly good tolerance profile. Preclinical data indicated synergism between gemcitabine and platinum compounds, such as cisplatin or carboplatin. The gemcitabine–cisplatin combination is considered one of the reference regimens for advanced NSCLC and the recommended schedule is gemcitabine 1000 – 1250 mg/m2 on days 1 – 8 and cisplatin 70 – 80 mg/m2 on days 1 or 2. In order to avoid many of the non-haematological toxicities associated with cisplatin, several trials evaluated the gemcitabine–carboplatin combination. Previous trials using the 28-day schedule showed unacceptable haematological toxicity. Recent studies demonstrated the activity and feasibility of gemcitabine–carboplatin combination using a 21-day schedule, with carboplatin administered on day 1 and gemcitabine on days 1 and 8. Gemcitabine can be combined with one of the other new agents, such as the taxanes or vinorelbine, to create novel non-platinum-doublets. Although encouraging, the available data are still conflicting and non-platinum-based combinations are not indicated outside clinical trials. Three-drug combinations increased toxicity and failed to demonstrate any advantage over standard doublets in advanced NSCLC. Gemcitabine is active and well tolerated in elderly patients and represents a reasonable therapeutic option. Although no Phase III trials have been conducted to compare gemcitabine to the best supportive care or docetaxel in pretreated NSCLC, gemcitabine alone or in combination with vinorelbine or one of the taxanes can be considered a valid option for second-line treatment in patients who had a previous response or who achieved stable disease witha platinum-containing regimen.Gemcitabine is considered the most radiopotentiating agent available amongst the newer agents we have in terms of activity and toxicity, but the routine use of gemcitabine in combination with radical thoracic radiotherapy, although promising, is not yet recommended. Further testing of gemcitabine-based combinations with concurrent radiation is underway.

Global named patient use program of afatinib in advanced non-small-cell lung carcinoma patients who progressed following prior therapies

AIMnA global afatinib named patient use program in non-small-cell lung carcinoma (NSCLC) commenced in 2010.nnnMATERIALS & METHODSnEligible NSCLC patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had activating EGFR/HER2 mutations, exhausted all other treatments, and were ineligible for afatinib trials.nnnRESULTSnData, as of January 2016, were reported on 3966 heavily pretreated NSCLC patients (41 countries; six continents). Among 2595/3966 (65.4%) patients with tumor EGFR status, 2407 (92.8%) were EGFR mutation positive. Median time to treatment failure (2862/3966 [72.2%] patients with available data) was 4.4xa0months. Amongxa01141/2862 (39.9%) patients with response reported, objective response rate was 23.4% (267/1141). Safety findings were as expected.nnnCONCLUSIONnTime to treatment failure durations and objective response rates were encouraging.

Use of nivolumab in elderly patients with advanced squamous non–small-cell lung cancer: results from the Italian cohort of an expanded access programme

AIMnThis analysis evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in elderly patients with stage IIIB or IV squamous non-small-cell lung cancer (NSCLC) enrolled in the expanded access programme (EAP) in Italy.nnnMETHODSnNivolumab was available on physician request. Safety data included adverse events (AEs). Efficacy data included investigator-assessed tumour response, progression datexa0and survival information. Results were analysed for patients aged <65, 65-<75xa0and ≥75 yearsxa0andxa0for the overall population.nnnRESULTSnA total of 371 patients with squamous NSCLC were enrolled at 96 centres between April 2015 and September 2015; 34% (nxa0=xa0126), 47% (nxa0=xa0175)xa0and 19% (nxa0=xa070) were aged <65, 65-<75xa0and ≥75 years, respectively. Efficacy was similar among patients aged <65, 65-<75xa0and ≥75 yearsxa0and the overall population (objective response rates: 18%, 18%, 19%xa0and 18%, respectively; disease control rates: 49%, 47%, 43%xa0and 47%, respectively). Median overall survival was reduced in patients aged ≥75 years (5.8 months) versus patients aged <65; years (8.6 months), patients aged 65-<75 years (8.0 months)xa0and the overall population (7.9 months). The incidence of grade 3-4 treatment-related AEs was low in patients aged 65, 65-<75xa0and ≥75 yearsxa0and the overall population (3%, 9%, 3%, 6%, respectively). Discontinuation rates due to treatment-related AEs were low irrespective of age (4-5%).nnnCONCLUSIONSnThese EAP results suggest that elderly patients with advanced squamous NSCLC benefit from nivolumab, with tolerability similar to that in the overall population.

Circulating programmed death ligand-1 (cPD-L1) in non-small-cell lung cancer (NSCLC)

Background This study aimed at investigating feasibility of programmed death ligand-1 (PD-L1) testing in plasma samples of advanced NSCLC patients receiving first-line treatment, assessing whether circulating (c)PD-L1 levels were modified by the therapy and whether baseline cPD-L1 levels were associated with patients’ clinical responses and survival outcome. Methods Peripheral blood samples were collected from 16 healthy volunteers and 56 newly diagnosed NSCLC patients before and at 12th week during the course of first-line therapy. The level of PD-L1 was measured in plasma samples using the human (PD-L1/CD274) ELISA kit (CUSABIO, MD, USA). The Mann Whitney test or Fisher’s test were used for comparisons. Survival analysis was performed using Kaplan Meyer method, providing median and p-value. Results Baseline median cPD-L1 was 42.21 pg/ml (range 12.00-143.49) in NSCLC patients and 37.81 pg/ml (range 9.73-90.21) in healthy control cohort (p = 0.78). Median cPD-L1 increased in patients treated with first-line chemotherapy (63.20 pg/ml vs 39.34 pg/ml; p = 0.002), with no changes in patients exposed to non-chemotherapy drugs (42.39 pg/ml vs 50.67 pg/ml; p = 0.398). Time to progression and overall survival were 4.4 vs 6.9 months (p = 0.062) and 8.8 vs 9.3 months (p = 0.216) in cPD-L1 positive vs cPD-L1 negative patients. Baseline cPD-L1 levels increased with the ascending number of metastatic sites, even if the association was not statistically significant (p = 0.063). Conclusions This study showed that cPD-L1 testing is feasible, with chemotherapy influencing PD-L1 plasma levels. The possibility of using such test for predicting or monitoring the effect of immunotherapy or combination of chemotherapy and immunotherapy warrant further investigations.

A consensus on the role of osimertinib in non-small cell lung cancer from the AME Lung Cancer Collaborative Group

The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have brought substantial clinical benefit to patients with advanced non-small cell lung cancer (NSCLC) and sensitizing EGFR mutation. However, acquired resistance is inevitable since the vast majority of patients experience disease relapse within ~1-2 years. Osimertinib is a novel irreversible, covalent third-generation EGFR-TKI and potent inhibitor of EGFR T790M mutation, the most common mechanism of acquired resistance to first-generation EGFR-TKIs. Several trials have consistently demonstrated the superior clinical activity and safety of osimertinib in patients with advanced NSCLC and acquired EGFR T790M mutation after treatment with a first-generation EGFR-TKI. Recently, the efficacy of osimertinib in a first-line setting was demonstrated to be clearly superior to standard-first line treatment in patients with EGFR-mutant NSCLC regardless of T790M mutation status. Nevertheless, this advance, several unresolved issues of osimertinib should be emphasized including the molecular mechanisms of acquired resistance to osimertinib, the feasibility of testing EGFR T790M mutation from plasma circulating tumor DNA, its efficacy to patients with central nervous system (CNS) metastases or exon 20 mutations, its combination with other therapeutic strategies such as immune checkpoint inhibitors and its role in adjuvant therapy.

HER2 deregulation in lung cancer: right time to adopt an orphan?

HER2-deregulated non–small cell lung cancer is an orphan of any specific therapy, probably because of lack of both accurate patient selection and effective drugs. Recent evidence suggests that osimertinib could be effective in HER2-amplified or mutated lung cancer as a single agent or in combination. Clin Cancer Res; 24(11); 2470–2. ©2018 AACR. See related article by Liu et al., p. 2594