Non-small-cell lung cancer (nsclc) has the highest prevalence of all types of lung cancer, which is the second most common cancer and the leading cause of cancer-related mortality in Canada. The need ...for more effective and less toxic treatment options for nsclc has led to the development of agents targeting the epidermal growth factor receptor (egfr)-mediated signalling pathway, such as egfr tyrosine kinase inhibitors (egfr-tkis). Although egfr-tkis are less toxic than traditional anti-neoplastic agents, they are commonly associated with acneiform-like rash and diarrhea. This review summarizes the clinical presentation and causes of egfr-tki-induced rash and diarrhea, and presents strategies for effective assessment, monitoring, and treatment of these adverse effects. Strategies to improve the management of egfr-tki-related adverse events should improve clinical outcomes, compliance, and quality of life in patients with advanced nsclc.
Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report ...the final overall survival (OS) analysis from the phase III AVAiL trial.
Patients (n=1043) received cisplatin 80 mg/m2 and gemcitabine 1250 mg/m2 for up to six cycles plus bevacizumab 7.5 mg/kg (n=345), bevacizumab 15 mg/kg (n=351) or placebo (n=347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point.
Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) 95% confidence interval (CI) 0.75 (0.64–0.87), P=0.0003 and 0.85 (0.73–1.00), P=0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab HR (95% CI) 0.93 (0.78–1.11), P=0.420 and 1.03 (0.86–1.23), P=0.761 for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients (∼62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported.
Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin–gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.
In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus ...gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.
LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.
Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
NCT01466660.
Afatinib 40mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events ...(AEs), the dose can be reduced by 10mg decrements to a minimum of 20mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials.
Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30mg versus those remaining at 40mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not.
Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months hazard ratio (HR) 1.25; LL6: 12.3 versus 11.0 months (HR 1.00)}.
Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy.
Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.
•Checkpoint inhibitors re-engage the immune system to fight cancer.•Survival benefits are confirmed for first- and later line advanced NSCLC.•Immune-related adverse events with checkpoint inhibitors ...are tolerable.•PD-L1 biomarker status can inform treatment decisions.•Agent-specific PD-L1 tests should be used until methods are standardized.
Lung cancer is the most common cause of cancer-related death among males and the second leading cause among females globally. Checkpoint inhibitors re-engage the immune system to fight cancer. This review evaluates phase III data on the use of checkpoint inhibitors in the treatment of advanced NSCLC and addresses PD-L1 expression in predicting efficacy.
Six phase III clinical trials investigating checkpoint inhibitors for NSCLC were identified through a search of PubMed (to November 15, 2016) and conference databases, with findings updated from a directed search of eligible studies conducted in January 2018.
Significant reductions in the risk of death ranging from 27% to 41% and were observed second-line and beyond. A relationship between PD-L1 expression and survival was apparent in most trials with optimal benefit for the highest expression levels (≥50%). Benefit was also observed at low or no PD-L1 expression levels and in third-line in some studies. Significantly improved PFS was observed for pembrolizumab at high PD-L1 expression levels (≥50%) first-line. Immune-related adverse events associated with checkpoint inhibitors are tolerable and rates of pneumonitis may be lower among PD-L1 inhibitors. Use of checkpoint inhibitors for tumors with driver mutations should only be considered after all appropriate targeted therapy and chemotherapy have been exhausted. PD-L1 testing presents a valuable tool to guide treatment sequencing and we recommend use of agent-specific PD-L1 tests and respective scoring systems until a standardized, convenient and broadly applicable test is identified.
Checkpoint inhibitors represent a major advance in the treatment of advanced NSCLC and PD-L1 status can inform treatment decisions.
For more than a decade, there has been no improvement in outcomes for patients with unresectable locally advanced (la) non-small-cell lung cancer (nsclc). The standard treatment in that setting is ...definitive concurrent chemotherapy and radiation (ccrt). Although the intent of treatment is curative, most patients rapidly progress, and their prognosis is poor, with a 5-year overall survival (os) rate in the 15%-25% range. Those patients therefore represent a critical unmet need, warranting expedited approval of, and access to, new treatments that can improve outcomes. The pacific trial, which evaluated durvalumab consolidation therapy after ccrt in unresectable la nsclc, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (pfs) and a significant improvement in os. Durvalumab thus fills a critical unmet need in the setting of unresectable la nsclc and provides a new option for patients treated with curative intent. Here, we review the treatment of unresectable la nsclc, with a focus on the effect of the clinical data for durvalumab.
Treatment for non-small-cell lung cancer (nsclc) is moving away from traditional chemotherapy toward personalized medicine. The reversible tyrosine kinase inhibitors (tkis) erlotinib and gefitinib ...were developed to target the epidermal growth factor receptor (egfr). Afatinib, an irreversible ErbB family blocker, was developed to block egfr (ErbB1), human epidermal growth factor receptor 2 (ErbB2), and ErbB4 signalling, and transphosphorylation of ErbB3. All of the foregoing agents are efficacious in treating nsclc, and their adverse event profile is different from that of chemotherapy. Two of the most common adverse events with egfr tkis are rash and diarrhea. Here, we focus on diarrhea. The key to successful management of diarrhea is to treat early and aggressively using patient education, diet, and antidiarrheal medications such as loperamide. We also present strategies for the effective assessment and management of egfr tki-induced diarrhea.
This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely ...to benefit from the combination.
Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m2 on day 1) was administered alone or with ganetespib (150 mg/m2 on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS).
Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191).
Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.
Background: Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown ...to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabine–cisplatin) in patients with HER2-positive NSCLC. Patients and methods: Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine 1250 mg/m2 (days 1 and 8) and cisplatin 75 mg/m2 (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression. Results: Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabine–cisplatin and 50 with gemcitabine–cisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabine–cisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabine–cisplatin were comparable to those of trastuzumab alone. Conclusions: Trastuzumab plus gemcitabine–cisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabine–cisplatin on trastuzumab pharmacokinetics was observed.
This analysis evaluates safety and efficacy in elderly (≥70 years old) versus younger patients enrolled in a phase III advanced non-small-cell lung cancer (NSCLC) trial.
Untreated stage IIIB/IV ...patients with PS 0/1 were randomly assigned (1:1) to carboplatin AUC6, day 1 every 3 weeks, and either nab-paclitaxel (Abraxane) 100 mg/m2 weekly (nab-P/C) or solvent-based paclitaxel (Taxol) 200 mg/m2 day 1 every 3 weeks (sb-P/C). The primary end-point was overall response rate (ORR).
Fifteen percent of 1052 enrolled patients were elderly: nab-P/C, n = 74; sb-P/C, n = 82. In both age cohorts, the ORR was higher with nab-P/C versus sb-P/C (age ≥70: 34% versus 24%, P = 0.196; age <70: 32% versus 25%, P = 0.013). In elderly patients, progression-free survival (PFS) trended in favor of nab-P/C (median 8.0 versus 6.8 months, hazard ratio (HR) 0.687, P = 0.134), and overall survival (OS) was significantly improved (median 19.9 versus 10.4 months, HR 0.583, P = 0.009). In younger patients, PFS (median 6.0 versus 5.8 months, HR 0.903, P = 0.256) and OS (median 11.4 versus 11.3 months, HR 0.999, P = 0.988) were similar in both arms. Adverse events were similar in both age groups, with less neutropenia (P = 0.015), neuropathy (P = 0.001), and arthralgia (P = 0.029), and increased anemia (P = 0.007) with nab-P/C versus sb-P/C.
In elderly NSCLC patients, nab-P/C as first-line therapy was well tolerated and improved the ORR and PFS, with substantially longer OS versus sb-PC.
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