Summary Background Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer ...(NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. Methods We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m2 on day 1 plus docetaxel (75 mg/m2 on day 1) or gemcitabine (1250 mg/m2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m2 or AUC 5 with gemcitabine 1000 mg/m2 ) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov , number NCT00446225. Findings Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p<0·0001). Main grade 3 or 4 toxicities were rash (11 13% of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 22%), anaemia (one 1% vs three 4%), and increased amino-transferase concentrations (two 2% vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Interpretation Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Funding Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.
Summary Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive ...non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov , number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months 95% CI 10·6–12·9 with afatinib vs 10·9 months 9·1–11·5 with gefitinib; hazard ratio HR 0·73 95% CI 0·57–0·95, p=0·017) and time-to-treatment failure (median 13·7 months 95% CI 11·9–15·0 with afatinib vs 11·5 months 10·1–13·1 with gefitinib; HR 0·73 95% CI 0·58–0·92, p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 13% of 160 patients given afatinib vs two 1% of 159 given gefitinib) and rash or acne (15 9% patients given afatinib vs five 3% of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 9% of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR -mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding Boehringer Ingelheim.
Current Challenges in Cancer Treatment Zugazagoitia, Jon, MD, PhD; Guedes, Cristiano, MD; Ponce, Santiago, MD ...
Clinical therapeutics,
07/2016, Letnik:
38, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Abstract Purpose In this review, we highlight the current concepts and discuss some of the current challenges and future prospects in cancer therapy. We frequently use the example of lung cancer. ...Methods We conducted a nonsystematic PubMed search, selecting the most comprehensive and relevant research articles, clinical trials, translational papers, and review articles on precision oncology and immuno-oncology. Papers were prioritized and selected based on their originality and potential clinical applicability. Findings Two major revolutions have changed cancer treatment paradigms in the past few years: targeting actionable alterations in oncogene-driven cancers and immuno-oncology. Important challenges are still ongoing in both fields of cancer therapy. On the one hand, druggable genomic alterations are diverse and represent only small subsets of patients in certain tumor types, which limits testing their clinical impact in biomarker-driven clinical trials. Next-generation sequencing technologies are increasingly being implemented for molecular prescreening in clinical research, but issues regarding clinical interpretation of large genomic data make their wide clinical use difficult. Further, dealing with tumor heterogeneity and acquired resistance is probably the main limitation for the success of precision oncology. On the other hand, long-term survival benefits with immune checkpoint inhibitors (anti−programmed death cell protein-1/programmed death cell ligand-1PD-1/L1 and anti−cytotoxic T lymphocyte antigen-4 monoclonal antibodies) are restricted to a minority of patients, and no predictive markers are yet robustly validated that could help us recognize these subsets and optimize treatment delivery and selection. To achieve long-term survival benefits, drug combinations targeting several molecular alterations or cancer hallmarks might be needed. This will probably be one of the most challenging but promising precision cancer treatment strategies in the future. Implications Targeting single molecular abnormalities or cancer pathways has achieved good clinical responses that have modestly affected survival in some cancers. However, this approach to cancer treatment is still reductionist, and many challenges need to be met to improve treatment outcomes with our patients.
Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin ...versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov , number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months 95% CI 10·4–12·6) vs 9·9 months 8·9–11·1; stratified hazard ratio 0·84 95% CI 0·74–0·96; p=0·01). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 72% of 538 patients) than in the gemcitabine and cisplatin group (333 62% of 541), as was the incidence of serious adverse events (257 48% of 538 patients vs 203 38% of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 9% of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six 1% of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 4% vs one <1%). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Interpretation Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
Summary Background Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival ...compared with chemotherapy alone (hazard ratio HR 0·871, 95% CI 0·762–0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0–300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov , number NCT00148798. Findings Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months 95% CI 10·2–15·2 vs 9·6 months 7·6–10·6; HR 0·73, 0·58–0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months 8·9–12·2 vs 10·3 months 9·2–11·5; HR 0·99, 0·84–1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding Merck KGaA.
Summary Background Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and ...vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. Methods Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov , number NCT00148798. Findings KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months 95% CI 11·7–23·4 vs 8·5 months 7·1–10·8, hazard ratio HR 0·52 0·32–0·84, p=0·0063; chemotherapy alone: 23·8 months 15·2–not reached vs 10·0 months 8·7–11·0, HR 0·35 0·21–0·59, p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months 8·6–13·6 vs 6·8 months 5·9–12·7, HR 0·80 0·55–1·16, p=0·24; chemotherapy alone: 11·0 months 9·2–12·6 vs 9·3 months 7·6–11·9, HR 0·77 0·54–1·10, p=0·16). Interpretation The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. Funding Merck KGaA.
Summary Background The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival ...compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit. Methods We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov , number NCT00148798. Findings 518 patients in the chemotherapy plus cetuximab group—290 of whom had first-cycle rash—and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months 95% CI 12·8–16·4 vs 8·8 months 7·6–11·1; hazard ratio HR 0·631 0·515–0·774; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months 5·2–5·7 vs 4·3 months 4·1–5·3; HR 0·741 0·607–0·905; p=0·0031) and response (rate 44·8% 39·0–50·8 vs 32·0% 26·0–38·5; odds ratio 1·703 1·186–2·448; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months 7·6–11·1 vs 10·3 months 9·6–11·3; HR 1·085 0·910–1·293; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, 14·1–20·6 vs 9·3 months 7·7–13·2; HR 0·614 0·453–0·832; p=0·0015), squamous-cell carcinoma (median 13·2 months 10·6–16·0 vs 8·1 months 6·7–12·6; HR 0·659 0·472–0·921; p=0·014), and carcinomas of other histology (median 12·6 months 9·2–16·4 vs 6·9 months 5·2–11·0; HR 0·616 0·392–0·966; p=0·033). Interpretation First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit. Funding Merck KGaA.
ABSTRACT Introduction/Background: This randomized, double-blind, placebo-controlled phase 1b/2 study assessed the efficacy/safety of rilotumumab or ganitumab combined with etoposide and carboplatin ...or cisplatin as first-line treatment in patients with extensive-stage small-cell lung cancer (ES-SCLC). Patients and Methods In the phase 1b study, patients received rilotumumab 15 mg/kg or ganitumab 18 mg/kg plus etoposide and carboplatin or cisplatin. In the phase 2 study, patients were randomly assigned 1:1:1 to receive placebo, rilotumumab, or ganitumab plus etoposide and carboplatin or cisplatin. Chemotherapy was administered for ≤6 cycles; rilotumumab, ganitumab, or placebo was then continued as maintenance therapy. The primary endpoints were incidence of dose-limiting toxicities (DLTs; phase 1b) and overall survival (OS; phase 2). Secondary endpoints included progression-free survival (PFS) and safety. Results In the phase 1b study (n=28), one patient treated with ganitumab experienced a DLT (grade 4 neutropenia/thrombocytopenia lasting ≥7 days). In the phase 2 study, 185 patients were enrolled (placebo, n=61; rilotumumab, n=62; ganitumab, n=62). Median OS was 10.8, 12.2 (hazard ratio HR=0.84; 95%CI=0.56−1.25; P =0.384), and 10.7 (HR=0.95; 95%CI=0.63−1.41; P =0.787) months, respectively. Median PFS was 5.4, 5.4 (HR=1.05; 95%CI=0.71−1.54; P =0.797), and 5.5 (HR=1.05; 95%CI=0.72−1.55; P =0.780) months, respectively. Adverse events resulting in treatment discontinuation occurred in 11 (19%), 10 (16%), and 7 (12%) patients, respectively. Serum biomarker analysis showed improved survival for patients with baseline hepatocyte growth factor levels below the median in the rilotumumab arm. Conclusions Although the addition of rilotumumab or ganitumab to chemotherapy was tolerable, overall outcomes were not improved in patients with ES-SCLC.
We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) ...for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials.
This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome.
Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 95% confidence interval (CI): 0.38‒1.07 and 0.64 95% CI: 0.42‒0.97, respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 95% CI: 0.50‒1.08 and 0.86 95% CI: 0.57‒1.28, respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status.
These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.
Pembrolizumab plus chemotherapy significantly improved survival outcomes versus placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC in the randomized, ...double-blind, phase 3 KEYNOTE-407 study. We present the results of Chinese patients enrolled in the KEYNOTE-407 global and China extension studies.
Patients enrolled from mainland China in the KEYNOTE-407 global (NCT02775435) and China extension studies (NCT03875092) were randomized 1:1 to 35 cycles of pembrolizumab or placebo plus four cycles of carboplatin and paclitaxel or nab-paclitaxel. Dual primary end points were overall survival (OS) and progression-free survival (PFS) (based on the Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review).
A total of 125 patients were randomized (pembrolizumab–chemotherapy, n = 65; placebo–chemotherapy, n = 60). As of September 30, 2020, median (range) study follow-up was 28.1 (25.1‒40.9) months. Pembrolizumab–chemotherapy improved OS (hazard ratio HR = 0.44, 95% confidence interval CI: 0.28–0.70) and PFS (HR = 0.35, 95% CI: 0.24–0.52) versus placebo–chemotherapy. Two-year OS and PFS rates for pembrolizumab–chemotherapy versus placebo–chemotherapy were 56.9% versus 31.7% and 24.2% versus 3.3%, respectively. Treatment-related grade 3 to 5 adverse events occurred in 81.5% and 81.7%, respectively. Relative to baseline, pembrolizumab–chemotherapy improved global health status/quality of life scores at week 18 versus placebo–chemotherapy (difference in least squares means = 7.6, 95% CI: 1.5–13.7) and prolonged time to deterioration in cough, chest pain, or dyspnea (HR = 0.50, 95% CI: 0.28–0.89).
Pembrolizumab–chemotherapy prolonged survival versus placebo–chemotherapy with manageable toxicity and preserved or improved health-related quality of life in Chinese patients with metastatic squamous NSCLC. These findings support pembrolizumab–chemotherapy as first-line therapy in this population.
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