Date: 2016-10-09
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
Company: Boehringer Ingelheim (Germany)
Product: Giotrif® (afatinib)
Action
mechanism: tyrosine kinase inhibitor. Afatinib is an irreversible ErbB Family Blocker which inhibits signal transduction of all kinase receptors from the ErbB Family, and is known to play a critical role in the growth and spread of the most pervasive cancers and cancers associated with high mortality (lung, breast, and head & neck cancers). Over-expression of the Epidermal Growth Factor Receptor (EGFR, also referred to as ErbB1) 1 is found in at least 90% of head and neck cancers and strongly correlates with poor prognosis and overall survival. Afatinib* is approved in over 70 countries for the first-line treatment of EGFR mutation-positive NSCLC. Approval of afatinib in this indication was based on the primary endpoint of PFS from the LUX-Lung 3 clinical trial where afatinib significantly delayed tumour growth when compared to standard chemotherapy. Afatinib is also approved in the EU, US and other markets for the treatment of patients with advanced squamous cell carcinoma (SqCC) of the lung whose disease has progressed on or after treatment with platinum-based chemotherapy. Approval of afatinib in this indication is based on results of the LUX-Lung 8 study, which showed a significantly improved overall survival and progression-free survival compared to erlotinib (Tarceva®) in patients with SqCC of the lung.
Disease: non-small cell lung cancer (NSCLC)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The LUX-Lung clinical trial program is investigating the use of afatinib in various settings of advanced NSCLC, including in patients harboring EGFR mutations and those with recurrent disease. These trials include:
•LUX-Lung 1, a Phase IIb/III trial investigating afatinib plus best supportive care (BSC) versus placebo plus BSC in NSCLC patients who were previously treated with first-line chemotherapy and the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib.
•LUX-Lung 2, a Phase II trial evaluating afatinib in NSCLC patients with EGFR mutations, either treatment-naive or after one line of treatment with chemotherapy.
•LUX-Lung 3, a Phase III trial investigating afatinib as a first-line treatment in patients with advanced NSCLC with EGFR mutations. The study randomly assigned 345 patients with EGFR mutation-positive NSCLC to receive afatinib (n=230) or pemetrexed/cisplatin (n=115). LUX-Lung 3 is the largest Phase III trial to date in first-line EGFR mutation-positive, advanced, metastatic NSCLC patients, and the first to use pemetrexed/cisplatin as a comparator in this population. The primary endpoint was PFS. Secondary endpoints of LUX-Lung 3 included objective response, duration of responses, patient-reported outcomes (including quality of life), safety and overall survival.
•LUX-Lung 4, a Phase I/II trial investigating afatinib in NSCLC patients who have progressed after conventional EGFR-TKI treatment.
•LUX-Lung 5, a Phase III trial investigating afatinib in patients with advanced or metastatic NSCLC previously treated with erlotinib or gefitinib.
•LUX-Lung 6, a Phase III trial investigating the efficacy and safety of afatinib compared to standard chemotherapy for first-line treatment of NSCLC patients with EGFR mutations.
•LUX-Lung 7, a Phase IIb trial evaluating afatinib head-to-head versus gefitinib as a first-line treatment in patients with advanced NSCLC with EGFR mutations.
•LUX-Lung 8, a Phase III trial evaluating afatinib head-to-head versus erlotinib in second-line treatment of squamous cell carcinoma of the lung.
Latest
news: * On October 2016, Boehringer Ingelheim announced results from the LUX-Lung 7 trial that directly compared the efficacy and safety of second-generation EGFR-directed therapy Giotrif® (afatinib*) and first-generation Iressa® (gefitinib), in the first-line treatment of patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). The trial investigated overall survival (OS) as a primary endpoint and a reduction in the risk of death (14 %) was observed for patients treated with afatinib versus gefitinib. The median survival of patients treated with afatinib was 27.9 months compared to 24.5 months for those receiving gefitinib, without reaching significance. The OS outcomes observed with afatinib were consistent across common EGFR mutation types. Updated results also confirmed the primary analysis that showed the global Phase IIb LUX-Lung 7 trial met two of its co-primary endpoints of progression-free survival (PFS) by independent review and time to treatment failure. Results from the primary analysis, presented in 2015, showed that afatinib significantly reduced the risk of lung cancer progression and the risk of treatment failure both by 27% versus gefitinib. The improvement in PFS became more pronounced over time. After two years of treatment, more than twice as many patients on afatinib were alive and progression-free than those on gefitinib (after 18 months; 27% vs 15% and after 24 months; 18% vs 8%). Additionally, significantly more patients experienced an objective response (ORR; a clinically meaningful decrease in tumour size) with afatinib when compared to gefitinib. Both afatinib and gefitinib demonstrated similar improvements in patient-reported outcome measures in the LUX-Lung 7 trial with no significant differences in health-related quality of life with afatinib compared to gefitinib treatment. Treatment with both afatinib and gefitinib was generally tolerable, leading to an equal rate of treatment-related discontinuation in both arms (6%). Adverse events (AEs) observed in the trial were consistent with the known safety profiles of both treatments.2 Dose modification of afatinib was available for patients who met a set criteria to better manage treatment-related AEs that showed no apparent impact on efficacy. As gefitinib is only available in one dose formulation, no dose reduction was administered. * On November 7, 2014, Boehringer Ingelheim announced data from a pre-specified subgroup-analysis of the pivotal Phase III LUX-Lung 3 trial which demonstrated that Asian non-small cell lung cancer (NSCLC) patients with the most common type of EGFR mutation, (exon 19 deletion; del19), lived significantly longer after receiving first-line treatment with afatinib compared to chemotherapy (33.3 vs 22.9 months, respectively). This equated to a significant 43% reduction in the risk of death. The data were presented at the 2014 IASLC Asia Pacific Lung Cancer Conference (APLCC), in Kuala Lumpur. Overall survival results from this pre-specified Asian subgroup-analysis are consistent with the overall del19 population in LUX-Lung 3,1 and with the previously reported Asian Phase III LUX-Lung 6 trial, in which patients with the del19 mutation lived a median of more than one year longer if they started treatment with afatinib rather than standard chemotherapy.2 No significant difference in overall survival was seen for Asian patients with the L858R mutation in the LUX-Lung 3 and LUX-Lung 6 subgroup-analyses, respectively.Previously reported data from the LUX-Lung 3 trial showed afatinib provided further benefits to NSCLC patients with common EGFR mutations (del19 and L858R), which account for 90% of all EGFR mutations.3 Patients with common EGFR mutations taking afatinib lived for over a year without their tumour growing (progression free survival; PFS of 13.6 months; primary endpoint) versus just over half a year (PFS of 6.9 months) for chemotherapy.3 In addition, more patients taking afatinib, experienced an improvement in lung cancer-related symptoms (cough, shortness of breath, chest pain) and a significantly better quality of life, when compared with chemotherapy. Furthermore, in a combined exploratory analysis of the LUX-Lung 3 and LUX-Lung 6 trials, afatinib prolonged overall survival (secondary endpoint) of patients with common EGFR mutations compared with standard chemotherapy by a median of 3 months (27.3 compared to 24.3 months, respectively).Adverse events for afatinib in the LUX-Lung 3 and 6 trials were as expected with EGFR inhibition, and were predictable, manageable and reversible.3,6 Diarrhoea and rash/acne were the most frequently reported side effects with afatinib therapy. * On September 27, 2014, phase III data from Boehringer Ingelheim’s LUX-Lung 8 trial have been presented at the European Society for Medical Oncology (ESMO) 2014 Congress (September 26-30). The study compares the efficacy of two different targeted agents in patients with advanced squamous cell carcinoma (SCC) of the lung. The study demonstrated superior progression-free survival (PFS: length of time before the tumour starts to progress) of afatinib compared to elotinib. Afatinib, an irreversible ErbB Family Blocker, showed significant improvement across several measures of efficacy, in particular for the primary endpoint of PFS compared to erlotinib in patients after failure of first-line chemotherapy. LUX-Lung 8 demonstrated that afatinib significantly reduced the risk of disease progression by 18% when compared to erlotinib, and delayed tumour growth (PFS by independent review: 2.4 vs. 1.9 months).1 In addition, afatinib showed an improvement in the secondary endpoint of disease control rate (DCR: the percentage of patients who achieved complete response, partial response or stable disease, 46% vs. 37%). The objective response rate (ORR: the percentage of patients who achieved a partial or complete response to therapy) was numerically higher with afatinib compared to erlotinib (5% vs. 3%). Favourable trends were noted in delaying the worsening of lung cancer symptoms and global health status/quality of life. The proportion of patients reporting improvement in cough and global health status/quality of life, respectively, was significantly higher with afatinib versus erlotinib.1 Results of overall survival (OS: length of time patients live for), the key secondary endpoint, are not yet mature, and will therefore be assessed at a later stage in the trial and reported at a future medical congress. The overall rate of severe (? grade 3) and serious adverse events was comparable between both therapies. Incidence of severe adverse events was 50.2% in patients treated with afatinib compared to 49.1% with erlotinib. A higher incidence of ? grade 3 diarrhoea and stomatitis were observed in patients treated with afatinib compared to erlotinib (? grade 3 diarrhoea: 9% vs. 2%; stomatitis: 3% vs. 0%), while there was a higher incidence of ? grade 3 rash/acne observed with erlotinib compared to afatinib (9% vs. 6%). (A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUX-Lung 8 (LL8), 27.09.2014, 16.00 – 17:45, Madrid) * On May 15, 2014, Boehringer Ingelheim announced new overall survival results from a post-hoc analysis combining the data of two Phase III trials (LUX-Lung 3 and LUX-Lung 6). The analysis showed patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or exon 21 [L858R] substitutions) lived longer if treated with first-line afatinib compared to chemotherapy.1 An oral presentation at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), on June 2nd (3:00 - 6:00 PM, E Hall D2; Abstract #8004, scheduled for 4:00 - 4:12 PM) will discuss these data in more depth, providing further insights into their impact on clinical practice and patient care. Data from 6 other abstracts involving afatinib and other compounds in Boehringer Ingelheim’s oncology portfolio, will also be presented or published at ASCO in Chicago, May 30-June 3. Overall survival results: In the combined analysis from two of the largest trials in this patient population, afatinib prolonged survival of lung cancer patients whose tumours harbour common EGFR mutations compared with standard chemotherapy by a median of 3 months (27.3 compared to 24.3 months), significantly reducing the risk of death by 19%. The most pronounced reduction in risk of death, by 41%, was noted for patients whose tumours have the most common type of EGFR mutation (deletion in exon 19 of the EGFR gene). See abstract #8004 for full details. The conclusions of this analysis further substantiate earlier published results on delay in tumour growth (progression-free survival), better control of lung cancer symptoms and adverse events associated with afatinib in comparison with standard chemotherapy.Treatment beyond disease progression: Another Phase III study in lung cancer patients (LUX-Lung 5) also presented at ASCO met its primary endpoint by showing the advantage of continuing treatment with afatinib, in combination with chemotherapy, after the tumour started to grow on afatinib alone (treatment beyond progression). This Phase III study compared afatinib with paclitaxel (a chemotherapy) versus investigator’s choice of chemotherapy alone in patients with late-stage lung cancer after failure of several treatments, including chemotherapy, erlotinib or gefitinib, and afatinib alone. Those patients who continued afatinib treatment with the addition of chemotherapy, after progressing on afatinib alone, had a further delay in tumour growth compared to the group who stopped afatinib treatment, and received chemotherapy only (tumour growth was delayed by 5.6 months and 2.8 months respectively). This corresponded to a 40% reduction in risk of disease progression. The most common adverse events in patients treated with afatinib and chemotherapy combination were diarrhea (often associated with EGFR inhibition), hair loss (alopecia) and weakness (asthenia – often associated with chemotherapy). See abstract #8019 for full details. * On August 1, 2013, Boehringer Ingelheim has announced that data from the LUX-Lung clinical trial programme, investigating afatinib in patients with advanced non-small cell lung cancer have been published in the Journal of Clinical Oncology. These data include results from the pivotal LUX-Lung 3 Phase III registration trial which show that afatinib delays tumour growth and improves disease-related symptoms and quality of life compared to standard chemotherapy, when used to treat patients with EGFR mutation positive NSCLC. Research has shown there are many different types of lung cancer requiring a unique treatment approach to improve patient outcomes. A distinct subtype of lung cancer is EGFR mutation positive NSCLC. The prevalence of tumours harbouring EGFR mutations is between 10-15% in Caucasian and 40% in Asian NSCLC patients. Clinical trial data has shown afatinib could offer benefits to patients with this type of lung cancer. Data published in the Journal of Clinical Oncology from the LUX-Lung clinical trial programme show the potential of afatinib to improve the lives of patients with lung cancer: • Data from the LUX-Lung 3 trial demonstrate superiority of afatinib over chemotherapy considered best-in-class (pemetrexed/cisplatin) in EGFR-mutation positive advanced NSCLC patients. Patients treated with afatinib lived for almost one year (progression-free survival (PFS) of 11.1 months) before their tumour started to grow again compared to just over half a year (PFS of 6.9 months) for those treated with chemotherapy.2 Importantly, patients taking afatinib with the most common EGFR mutations (del19 and L858R, accounting for 90% of all EGFR mutations) lived for well over a year without progression (PFS of 13.6 months) versus just over half a year (PFS of 6.9 months) for those in the comparator arm. Adverse events (AEs) in LUX-Lung 3 were as expected with EGFR inhibition, consistent with previous studies, and were predictable, manageable and reversible. The most common adverse events associated with afatinib were diarrhea and skin-related side effects, which rarely led to discontinuation of treatment. • Additional data from the LUX-Lung 3 trial demonstrate patients taking afatinib also experienced an improvement in life-restricting lung cancer symptoms and a better quality of life (QoL) compared to those receiving standard chemotherapy treatment.3 Afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; P=0.007) and dyspnoea (HR, 0.68; P=0.015). Afatinib also showed significantly better mean scores over time in global health status/QoL (P=0 .015) and physical (P<0.001), role (P=0.004), and cognitive (P=0.007) functioning compared with chemotherapy, as measured by standard questionnaires. • Data from the LUX-Lung 4 trial, a Japanese single-arm Phase II trial in NSCLC patients who have progressed after EGFR-tyrosine kinase inhibitor treatment, demonstrated afatinib*treated patients experienced a median overall survival (OS) of just over a year and a half (19.0 months) and median PFS of 4.4 months.5 This highlights the efficacy of afatinib in this difficult-to-treat patient population. Adverse events were as expected with EGFR inhibition. The LUX-Lung clinical trial programme continues to investigate afatinib in advanced NSCLC in different settings and patient populations, in order to fully evaluate the potential of this treatment option. Based on this comprehensive programme, afatinib has been submitted to regulatory bodies worldwide for the treatment of patients with locally advanced or metastatic NSCLC with EGFR mutations. Afatinib is approved in the U.S. under the U.S. brand name Gilotrif™, and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion for afatinib. publication of data from the LUX-Lung clinical trial programme in the Journal of Clinical Oncology : Sequist L, Yang J, Yamamoto N, et al. Phase III Stuy of Aaftinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With Epidermal Growth Factor Receptor Mutations. J Clin Oncol 2013;DOI: 10.1200/JCO.2012.44.2806. Yang J, Hirsh V, Schuler M, et al. Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With Epidermal Growth Factor Receptor Mutations. J Clin Oncol 2013;DOI: 10.1200/JCO.2012.46.1764. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non Small-Cell Lung Cancer Who Progressed on Prior Treatment With Erlotinib, Gefitinib, or Both. J Clin Oncol 2013;DOI: 10.1200/JCO.2012.45.098 * On June 1, 2013, data from LUX-Lung 6 trial have been presented at the American Society of Clinical Oncology (ASCO) Annual Conference. These date demonstrate that patients treated with afatinib lived for almost one year before their tumour started to grow again, compared to less than half a year for those on standard chemotherapy (gemcitabine/cisplatin). Tumour assessment was based on independent review of the data showing progression-free survival (PFS) of 11.0 months for afatinib and PFS of 5.6 months for chemotherapy.In addition, 47% of afatinib-treated patients were alive and progression-free after one year of treatment compared to only 2% on chemotherapy. LUX-Lung 6 is the second Phase III trial after LUX-Lung 3 to show superiority of afatinib* over standard chemotherapies2 in patients with EGFR (ErbB1) mutation-positive non-small cell lung cancer (NSCLC). The consistent results in two large prospective trials in this patient population substantiate the robust efficacy of afatinib. The delay in tumour growth compares well in both registration studies, underlining the robustness of the data. • LUX-Lung 3: PFS = 11.1 vs. 6.9 months - afatinib* vs. pemetrexed/cisplatin • LUX-Lung 6: PFS = 11.0 vs. 5.6 months – afatinib* vs. gemcitabine/cisplatin. (These are data from primary analyses based on independent review.) Consistent with LUX-Lung 3, afatinib* treatment led to significant and sustained tumour shrinkage compared to chemotherapy (gemcitabine/ cisplatin) in LUX-Lung 6. Specifically, in approximately two thirds of patients (66.9%) taking afatinib*, the tumour shrank (objective response) significantly in size compared to 23% in the chemotherapy arm (gemcitabine/cisplatin), by independent review. Tumour shrinkage with afatinib* translated into improvements in life-restricting, disease-related symptoms such as cough, pain and shortness of breath (dyspnoea) as measured by standard lung cancer questionnaires. In addition, afatinib-treated patients also reported to have a significantly better quality of life (e.g. at work and during household activities) than those on gemcitabine/cisplatin (as measured by standard lung cancer questionnaires).4 These quality of life results are also consistent with data from the LUX-Lung programme, including the LUX-Lung 3 clinical trial results presented at last year’s ASCO. The most common Grade 3 adverse events (AEs) associated with afatinib* in LUX-Lung 6 were rash (14.2%), diarrhoea (5.4%) and stomatitis/mucositis (inflammation of the mouth and throat) (5.4%). These side effects are as expected with EGFR inhibition, consistent with previous studies, and were predictable, manageable and reversible. The most common AEs associated with chemotherapy were neutropenia (an abnormally low level of neutrophils, a type of white blood cell) (17.7%), vomiting (15.9%) and leukopenia (a decrease in the number of white blood cells) (13.3%). The discontinuation rate due to AEs related to treatment was 5.9% of patients on the afatinib* arm and 39.8% of patients on the chemotherapy arm. Importantly, only 2% of patients on afatinib* decided to discontinue due to rash and none for diarrhoea. * On June 4, 2012, Boehringer Ingelheim Pharmaceuticals has announced that its pivotal Phase III clinical trial, LUX-Lung 3, investigating afatinib as a first-line treatment in patients with stage IIIb or IV non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, met its primary endpoint of progression-free survival (PFS). The study evaluated 345 patients with NSCLC across a variety of EGFR mutations. Results showed that within the general study population, patients assigned to the afatinib arm lived for 11.1 months before their tumor started to grow again (PFS) versus 6.9 months for those patients in the chemotherapy arm (pemetrexed/cisplatin). The hazard ratio was 0.58 (95% CI: 0.43-0.78) (p=0.0004). Approximately 90 percent of patients in the study had the most common EGFR mutations (Del19 and L858R). In this subset, patients in the afatinib arm lived for a median of 13.6 months before their tumor started to grow again, versus a median of 6.9 months for those patients in the chemotherapy arm. The hazard ratio in this patient subset was 0.47 (95% CI: 0.34-0.65) (p<0.0001). Data were presented in a late-breaking oral presentation at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The most common drug-related adverse events observed in the afatinib treatment arm were diarrhea (95%), rash (62%) and paronychia (57%). The most common drug-related adverse events observed in the chemotherapy arm (pemetrexed /cisplatin) were nausea (66%), decreased appetite (53%) and vomiting (42%). There was a low discontinuation rate associated with treatment-related adverse events in the trial (8% discontinuation rate for afatinib; 12% for chemotherapy). One percent of patients in the afatinib arm discontinued due to diarrhea.
Details of the analysis have been presented at the European Society for Medical Oncology (ESMO) 2016 Congress in Copenhagen, Denmark, 7 – 11 October (abstract #LBA43).
