ErbB Family Blocker Research Articles

Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations.

The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

235 (PB115) - Phase II trial of afatinib in patients with EGFR-mutated solid tumors excluding lung cancer: results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol A

Background: Molecularly targeted treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have prolonged survival of pts with activating EGFR mutations in non-small cell lung cancer (NSCLC). Afatinib is an ErbB family blocker that demonstrated clinical benefit in pts with NSCLC with common and uncommon activating EGFR mutations. The activity of afatinib in other tumor types with EGFR mutations is less well known. National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) Arm EAY131-A evaluated afatinib in tumors beyond lung cancer that harbored EGFR activating alterations.

Afatinib alone and in combination with vinorelbine or paclitaxel, in patients with HER2-positive breast cancer who failed or progressed on prior trastuzumab and/or lapatinib (LUX-Breast 2): an open-label, multicenter, phase II trial

PurposeResistance to HER2 (ErbB2)-targeted therapy may be mediated by other members of the ErbB family. We investigated the efficacy and safety of the irreversible ErbB family blocker, afatinib, alone as first-line therapy in the advanced setting and in combination with vinorelbine or paclitaxel for those who progressed on afatinib monotherapy, in female patients with metastatic breast cancer who had failed or progressed on prior HER2-targeted therapy in the early disease setting.MethodsIn this phase II, single-arm, two-part study (ClinicalTrials.gov: NCT01271725), patients in part A received afatinib 40 mg/day in 21-day cycles until disease progression or intolerable adverse events (AEs). Patients with progressive disease could then receive afatinib plus weekly vinorelbine 25 mg/m2 or paclitaxel 80 mg/m2 until disease progression or intolerable AEs (part B). The primary endpoint was confirmed objective response rate (RECIST v1.1).ResultsEighty-seven patients were enrolled and 74 were treated in part A (median age: 51 years [range 27–76]; 31 [42%] estrogen receptor-positive, 26 [35%] progesterone receptor-positive). Of these, 39 (53%) patients went on to receive afatinib plus vinorelbine (13 patients) or paclitaxel (26 patients) in part B. Thirteen (18%) and 12 (31%) patients achieved an objective response in parts A and B, respectively. The most common treatment-related AEs with afatinib monotherapy (any/grade ≥ 3) were diarrhea (68%/8%) and rash (49%/4%). Combination therapy was generally well tolerated, with no additive toxicity observed.ConclusionAfatinib treatment, alone or in combination with vinorelbine or paclitaxel, was associated with objective responses in ≥ 18% of patients with metastatic breast cancer for whom prior HER2-targeted therapy has failed. Treatment-related AEs were generally manageable, with few grade ≥ 3 AEs reported.Trial registrationClinicalTrials.gov, NCT01271725, registered 1 July 2011.

CTNI-46. PHASE I OPEN-LABEL, SINGLE-CENTER, DOSE ESCALATION STUDY (NCT02423525) OF PULSATILE AFATINIB IN PATIENTS WITH BRAIN CANCER

Abstract Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in tumor growth inhibition and is approved for the treatment of EGFR-mutated metastatic non-small cell lung carcinoma and metastatic squamous cell lung carcinoma. Pulse dosing afatinib could potentially increase CNS exposure to reach therapeutic levels while allowing a recovery period to mitigate toxicities. We are reporting the results of a Phase I open-label, single-center, ‘3 + 3’ dose escalation study to determine the safety and tolerability of pulsatile Afatinib in patients with brain cancer and to define a recommended phase 2 dose. The study assessed the exposure of Afatinib in cerebrospinal fluid and serum, objective tumor response according to RANO criteria, progression-free survival, and overall survival, and will explore the association between molecular phenotypes and patient response. In total, 26 patients were screened and 24 were enrolled (median age 60, 78% male, 87.5% Caucasian, glioblastoma N=16, chordoma N=3, brain metastases N=2, meningioma N=1, anaplastic mixed oligoastrocytoma N=1). Patients had received a median of 2.5 prior treatments. The study proceeded through the 4 dosing cohorts without reaching dose-limiting toxicity: Cohort 1 (80mg every 4 days) N=3; Cohort 2 (120mg every 4 days) N=3; Cohort 3 (180mg every 4 days) N=7, including replacement patients; Cohort 4 (280mg every 7 days) N=11. Diarrhea (75%), rash (75%), nausea/vomiting (37.5%), fatigue (29.2%), anorexia (25%), and limb edema (16.7%) were the most common side effects. There were no CTCAE defined grade 4 toxicities. Grade 3 side effects infrequently occurred in the highest dosing cohort and once in each cohort 2 and 3. These results demonstrate that pulsatile Afatinib at a dose of 280mg every 7 days is safe and tolerable for patients with brain involving cancers.

Lipid polymeric nanoparticles modified with tight junction-modulating peptides promote afatinib delivery across a blood\u2013brain barrier model

BackgroundBrain metastases from non-small cell lung cancer (NSCLC) remain one of the most challenging malignancies. Afatinib (Afa) is an orally administered irreversible ErbB family blocker approved for epidermal growth factor receptor (EGFR)-mutated NSCLC. However, the incidence of brain metastases in patients with NSCLC and EGFR mutation is high. One of the major obstacles in the treatment of brain metastases is to transport drugs across the blood–brain barrier (BBB). A lipid polymeric nanoparticle (LPN) modified with a tight junction-modulating peptide is a potential formulation to deliver therapeutics across the BBB. FD7 and CCD are short peptides that perturb the tight junctions (TJs) of the BBB. In this study, the use of LPN modified with FD7 or CCD as a delivery platform was explored to enhance Afa delivery across the BBB model of mouse brain-derived endothelial bEnd.3 cells.ResultsOur findings revealed that Afa/LPN-FD7 and Afa/LPN-CCD exhibited a homogeneous shape, a uniform nano-scaled particle size, and a sustained-release profile. FD7, CCD, Afa/LPN-FD7, and Afa/LPN-CCD did not cause a significant cytotoxic effect on bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD across the bEnd.3 cells enhanced the cytotoxicity of Afa on human lung adenocarcinoma PC9 cells. FD7 and CCD-modulated TJ proteins, such as claudin 5 and ZO-1, reduced transendothelial electrical resistance, and increased the permeability of paracellular markers across the bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD were also partially transported through clathrin- and caveolae-mediated transcytosis, revealing the effective activation of paracellular and transcellular pathways to facilitate Afa delivery across the BBB and cytotoxicity of Afa on PC9 cells.ConclusionTJ-modulating peptide-modified LPN could be a prospective platform for the delivery of chemotherapeutics across the BBB to the brain for the potential treatment of the BM of NSCLC.

Second-line Afatinib or Chemotherapy Following Immunochemotherapy for the Treatment of Metastatic, Squamous Cell Carcinoma of the Lung: Real-world Effectiveness and Safety From a Multisite Retrospective Chart Review in the USA

BackgroundThe ErbB family blocker, afatinib, is approved for patients with squamous cell carcinoma (SqCC) of the lung following platinum-doublet chemotherapy but has not been explored following immunochemotherapy. Here, we assessed the characteristics and outcomes of patients with SqCC of the lung who received second-line afatinib or chemotherapy after first-line pembrolizumab plus chemotherapy in a “real-world” setting. MethodsIn this retrospective, multisite cohort study, community oncologists identified eligible patients and extracted data from electronic health records. Primary outcome measures were patient demographics and clinical characteristics, time on treatment, and incidence of severe immune-related adverse events (irAEs). ResultsTwo hundred patients were included: 99 received second-line afatinib and 101 received second-line chemotherapy. Median age was 68 and 66 years, respectively; 35% and 3% of patients had mixed histology tumors, and 39% and 5% of tumors were epidermal growth factor receptor (EGFR) mutation-positive (EGFRm+). Median time on treatment was 7.3 months with afatinib (mixed histology/SqCC tumors: 8.1/5.8 months; EGFRm+/EGFRm– tumors: 7.4/5.9 months) and 4.2 months with chemotherapy. Grade 3/4 irAEs were observed in 6 patients in the afatinib cohort (all had a prior grade 3/4 irAE during first-line therapy) and no patients in the chemotherapy cohort. The most common adverse drug reactions with afatinib were diarrhea (26%), rash (6%), stomatitis, fatigue, and nausea (5% each). ConclusionEncouraging time on treatment, and absence of newly diagnosed irAEs, indicate that afatinib is a treatment option following immunochemotherapy in patients with SqCC of the lung, and is currently the only approved oral agent in this setting.

Treatment outcomes and safety of afatinib in advanced squamous cell lung cancer progressed after platinum-based doublet chemotherapy and immunotherapy (SPACE study).

Afatinib is an ErbB family blocker approved for the treatment of epidermal growth factor receptor mutation‐positive nonsmall‐cell lung cancer. A pivotal trial demonstrated significant clinical benefits with manageable toxicity of afatinib as a second‐line treatment option in squamous cell carcinoma of the lung (SCC) which led to approval in >60 countries. However, these results were derived from a controlled study conducted in selected patients and are not necessarily representative of the real‐world use of this drug. In addition, data on afatinib use after immunotherapy in this clinical setting are lacking. The aim of this study is to evaluate the treatment outcomes and safety of afatinib as a second‐ or later‐line treatment for SCC and to identify potential predictive biomarkers. As a real‐world observational study, 130 eligible patients with advanced SCC, who progressed after platinum‐based chemo‐ and immunotherapy, will be enrolled. Treatment outcomes and safety data will be collected for both the retrospective and prospective cohorts, and molecular profiling using tissue and plasma will be performed for the prospective cohort. The primary endpoint is time to treatment failure, and the secondary endpoints are objective response rate, progression‐free survival, overall survival, and safety. Comparison of clinical outcomes with respect to the different programmed death‐ligand 1 expression and molecular characteristics will also be carried out. This study will provide additional evidence on the usefulness of afatinib as a subsequent treatment, as well as feasible molecular biomarkers to predict its efficacy in this clinical setting.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the ‘burden of therapy’ method

BackgroundTargeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non–small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. Patients and methodsPatients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the ‘Burden of Therapy/Toxicity’ (BOTh) for each patient on every day during the clinical study. ResultsOne hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). ConclusionThe addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period.The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib.

Options for the treatment of squamous cell lung carcinoma expanded in recent years with the introduction of the immune checkpoint inhibitors into routine clinical practice in both the first- and second-line settings but are still limited. As a result, pembrolizumab, given either alone or in combination with platinum-based chemotherapy, is now a standard first-line treatment for squamous cell lung cancer. However, few options exist once patients have progressed on immune checkpoint inhibitors and chemotherapy. In this setting, the irreversible ErbB family blocker, afatinib, has a potential role as second or subsequent therapy for some patients. The Phase III LUX-Lung 8 study demonstrated that afatinib significantly prolonged progression-free and overall survival compared with erlotinib in patients with squamous cell lung carcinoma. Notably, retrospective, ad-hoc biomarker analyses of a subset of patients from LUX-Lung 8 suggested that patients with ErbB family mutations derived particular benefit from afatinib, especially those with ErbB2 (HER2) mutations. Afatinib has a manageable and predictable safety profile, and adverse events can be managed with the use of a tolerability-guided dose modification protocol. Until more data are available, afatinib could be considered as a potential second-line treatment option for patients who have progressed on combined pembrolizumab and platinum-based chemotherapy and are ineligible for more established second-line options, or as a third-line option in patients who have received first-line immunotherapy, and second-line chemotherapy or chemotherapy and antiangiogenesis therapy. However, further data are required to support the use of afatinib following immunotherapy. Given that treatment options are limited in both of these settings, investigating an agent with an entirely new mechanism of action is warranted. If available, molecular analysis to identify ErbB family mutations or the use of proteomic profiling could help to further isolate patients who are likely to derive the most benefit from afatinib.

Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of EGFRm+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring EGFR mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon EGFR mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with EGFRm+ NSCLC.

Efficacy of afatinib in the clinical practice: Final results of the GIDEON study in EGFR mutated non-small cell lung cancer (NSCLC) in Germany.

e21636 Background: Afatinib is an irreversible ErbB family blocker, which is approved for the treatment of advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. Here we report the final results of the prospective non-interventional study (NIS) GIDEON, which was initiated to investigate the efficacy and tolerability of afatinib in the daily clinical routine in Germany. Methods: EGFR-mutated NSCLC patients were treated with afatinib according to label until progression, death or discontinuation. Efficacy (progression-free survival (PFS) rate at 12 months, objective response rate, ORR; disease control rate, DCR; progression-free survival, PFS and overall survival, OS) was prospectively assessed by investigators. Data about tolerability were collected during routine treatment. Results: In total, 161 patients were enrolled at 41 sites in Germany, 152 patients received at least one dose of afatinib (treated set; TS) and 146 patients were treated according to the protocol (PPS). The majority of patients for the entire TS had exon 19 deletions (64.5%), followed by L858R point mut. (22.4%) and uncommon mut. (exon 18-21 point mut.; 13.1%). The primary objective was PFS-rate at 12 months, which was 50.2% in the PPS. Median PFS amounted to 12.2 months. ORR and DCR were 74.6% and 91.5% in the PPS, respectively. Median OS was 30.4 months with 1- and 2-year survival rates of 79.1% and 57.7%, respectively. Among pat. with uncommon EGFR-mut., the 12-months PFS rate was 40.2% with a mPFS of 10.7 months. ORR and DCR were 83.3% and 91.7%, respectively. The most frequent documented adverse drug reactions (ADRs) were diarrhea and rash/acne with 13.8% and 7.2% of grade 3 but no grade 4 or higher. Conclusions: Afatinib is a standard therapy for patients with activating EGFR mut. in Germany. The final results of this prospective NIS confirm the robust clinical data for afatinib in the clinical routine setting, including patients with uncommon exon 18-21 point mutations. Clinical trial information: NCT02047903.

Afatinib is active in osteosarcoma in osteosarcoma cell lines.

Osteosarcoma is the most common bone tumor, mainly affecting adolescents and young adults, and metastatic disease has poor outcomes with a dismal overall survival. Currently, chemotherapy is the standard of care with limited results, finding that new therapies could improve these outcomes. Preclinical and clinical studies have suggested a possible important role of ErbB pathway aberrations in osteosarcoma etiology. The present study shows the effect of afatinib, an irreversible ErbB family blocker in osteosarcoma cell lines. Within a panel of human osteosarcoma cell lines, we addressed cell viability assay using afatinib at increasing concentrations. Motility was measured in wound-healing assays and invasion capacity was assessed in Transwell chamber assays. Finally, to monitor ErbB pathway modulation by afatinib and related compounds, we used Western blot analyses. Cell viability inhibition, as well as a reduction of motility and migration of osteosarcoma cell line were observed after treatment with afatinib. Likewise, in the HOS cell line, afatinib decreased phosphorylation of key components in the ErbB signaling pathway. Afatinib shows relevant antitumor effect in several osteosarcoma cell lines, as it causes a significant impact on cell viability, motility, and migration with a significant decrease in the activation of ErbB pathway activity.

63O - NRG1-fusion-driven solid tumours: A case series indicating the therapeutic potential of afatinib

63O - NRG1-fusion-driven solid tumours: A case series indicating the therapeutic potential of afatinib

Afatinib as a novel potential treatment option for NRG1 fusion-positive tumors.

110 Background: Neuregulin 1 (NRG1) is a growth factor that binds HER3/4 and activates ErbB signalling pathways. NRG1 gene fusions function as oncogenic drivers and represent a potential therapeutic target across tumour types. Afatinib, an ErbB-family blocker, is a potential treatment option for some patients with NRG1 fusion-positive ( NRG1+) tumours, as supported by preclinical evidence and clinical case reports. Of 13 patients with NRG1+ lung adenocarcinoma (ADC; n = 9), pancreatic ADC (n = 2), cholangiocarcinoma (n = 1), and ovarian cancer (n = 1) treated with afatinib, eight patients achieved a best response of partial response (PR; median duration 7.3 months, range 3–12), three patients had stable disease (SD) and two patients had progressive disease. Methods: Here, we report the clinico-pathological and molecular characteristics and current status of four additional cases of afatinib-treated NRG1+ tumours. Results: Patient 1, 66 year-old female, never-smoker with metastatic non-mucinous lung ADC. CD74-NRG1 fusion was identified, and 5th-line afatinib initiated. PR is ongoing after 16 months. Patient 2, 43 year-old female, non-smoker with advanced invasive mucinous lung ADC. CD74-NRG1 fusion was identified and 3rd-line afatinib initiated (PR, 18 months); treatment is ongoing following local progression. Patient 3, 69 year-old male, with KRAS-mutated metastatic colorectal cancer. Following a right hemicolectomy and liver/lung metastasectomies, a novel POMK-NRG1 fusion was detected and afatinib initiated (SD, 4 months). Eight months after initiation, afatinib treatment is ongoing, in combination with radiotherapy, with SD. Patient 4, 54 year-old male, with KRAS-wild-type metastatic pancreatic cancer. Following progression on chemotherapy, APP-NRG1 fusion was detected as part of the Personalized Oncogenomics study (NCT02155621), and afatinib initiated; PR is ongoing after 7 months. Conclusions: These findings add to a growing body of evidence that afatinib is a potential treatment option for patients with NRG1+ tumours. Prospective study is ongoing/planned in the Drug Rediscovery Protocol trial (DRUP; NCT02925234) and Targeted Agent and Profiling Utilization Registry study (TAPUR; NCT02693535).

1969P - Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option

1969P - Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option

1476P - Definition of an afatinib trough concentration threshold in the treatment of NSCLC

BackgroundAfatinib (AFA), an irreversible ErbB family blocker, is used at the standard starting dose of 40mg for the treatment of patients with EGFR M+ NSCLC. It has been shown previously tolerability guided dose reduction effectively decreases incidence and severity of treatment related adverse events (AEs) during the treatment, and that treatment-related dose reduction was more likely in patients who had higher plasma concentrations of AFA before dose adaptation (Yang et al., Annals of Oncology 2016). After dose reduction, concentrations were similar to those obtained in patients who did not experience AEs, with comparable efficacy. We thus intended to determine a threshold concentration related with dose-reduction or AEs leading to dose-reduction (AELDR). MethodsPatients (N=390) with AFA treatment, analyzable trough plasma concentration (Cmin) determination at D22 and follow-up of at least 6 months were identified from LUX-Lung (LL3 & LL6) studies. Receiver operating characteristic (ROC) curve analysis (univariable regression model) was performed to assess a discrimination potential of AFA Cmin for AELDR. ResultsThe most discriminating threshold of AFA Cmin associated with dose reduction or AELDR between D22 sampling and M6 is at 34ng/ml. With this concentration threshold, there is a maximal AUC of 0.63 (95%CI: [0.58 – 0.69], a maximal Younden index of 0.267 (49% sensitivity, 78% specificity), with an odds ratio of 3.37 [2.10 – 5.40]) indicating that dose reduction or AELDR are more frequent in patients with concentration ≥34ng/mL. The analysis also showed that concentration is more often elevated in female, older (>65y), eastern Asian and low-body weight patients. ConclusionsMonitoring of AFA plasma levels might be useful for the management of AEs in patients with NSCLC, especially for patients having factors known to be associated with higher AFA plasma exposure or toxicities. These results support the approach of adapting treatment dose based on plasma concentrations of AFA both forAEs and efficacy. Clinical trial identificationNCT01121393, NCT00949650. Legal entity responsible for the studyM. Molimard. FundingBoehringer Ingelheim. DisclosureC. Frohn: Full / Part-time employment: Boehringer Ingelheim International GmbH. C. Maritaz: Full / Part-time employment: Boehringer Ingelheim France. All other authors have declared no conflicts of interest.

Long-term efficacy of afatinib in a patient with squamous cell carcinoma of the lung and multiple ERBB family aberrations

In the phase 3 LUX-Lung 8 study, the ERBB family blocker, afatinib, significantly prolonged progression-free survival and overall survival relative to erlotinib in patients with relapsed/refractory squamous cell carcinoma of the lung. We describe the case of a 53-year-old Asian male enrolled in LUX-Lung 8 who experienced long-term benefit from afatinib following failure of platinum-based chemotherapy. The patient received afatinib, and remained progression-free for 14.7 months according to investigator review. Overall survival was 17.7 months. Tolerability-guided dose adjustments helped facilitate long-term afatinib use by mitigating drug-related adverse effects. Next-generation sequencing revealed that multiple genetic aberrations were present, including epidermal growth factor receptor copy number amplification, and mutations in ERBB4, ALK, RET, and BRCA2. These findings may help to explain the enhanced response to afatinib and highlight the importance of biomarker analysis in guiding treatment decisions in patients with squamous cell carcinoma of the lung.

Abstract CT139: NCI Molecular Analysis for Therapy Choice (NCI-MATCH EAY131) arm B: Phase II study of afatinib in patients (pts) with HER2 (ERBB2) activating mutations

Abstract BACKGROUND: NCI-MATCH is a multi-cohort, signal finding trial that assigns pts with advanced cancers to targeted therapies based on central tumor genomic testing. Arm B evaluated afatinib, an ErbB family blocker, in pts with ERBB2 activating mutations. METHODS: Eligible pts had advanced refractory solid tumors, lymphoma, or multiple myeloma, tumor biopsies with selected ERBB2 single nucleotide variants or insertions/deletions, but no ERBB2 amplification detected by the NCI-MATCH next generation sequencing assay. Pts had performance status (PS) ≤1, left ventricular ejection fraction >50%, grade ≤1 diarrhea, and no prior HER2 therapy. Non-small cell lung cancers were excluded. Pts received afatinib 40 mg daily in 28 day cycles. Concomitant endocrine therapy was not allowed. Tumor assessments were every two cycles. The primary objective was overall response rate (ORR). Secondary objectives were: 6-month progression-free survival (PFS6), overall survival, toxicity and molecular correlates. Initial planned enrollment was 35 pts, but a subsequent amendment permitted accrual of up to 70 pts to provide additional information in rarer histologies. RESULTS: 59 pts were assigned and 40 enrolled (37 evaluable) to Arm B. Median age was 62 (range 29-83), 78% female, 32% PS0, and 58% had received >3 prior therapies. Tumor histologies: breast (n=12; 5 lobular/7 ductal, all ER+), colorectal (n=5), urothelial (n=4), biliary (n=3), cervix (n=2), small bowel (n=2) and other (n=9). The qualifying ERBB2 variants were L755S (n=6), V777L (n=6), V842I (n=6), S310F (n=6), D769Y (n=5), S310Y (n=4), V777_G778insGSP (n=2), and other (n=7). The ORR was 2.7% (n=1/37; 90% CI 0.14%-12.2%) and PFS6 was 11% (90% CI 5.0%-23.5%). A confirmed partial response (PR) occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed PRs were observed (low grade serous gynecological tract and ER+/HER2- IHC breast ductal carcinoma). Of 12 evaluable breast cancer pts, there was 1 additional pt with lobular carcinoma (ER+/HER2-FISH) who had 51% reduction in target lesions but progressed due to a new lesion at cycle 6. The most common (>20%) treatment-related AEs were: diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%) dehydration (27%), vomiting (27%), nausea (27%), anemia (27%) and anorexia (22%). Most AEs were grade ≤2. Four pts (11%) discontinued due to AEs. CONCLUSION: Although afatinib did not meet the pre-specified threshold for anti-tumor activity, the response in a rare tumor type is notable. The results in breast/gynecologic malignancies, along with the SUMMIT trial (Hyman Nature 2018), suggest differential activity of HER2 inhibitors in ERBB2 mutant cancers by tumor histology. The safety profile of afatinib was consistent with prior studies. Citation Format: Philippe L. Bedard, Shuli Li, Kari B. Wisinski, Eddy S. Yang, Sewanti A. Limaye, Edith P. Mitchell, James A. Zwiebel, Jeffrey Moscow, Robert J. Gray, Lisa M. McShane, Larry V. Rubenstein, David R. Patton, P Mickey Williams, Stanley R. Hamilton, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty. NCI Molecular Analysis for Therapy Choice (NCI-MATCH EAY131) arm B: Phase II study of afatinib in patients (pts) with HER2 (ERBB2) activating mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT139.

Afatinib, an irreversible ErbB family blocker for the treatment of epidermal growth factor receptor mutation-positive non-small cell lung cancer

Abstract Targeted inhibition of epidermal growth factor receptor (EGFR) signaling has emerged as the standard of care for EGFR mutation-positive non-small cell lung cancer (EGFRm+ NSCLC). Afatinib, an oral irreversible ErbB-family blocker, has been extensively studied in this context. Recent studies have highlighted the benefit and tolerability of afatinib treatment in patients with EGFRm+ advanced/metastatic NSCLC. The LUX-Lung 3 and 6 phase III studies showed greater efficacy with first-line afatinib compared with platinum-doublet chemotherapy, whereas LUX-Lung 7 highlighted the enhanced benefits of afatinib over the first-generation EGFR tyrosine kinase inhibitor (TKI), gefitinib. The nearly inevitable emergence of resistance to afatinib, coupled with recent data for the third-generation TKI osimertinib, highlight the need to identify an optimal treatment sequencing strategy to achieve long-term benefit and survival. The available data suggest that optimal treatment could involve first-line afatinib, followed by osimertinib upon acquired resistance to afatinib through the T790M mutation. This review discusses the pharmacology of afatinib, efficacy and safety results of key trials in the afatinib clinical study program, management of adverse events, and sequencing strategies following acquired resistance. Afatinib data are discussed in the context of recent studies of other EGFR TKIs, to provide considerations around their use and inform potential sequential treatment approaches.