Efficacy Of Afatinib In Patients Research Articles

Prospective exosome-focused translational research for afatinib (EXTRA) study of patients with nonsmall cell lung cancer harboring EGFR mutation: an observational clinical study.

The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses. We report details of the clinical portion prior to omics analyses. A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed. Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. A total of 103 patients (median age 70 years, range 42-88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 (n = 27), 30 (n = 23), and 20 mg/day (n = 35), and 20 mg every other day (n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did (n = 25) and did not (n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively (p = 0.654). As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib. UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688.

Non-small cell lung cancer harboring EGFR G724S mutation and exon 19 deletion responded to afatinib monotherapy after multiple lines of target therapies.

Epidermal growth factor receptor (EGFR) G724S mutation represents a resistance mechanism to first- and third-generation EGFR tyrosine kinase inhibitors. Limited data are available regarding the efficacy of afatinib in patients with non-small cell lung cancer (NSCLC) harboring G724S mutation, particularly after osimertinib. A patient diagnosed with advanced EGFR-mutated (exon 19 deletion) NSCLC after several lines of treatment – gefitinib, osimertinib, heat shock protein inhibitors and chemotherapy-developed EGFR G724S mutation retaining the exon 19 deletion. She was then treated successfully with afatinib leading to a progression free survival of 9 months (and counting). This is the first report of the emergence of G724S mutation, together with ex19del, after three subsequent lines of therapy following progressive disease to Osimertinib, and we report for the first time the activity of afatinib against EGFR exon 18 G724S mutation in this setting.

Efficacy of afatinib in patients with advanced/metastatic solid tumors harboring NRG1 gene fusions: A novel, prospective real-world outcomes study based on single-patient protocol data.

TPS3180 Background: Oncogenic neuregulin 1 ( NRG1) gene fusions occur in ̃0.2% of solid tumors overall and in up to 31% of cases of invasive mucinous lung adenocarcinoma [Laskin et al. Ann Oncol. 2020;31(12):1693–1703; Cadranel et al. Oncologist. 2021;26(1):7–16]. NRG1 fusion proteins provide an extracellular anchor for the epidermal growth factor (EGF) domain of NRG1 to bind to ErbB3 (HER3), leading to HER3 heterodimerization and activation of downstream signaling pathways, resulting in oncogenesis. Afatinib, an irreversible pan-ErbB tyrosine kinase inhibitor, represents a potential treatment for NRG1-fusion positive ( NRG1+) tumors. This study aims to examine the safety and efficacy of afatinib in patients with NRG1+ solid tumors, for which no authorized targeted therapy exists. Methods: This prospective, decentralized, US study (NCT05107193) will include 40 evaluable patients aged ≥18 years. Participating molecular test providers across the USA will identify eligible fusions in the course of routine diagnostic assays. When a patient with an NRG1 fusion is identified, participating test providers will notify the treating physician of the study as a treatment option for the patient. Patients’ primary oncologists will then contact the trial sponsor to confirm patient eligibility. Once approved by the central Institutional Review Board, patients will receive afatinib on a single-patient protocol basis, until disease progression or treatment is no longer tolerated. The recommended dosage per SmPC is 40 mg orally QD. Patients will be screened and enrolled into the study at their existing point-of-care setting. Inclusion criteria include a histologically or cytologically confirmed diagnosis of an advanced, unresectable/metastatic, non-hematologic malignancy with an NRG1 fusion, evaluable per RECIST 1.1. Any coding gene as the NRG1 fusion partner is permitted. Fusion status will be confirmed prospectively by a contracted molecular test provider. Exclusion criteria include prior systemic anti-cancer therapy or investigational drug within 14 days or 5 half-lives (whichever is shorter) of the start of afatinib treatment; an actionable driver mutation other than NRG1 fusion for which FDA-approved targeted therapy is available; and prior treatment with an ErbB-targeted therapy. The primary endpoint of the study is confirmed objective response (OR) by independent central review per RECIST 1.1, defined as best overall response of either complete response or partial response and analysed as the proportion of patients with an OR. The key secondary endpoint is duration of response, defined as the time from the first documented OR to progression or death. Secondary endpoints include time to OR and disease control per investigator assessment. Safety will also be assessed. The study is open for recruitment. Clinical trial information: NCT05107193.

First-line Afatinib in Patients With Non-small-cell Lung Cancer With Uncommon EGFR Mutations in South Korea

Non-small cell lung cancers (NSCLCs) harboring uncommon epidermal growth factor receptor (EGFR) mutations are heterogeneous and show variable prevalence and clinical responses to EGFR tyrosine kinase inhibitors. We investigated the characteristics of uncommon EGFR mutations and the clinical efficacy of afatinib in patients with NSCLC harboring uncommon EGFR mutations. In this multicenter, retrospective study, we analyzed patients with NSCLC with uncommon EGFR mutations in 16 South Korean institutes. Mutations were categorized according to their incidence: 1) major uncommon mutations (G719X and L861Q), 2) compound mutations, and 3) minor uncommon mutations (exon 20 insertion, S768I, and de novo T790M). Of 703 patients with EGFR-mutant NSCLC, 64 (9.1%) had uncommon EGFR mutations. Afatinib demonstrated activity against tumors harboring major uncommon mutations [median time of treatment (TOT): 20.3 months, 95% confidence interval (CI)=15.1-25.5; overall survival (OS): 30.6 months, 95% CI=26.3-34.8] and compound mutations (median TOT: 12.3 months, 95% CI=7.7-17.0; OS: 29.1 months, 95% CI=20.4-37.7) but not against tumors harboring minor uncommon mutations (median TOT: 3.8 months, 95% CI=1.7-6.0; OS: 8.5 months, 95% CI=5.2-11.7). The S768I mutation was present in 14 patients (1.99%). The median TOT and OS were not significantly different between S768I mutations and resistant exon 20 mutations. Afatinib is effective in patients with NSCLC harboring major uncommon and compound EGFR mutations.

Afatinib as a Potential Therapeutic Option for Patients With NSCLC With EGFR G724S

IntroductionEGFR G724S has been described to mediate resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs). In vitro experiments have provided compelling evidence that G724S retains sensitivity for afatinib. Nevertheless, limited data have reported the clinical efficacy of afatinib in patients with NSCLC harboring G724S mutation. MethodsWe identified 52 patients with NSCLC with EGFR G724S from an inhouse database and comprehensively profiled their concurrent mutation statuses. Treatments and clinical outcomes were also collected. ResultsOf 52 G724S-positive patients, 39 harbored concomitant EGFR exon 19 deletion (19del), and all 37 of the 39 patients who had available clinical data were detected with a G724S mutation after receiving EGFR TKIs. A rare variant of 19del E746_S752delinsV co-occurred with G724S the most frequently (n = 29), whereas 7 of 10 patients with concomitant EGFR exon 20 mutation were TKI treatment naive. S768I was the most common mutation in exon 20 (n = 7). One patient harbored a concomitant EGFR exon 21 mutation, and two lacked co-occurring EGFR mutations. A total of 23 patients provided valid clinical outcome data, of whom eight were treated with afatinib after the emergence of G724S, whereas 15 received non-afatinib treatment (alternative EGFR TKI, chemotherapy, or best supportive care). The disease control rate in afatinib-treated patients (n = 8) reached 100% with a median progression-free survival of 4.5 months, significantly longer than that of non–afatinib-treated (n = 15, 1.7 mo, hazard ratio [HR] = 0.32, p = 0.037) and alternative EGFR TKI-treated (n = 11, 1.8 mo, HR = 0.28, p = 0.042) patients. In the subset who had progressed on osimertinib, afatinib also yielded a superior progression-free survival (6.2 mo) than non-afatinib therapies (1.0 mo, HR = 0.04, p = 0.005) and alternative EGFR TKIs (1.8 mo, HR = 0.06, p = 0.033). Analysis of acquired mutations at afatinib progression revealed re-emergence of EGFR T790M or MET amplification as the potential mechanism of afatinib resistance. ConclusionsEGFR G724S emerges as a resistant mutation against EGFR TKI preferentially in the context of a rare variant of 19del, whereas it might mediate differential mechanisms in the context of exon 20 mutation. We also found that afatinib could be a potential therapeutic option for patients with NSCLC with G724S.

The efficacy of afatinib in patients with HER2 mutant non-small cell lung cancer: a meta-analysis.

BackgroundErb-b2 receptor tyrosine kinase 2 (ErbB2/HER2) mutation has been found in approximately 2–4% of non-small cell lung cancer (NSCLC) patients and has been identified as one of carcinogenic mutations. Afatinib, a member of irreversible HER family inhibitor, has been investigated by a number of literatures, yet whose therapeutic efficiency remains uncertain in NSCLC with HER2 mutation. To elucidate the clinical efficacy and safety of afatinib in treating HER2 mutant NSCLC, we integrated and reanalyzed the data from current available studies.MethodsWe conducted a systematic literature search for published articles regarding afatinib treating HER2-mutant lung cancer. Eight studies met the inclusion and exclusion criteria. The main outcomes were the objective response rate (ORR) and disease control rate (DCR).ResultsNinety-five patients with HER2 mutations were identified from eight studies. The pooled ORR was 21% (95% CI: 11–34%) and the pooled DCR was 66% (95% CI: 57–76%). The patients harboring A775-G776ins YVMA mutation, the most common subtype of HER2 exon 20 mutation, derived greater clinical benefit. Most adverse events were grade 1–2, except a case of fatal acute renal injury, possibly related to afatinib.ConclusionsAfatinib monotherapy demonstrated frustrating anti-tumor activity with tolerable toxicity in HER2 mutant NSCLC. Based on current available data, we do not recommend the regular application of afatinib in NSCLC with HER2 mutations unless the response heterogeneity with specific genomic variant of HER2 mutation was further clarified.

527P - A multicenter study of NRG1 fusions in Chinese non-small cell lung cancer patients and response to afatinib using next generation sequencing

BackgroundNRG1 fusions are potentially actionable genomic events seen in non-small cell lung cancers (NSCLC) and there are reports of therapeutic efficacy with agents that target Erb-B2/Erb-B3, while little is known about NRG1 fusions association with outcomes of afatinib. The aim of this study was to investigate the efficacy of afatinib in patients with advanced NRG1 fusion NSCLC. MethodsA multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. To determine the frequency of the NRG1 fusions in NSCLC and other tumors, we analyzed data from 2743 clinical NSCLC cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. ResultsOf this entire cohort, only one (0.04%) patient was identified with a CD74-NRG1 fusion. The patient was a 55-year-old never smoking male, who was diagnosed with lung adenocarcinoma from biopsies obtained, CD74-NRG1 fusion was found by NGS, the genes co-altered with NRG1 fusion was no concurrent with KRAS, EGFR, ALK, ROS1, RET, or other known drivers were identified in the study cohort cases, and NRG1 fusion driven NSCLC responding to afatinib will be presented. The patient was considered to have a partial response (PR) to afatinib, and he was alive up to now. ConclusionsNRG1 fusions were detected at a low incidence (0.04%) in Chinese patients. Patients with advanced NRG1 fusion NSCLC showed a good outcome of afatinib compared to those with ALK/ROS1 fusion which response to crizotinib, which will influence the development of strategies to detect these events on a large scale. Legal entity responsible for the studyXingliang Li. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Real-world large-scale study of ERBB2 gene fusions and its response to afatinib in Chinese non-small cell lung cancer (NSCLC): A multicenter study.

e13002 Background: ERBB2 mutation has been found to be an oncogenic driver gene in non-small cell lung cancers (NSCLC) and ERBB2-directed therapies have shown promising results in this unique population, while little is known about ERBB2 fusion association with outcomes of afatinib. The aim of this study was to investigate the efficacy of afatinib in patients with advanced ERBB2 fusion NSCLC. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. To determine the frequency of the ERBB2 fusions in NSCLC and other tumors, we analyzed data from 2743 clinical NSCLC cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort, eight (0.29%) patients were identified with an ERBB2 fusion, including TNS4-ERBB2 (1), ERBB2-CD79B (1), IGFBP4-ERBB2 (1), ERBB2-PSMD3 (1), SEZ6-ERBB2 (1), ERBB2-PGAP3 (1), ARL5C-ERBB2 (1) and B3GNTL1-ERBB2 (1). The genes most frequently co-altered in patients with ERBB2 fusions were TP53 (37.50%), CDKN2A (25.00%), RB1 (25.00%) and RBM10 (25.00%). Overall TMB in the ERBB2 fusions was low (median 2.97 mut/Mb). For treatments, 25.00% patients chose afatinib, another patients chose chemotherapy or chemoradiotherapy, and case examples of advanced ERBB2 fusion driven NSCLC patients responding to afatinib were actively being sought thru our database. Conclusions: Patients with advanced ERBB2 fusion NSCLC showed a good outcome of afatinib compared to those with ALK/ ROS1 fusion which response to crizotinib, which strengthen the need for effective ERBB2-targeted drugs in clinical practice.

EGFR mutation type and efficacy of afatinib in patients who previously treated with EGFR-TKI.

e20535Background: Recent phase III studies demonstrated that afatinib improve overall survival in NSCLC patient with common EGFR mutation as compared with 1st line chemotherapy. The different effic...

138PD Impact of dose adjustment on the safety and efficacy of afatinib in patients (pts) with advanced EGFR mutation-positive non-small cell lung cancer (NSCLC): Post-hoc analyses of LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6)

Background Afatinib 40 mg/day is approved for the first-line treatment of pts with EGFR mutation-positive NSCLC. The dose can be adjusted based on individual tolerability. Post-hoc analyses assessed the impact of afatinib dose adjustment on adverse events (AEs), pharmacokinetics (PK) and progression-free survival (PFS) in LL3 and LL6. Methods All afatinib-treated pts in LL3 (n = 229) and LL6 (n= 239) were included. In case of drug-related grade 3 or selected prolonged grade 2 AEs with afatinib 40 mg, the dose could be reduced by 10 mg decrements to a minimum of 20 mg. We analysed the incidence and severity of common AEs before and after dose reduction and compared PK data collected as part of the standard visit schedule on Day 43 in pts who reduced to 30 mg vs those remaining at 40 mg. PFS in pts who dose reduced within the first 6 months of treatment was compared with those who remained on afatinib 40 mg/day. Results Dose reductions occurred in 53% (122/229) and 28% (67/239) of pts in LL3 and LL6, respectively; the majority (86% and 82%, respectively) within the first 6 months of treatment. Dose reduction led to decreases in the incidence and severity of EGFR-mediated drug-related AEs (table). Combined PK analysis of LL3 and LL6 suggested that dose reduction was more likely in pts with higher plasma concentrations of afatinib. On Day 43, pts who had dose reduced to 30 mg (n = 59) had geometric mean plasma afatinib concentrations of 23.3 ng/mL, vs 22.8 ng/mL in pts who remained on the 40 mg dose (n = 284). Median PFS was similar in pts who dose reduced during the first 6 months of treatment vs those who did not in LL3 (11.3 vs 11.0 months [HR = 1.25; 95% CI, 0.91–1.72]) and LL6 (12.3 vs 11.0 months [HR = 1.00; 95% CI, 0.69–1.46]).

A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab refractory esophagogastric (EG) cancer.

59 Background: Trastuzumab combined with chemotherapy is the standard of care for pts with HER2+ EG cancer. Resistance to trastuzumab clearly emerges in this population. Afatinib, a potent ErbB Family Blocker, induced tumor regression in MSKCC HER2+ patient derived xenografts (PDX). This study assesses safety and preliminary efficacy of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma, after progression on trastuzumab, received oral afatinib 40 mg daily. Archival pre-trastuzumab tissue, tumor biopsy after progression on trastuzumab and after 1 week on afatinib is mandated on protocol for next generation sequencing (NGS), proteomics and establishment of PDX. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 20 pts treated with afatinib; median age 61, KPS 80; median 2 (1 to 4) prior trastuzumab regimens, 67% of tumors IHC3+; 33% IHC2+/FISH>2.0. Common adverse events included: rash or dry skin (Grade 1/2:80%), diarrhea (Grade 1/2:60%), nausea/vomiting (grade 1/2:40%) fatigue (grade1/2: 25%). To date, 19 pts evaluable for response, 2 PRs and 6 SD, 42% disease stabilization rate (PR+SD) at 4months (4 to 13 mos). PDXs established from biopsies of 7 pts. EGFR amplification was detected in the tumor of 2 pts with PRs and 1 of 6 pts with SD. Recurrent PIK3CA, ERBB3 and MTORmutations were observed. Conclusions: Afatinib shows clinical efficacy and is well tolerated in patients with trastuzumab refractory, heavily pretreated EG cancer. Enrollment has now begun in an afatinib + trastuzumab cohort. Efforts to elucidate the mechanisms of trastuzumab resistance including validation of potential drivers of trastuzumab resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.

A phase II study of afatinib (BIBW 2992) in patients with advanced HER2-positive trastuzumab-refractory esophagogastric cancer.

TPS4144 Background: Trastuzumab, approved by the FDA, has been the standard of care for patients (pts) with HER2-positive esophagogastric cancer. Acquired and de novo resistance to trastuzumab is an important clinical issue. Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination with cetuximab, demonstrated a 40% partial response (PR) rate, with clinical benefit in >90% in lung cancer patients with acquired resistance to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive NCI-N87 gastric cancer xenograft showed that while trastuzumab alone was minimally effective, single-agent afatinib resulted in near complete tumor regression by inducing apoptosis and downregulation of HER2, p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In light of these data and the efficacy of afatinib in patients with trastuzumab-refractory breast cancer, we designed a phase II study to determine if afatinib will benefit patients with trastuzumab-refractory HER2-positive esophagogastric cancer. We hypothesize that simultaneous inhibition of ErbBB receptor family components with afatinib will overcome trastuzumab resistance. Molecular bases of trastuzumab resistance will be examined. Methods: Pts with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression on a trastuzumab-containing regimen will receive afatinib 40 mg once daily. Primary endpoint RECIST 1.1 response (SD+CR+PR) at 4 months, with imaging every 8 wks. 13 pts will be enrolled in the 1st stage and if ≥1 responses are observed, additional 14 ps (total of 27) will be treated. An initial biopsy prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis of archival pre-trastuzumab tissue and blood sample for matched normal DNA control are mandated. Changes in signaling following afatinib therapy will provide insight into response heterogeneity. Degree of target inhibition will be correlated with responses. Archival baseline (pre-trastuzumab) and pre-afatinib tissue will be assessed for abnormalities in pathways implicated in trastuzumab resistance.

Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial

Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Boehringer Ingelheim Inc.