Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non–small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.     

Activity of the EGFR-HER2 Dual Inhibitor Afatinib in EGFR-Mutant Lung Cancer Patients With Acquired Resistance to Reversible EGFR Tyrosine Kinase Inhibitors

BackgroundThe purpose of this study was to evaluate the efficacy of afatinib in EGFR-mutant metastatic NSCLC patients with acquired resistance to erlotinib or gefitinib.Materials and MethodsWe retrospectively analyzed the outcome of patients with EGFR-mutant advanced NSCLC treated with afatinib after failure of chemotherapy and EGFR TKIs.ResultsA total of 96 individuals were included in the study. According to EGFR status, most patients (n = 63; 65.6%) harbored a deletion in exon 19, and de novo T790M mutation was detected in 2 cases (T790M and exon 19). Twenty-four (25%) patients underwent repeated biopsy immediately before starting afatinib and secondary T790M was detected in 8 (33%) samples. Among the 86 patients evaluable for efficacy, response rate was 11.6%, with a median progression free-survival (PFS) and overall survival (OS) of 3.9 and 7.3 months, respectively. No significant difference in PFS and OS was observed according to type of last therapy received before afatinib, type of EGFR mutation or adherence to Jackman criteria, and patients benefiting from afatinib therapy had longer PFS and OS (P < .001). Outcome results for repeated biopsy patients were similar to the whole population, with no evidence of response in T790M-positive patients. All patients were evaluable for toxicity, and 81% experienced an AE of any grade, with grade 3 to 4 AEs, mainly diarrhea and skin toxicity, occurring in 19 (20%) patients.ConclusionOur results showed that afatinib has only modest efficacy in a real life population of EGFR mutant NSCLC patients with acquired resistance to erlotinib or gefitinib.     

Molecular Characteristics of the Uncommon EGFR Exon 21 T854A Mutation and Response to Osimertinib in Patients With Non-Small Cell Lung Cancer

BackgroundEpidermal growth factor receptor (EGFR) T854A is an uncommon exon 21 mutation in patients with non-small cell lung cancer (NSCLC). It was first reported in samples collected after first generation EGFR tyrosine kinase inhibitor (TKI) treatment as an acquired resistant mutation to first generation EGFR-TKI. The efficacy of osimertinib, a third generation EGFR-TKI, in these patients was not clear.MethodsIn this study, a total of 8932 NSCLC patients with NGS data were retrospectively analyzed to investigate the molecular characteristics and clinical outcomes of patients with EGFR T854A mutation.ResultsEight of 8932 patients (0.09%) had EGFR T854A mutation, and 5 of them (62.5%) were treatment-naïve. Interestingly, all EGFR T854A mutations were co-occurred with EGFR L858R mutation in cis. TP53 was the most common concomitant mutation and no other driver mutation was found. Five of the 8 patients received treatment of osimertinib. Four patients achieved partial response, and one had stable disease, resulting in an overall objective response rate of 80% and disease control rate of 100%. The median progression-free survival of patients who received osimertinib was 10 months. Moreover, EGFR C797S mutation was detected in 1 patient after resistant to osimertinib treatment.ConclusionPresence of EGFR T854A mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that osimertinib may be an effective treatment to improve survival outcomes in patients with EGFR T854A.     

Afatinib in Non‐Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors

Background.

Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naïve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown.

Materials and Methods.

In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported.

Results.

In 60 patients (63% female, median age 63 years [range: 30–84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected.

Conclusion.

Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naïve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations.

Implications for Practice:

This analysis consists of a large database of non-small cell lung cancer patients with uncommon EGFR mutations who were previously treated with reversible EGFR tyrosine kinase inhibitors. Although indirectly assessed, the results indicate that patients with uncommon EGFR mutations can derive benefit from treatment with the irreversible ErbB family blocker afatinib, even in some cases of tumors harboring resistance-mediating exon 20 mutations. In this study, adverse events were modest and consistent with previous reports on afatinib.     

Intensified Total Neoadjuvant Therapy in Patients With Locally Advanced Rectal Cancer: A Phase II Trial

AimsWe assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer.Materials and methodsThis was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin–5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%.ResultsBetween October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases.ConclusionFOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies.     

Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

IntroductionOsimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments.MethodsAdults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety.ConclusionsORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.     

Docetaxel and Oxaliplatin as First-Line Therapy for Advanced Non-Small Cell Lung Cancer: A Phase II Trial

Abstract

We sought to evaluate the safety and efficacy of docetaxel and oxaliplatin combination as first-line therapy for patients with stage IV or wet III_B non small cell lung cancer. Patients received oxaliplatin at 85 mg/m² intravenously over 2 hours on days 1 and 15 along with docetaxel at 30 mg/m² intravenously on days 1 and 8; both given every 28 days. Cycles were repeated every 4 weeks for a maximum of 6. Fifteen patients were enrolled for an overall response rate of 50% (95% CI 21-74%). Median progression-free survival was 2.4 months with a 1-year progression free survival of 10%. Median overall survival was 7.9 months with 49% of patients alive at 1 year. Most common toxicities were nausea, vomiting, and dehydration. This combination has notable activity in advanced non-small cell lung cancer with a favorable toxicity profile.     

Effectiveness and Tolerability of First-Line Afatinib for Advanced EGFR-Mutant Non-Small Cell Lung Cancer in Vietnam

Background: We aimed to evaluate the effectiveness and tolerability of Afatinib as first-line treatment of advanced epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC) in a real-world setting. Patients and methods: This is a retrospective study of Vietnamese patients  with advanced EGFR-mutant NSCLC treated with first-line afatinib at the National Cancer Hospital from 1st January 2018 to 31st October 2020. Patients’ demographic, clinical and treatment data were captured. Objective response rate (ORR), disease control rate (DCR), time to treatment failure (TTF) and tolerability were evaluated. We used Kaplan-Meier curve and log-rank test for survival, and Cox regression model for multivariate analysis. Results: A total of 44 patients were included. Common EGFR mutations (Del 19/L858R) were detected in 61% patients. Fifty percent of patients with uncommon mutations had compound mutations of G719X, L861Q and S768I. The ORR was 75% while DCR rate was 98%. The median TTF was 12.3 months (95% CI: 7.2-17.3); the mTTFs were 12.3 and 10.8 months for patients with common and uncommon mutations (p = 0.001), respectively, and 14.0 and 7.5 months for patients with Del 19 and L858R mutations (p = 0.067), respectively. Afatinib 30 mg once daily was the most common starting (77%) and maintenance (64%) doses. The mTTFs were 12.3 and 7.5 months for patients with 30 mg starting dose vs 40 mg dose (p = 0.256), respectively. Diarrhea, skin rash, paronychia and fatigue were observed in 32%, 30%, 25% and 9%, respectively. There was no grade 4 toxicity except three patients with grade 3 paronychia. Conclusions: First-line afatinib is beneficial for Vietnamese patients with advanced EGFR-mutant NSCLC with a good response rate and prolonged TTF with manageable adverse event profile. Baseline brain metastasis status and starting doses do not significantly impact TTF.     

EGFR Mutation Analysis for Prospective Patient Selection in Two Phase II Registration Studies of Osimertinib

IntroductionOsimertinib is an oral, central nervous system–active, EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR T790M–positive advanced NSCLC. Here we have evaluated EGFR mutation frequencies in two phase II studies of osimertinib (AURA extension and AURA2).MethodsAfter progression while receiving their latest line of therapy, patients with EGFR mutation–positive advanced NSCLC provided tumor samples for mandatory central T790M testing for the study selection criteria. Tumor tissue mutation analysis for patient selection was performed with the Roche cobas EGFR Mutation Test (European Conformity–in vitro diagnostic, labeled investigational use only) (Roche Molecular Systems, Pleasanton, CA). Patients should not have been prescreened for T790M mutation status. The cobas test results were compared with those of the MiSeq next-generation sequencing system (Illumina, San Diego, CA), which was used as a reference method.ResultsSamples from 324 and 373 patients screened for AURA extension and AURA2, respectively, produced valid cobas test results. The T790M detection rates were similar between AURA extension and AURA2 (64% and 63%, respectively). The pooled T790M rate was 63%, with no difference by ethnicity (63% for Asian and non-Asian patients alike) or immediately prior treatment with an EGFR TKI (afatinib, 69%; erlotinib, 69%; and gefitinib, 63%). A higher proportion of patients had T790M detected against a background of exon 19 deletions versus L858R mutation (73% versus 58% [p = 0.0002]). In both trials the cobas test demonstrated high sensitivity (positive percent agreement) and specificity (negative percent agreement) for T790M detection when compared with the next-generation sequencing reference method: positive percent agreement of 91% versus 89% and negative percent agreement of 97% versus 98%.ConclusionsIn both trials, the rate of detection of T790M mutation in patients with advanced NSCLC was approximately 63% and was unaffected by immediately prior treatment with an EGFR TKI or ethnicity.     

ShorTrip Trial: A Prospective,Multicentric Phase II Single-Arm Trial of Short-Course Radiotherapy Followed by Intensified Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer

BackgroundIn patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence.Patients and MethodsShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle.Aim of the studyThe aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.     

Novel EGFR Inhibitors in Non-small Cell Lung Cancer: Current Status of Afatinib

Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been approved worldwide as a first-line treatment for advanced non-small cell lung cancer (NSCLC) that harbors activating EGFR mutations. Here, we have reviewed the recent clinical developments in the treatment of lung cancer using afatinib. Emerging data have revealed the overall survival benefit of first-line afatinib therapy in patients with advanced EGFR ^del19-positive NSCLC. Phase III studies of afatinib have shown the effectiveness of afatinib as a second-line treatment for advanced lung squamous cell carcinoma, as well as the benefit of continuing afatinib therapy in combination with cytotoxic chemotherapy for advanced NSCLC after the occurrence of disease progression in patients who are receiving afatinib monotherapy. Therapeutic benefits of afatinib have also been reported in studies of patients with central nervous system metastasis and patients with HER2 mutation. The utility of afatinib-based combination therapies is being investigated in ongoing research.     

A Phase II Trial of Prexasertib (LY2606368) in Patients With Extensive-Stage Small-Cell Lung Cancer

BackgroundThis study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC).Patients and MethodsThis was a parallel-cohort phase II study of 105 mg/m² prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m² days 1-3, 14-day cycle).ResultsIn Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ≥3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified.ConclusionPrexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC.     

Dynamics of EGFR Mutation Load in Plasma for Prediction of Treatment Response and Disease Progression in Patients With EGFR-Mutant Lung Adenocarcinoma

Background

The assessment of epidermal growth factor receptor (EGFR) mutations is crucial for the management of patients with lung adenocarcinoma. Circulating tumor DNA (ctDNA)-based assessment offers advantages over tumor as a minimally invasive method able to capture tumor heterogeneity.