Sensitizing EGFR Mutations Research Articles

Efficacy and Safety of SH-1028 in Patients With EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial

IntroductionAs a novel third-generation EGFR tyrosine kinase inhibitor (TKI), SH-1028 (formerly oritinib) is developed to inhibit both sensitizing EGFR mutations and EGFR T790M mutation. MethodsThis was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807). Eligible patients were those with advanced NSCLC with centrally confirmed EGFR T790M mutation who progressed after first- or second-generation EGFR TKIs or with primary EGFR T790M mutations. Each patient received SH-1028 tablets orally at 200 mg/d until disease progression or intolerable toxicity. Tumor response was evaluated every 6 weeks per the Response Evaluation Criteria in Solid Tumors, version 1.1. The primary end point was objective response rate by an independent review committee. The secondary end points were progression-free survival, overall survival (OS), disease control rate, safety, and so on. ResultsA total of 286 patients with EGFR T790M-positive advanced NSCLC were enrolled in this study, including 59 patients in part A (dose-verification study) and 227 patients in part B (second-line registration study). By data cutoff on September 17, 2021, the independent review committee–assessed objective response rate was 55.9% (95% confidence interval [CI]: 42.4–68.8) in part A and 60.4% (95% CI: 53.7–66.8) in part B. The median progression-free survival was 12.4 months (95% CI: 8.3–20.8) in part A and 12.6 months (95% CI: 9.7–15.3) in part B. The median OS was 26.0 months (95% CI: 23.3–not reached) in part A, and OS was immature in part B. Among the 286 patients, 44 of them experienced at least one grade 3 or higher treatment-related adverse event, with the most common ones as increased serum creatinine phosphokinase level (13 [4.5%]), diarrhea (six [2.1%]), and prolonged QT interval (three [1.0%]). Treatment-related skin rash was reported in 26 patients (9.1%), all grade 1 or 2. There was no interstitial lung disease reported in this study. ConclusionsSH-1028 is efficacious and tolerable in second-line treatment of patients with advanced NSCLC with positive EGFR T790M.

A lung adenocarcinoma patient with co-mutations of MET and EGFR exon20 insertion responded to crizotinib

BackgroundTargeted therapy has revolutionized the treatment of patients with malignancies harboring mutations in driver genes and has brought a favorable survival benefit to the population with actionable oncogenic mutations. In recent years, the MET exon14 skipping mutation has been recognized as a potentially promising therapeutic target in non-small cell lung cancer (NSCLC). These changes are mutually exclusive with molecular drivers such as EGFR, KRAS, HER-2, BRAF, ALK and ROS1. The prevalence rate of coexisting MET exon 14 mutations and EGFR sensitive mutations (L858R, exon 19 deletions) in Chinese population was reported to be 0.2% (3/1590). However, the coexistence of MET exon 14 mutations with EGFR exon 20 insertion mutations has never been reported and the management of this subtype is not identified.Case presentationA 69-year-old male with a right lung adenocarcinoma (T4N2M0, IIIB) was confirmed to be positive for MET exon 14 skipping (c.3028_3028+1delGGinsTT, 44.4%), MET amplification (copy number 4.4), and EGFR exon 20 insertion (p. N771_H773dup, 22.1%) mutations. After the progression of one cycle of chemotherapy (Pemetrexed 0.8 g d1), the patient was subsequently accepted treatment with Crizotinib (250 mg twice a day) and achieved an important clinical remission for six months until the development of brain metastases. Then, he was submitted to a cycle of anti-programmed cell death-1 (PD-1) therapy after failure of Crizotinib and eventually acquired resistance despite of the high expression of programmed death ligand-1 (PD-L1) and tumor mutational burden (TMB) status.ConclusionThis case report provides treatment strategies for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-untreated lung adenocarcinoma patients simultaneously carrying MET alterations and EGFR exon 20 insertion mutations. In addition, the signatures of PD-L1 or TMB expression were not the candidate for predicting the efficacy of immunotherapy in this context.

Abstract CT124: NeoCOAST-2: a randomized, open-label, phase 2 study of neoadjuvant durvalumab plus novel immunotherapies and chemotherapy (CT) followed by adjuvant durvalumab plus novel agents, in patients with resectable non-small-cell lung cancer (NSCLC)

Abstract Background: Neoadjuvant and adjuvant platinum-based CT improve survival rates in patients with resectable, early-stage NSCLC vs surgery alone. PD-1/PD-L1 inhibitors have shown clinical efficacy in patients with resectable, early-stage NSCLC, in both the neoadjuvant and adjuvant settings. The anti-PD-L1 monoclonal antibody (mAb) durvalumab, in combination with either the anti-CD73 mAb oleclumab or the anti-NKG2A mAb monalizumab, improved response rates and progression-free survival in patients with unresectable, Stage III NSCLC in the phase 2 COAST trial (NCT03822351). The NeoCOAST trial (NCT03794544) is currently evaluating the combination of durvalumab with oleclumab or monalizumab as neoadjuvant treatment in patients with resectable, early-stage NSCLC. NeoCOAST-2 (NCT05061550) is a multicenter study of neoadjuvant durvalumab combined with CT and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab, in patients with resectable, Stage IIA-IIIA NSCLC. Methods: Eligible patients must have previously untreated, histologically/cytologically confirmed NSCLC, a WHO/ECOG performance status of 0 or 1, and life expectancy of ≥12 weeks. Patients must have tumor samples available for biomarker analyses, have planned surgery consisting of lobectomy, sleeve resection, or bilobectomy, and have a pre- or post-bronchodilator FEV1 of 1.0 L and DLCO >40% postoperative predictive value. Patients with sensitizing EGFR mutations or ALK translocations, history of allogeneic organ transplantation, active or prior documented autoimmune or inflammatory disorders, or uncontrolled intercurrent illness, are excluded. Approximately 140 patients will be randomized 1:1, stratified by PD-L1 expression (<1% vs ≥1%), to receive IV durvalumab + oleclumab or monalizumab + CT Q3W for 4 cycles prior to surgery, followed by durvalumab + oleclumab or monalizumab Q4W post surgery. Surgery must occur within 40 days of the last dose of neoadjuvant therapy. Patients will receive adjuvant therapy starting within 10 weeks after surgery, for 12 cycles or until disease progression (per RECIST v1.1). The primary endpoints are pathological complete response rate per blinded independent pathologist review, and safety and tolerability. Secondary endpoints include investigator-assessed event-free survival and disease-free survival, feasibility of planned surgery, major pathological response rate, changes in circulating tumor DNA, investigator-assessed objective response rate following neoadjuvant therapy, overall survival, pharmacokinetics and immunogenicity. Citation Format: Tina Cascone, Alexander Spira, Rosario G. Campelo, Dong-Wan Kim, Oday Hamid, Yee Soo-Hoo, Rakesh Kumar, Italia Grenga, Patrick Forde. NeoCOAST-2: a randomized, open-label, phase 2 study of neoadjuvant durvalumab plus novel immunotherapies and chemotherapy (CT) followed by adjuvant durvalumab plus novel agents, in patients with resectable non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT124.

Survival benefits from afatinib compared with gefitinib and erlotinib among patients with common EGFR mutation in first-line setting.

BackgroundEpidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are recommended as first‐line treatment in non‐small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The sequential use of different EGFR‐TKIs has been reported to demonstrate improvement in overall survival of NSCLC patients with EGFR mutations. There are limited reports on comparisons between regimens with first‐line use of afatinib, gefitinib or erlotinib, followed by osimertinib upon disease progression with acquired T790M mutation.MethodsA retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first‐line gefitinib, erlotinib or afatinib treatment, followed by osimertinib upon disease progression with acquired T790M mutation, was conducted. The differences in overall survival (OS) and progression‐free survival (PFS) with first‐line EGFR‐TKI (PFS1) and time to second objective disease progression (PFS2) were compared among patients on different first‐line EGFR‐TKIs.ResultsAmong 155 patients, 101 (65.2%), 38 (24.5%) and 16 (10.3%) patients were on first‐line gefitinib, erlotinib or afatinib, respectively. Patients treated with afatinib in the first‐line setting had significantly longer OS compared with those on gefitinib or erlotinib, while the PFS1 and PFS2 were longer for patients on afatinib but did not reach statistical significance.ConclusionsFirst‐line afatinib, followed by osimertinib upon disease progression with T790M mutation, demonstrated significantly longer OS compared to that using other EGFR‐TKI in the first‐line setting.

Improved survival from early combined radiotherapy: A phase II clinical study and underlying mechanisms of delaying EGFR-TKI acquired resistance in patients with advanced lung cancer.

9114 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC). However, patients treated with EGFR-TKIs had a median progression-free survival (PFS) of only 8 to 18 months. The occurrence of acquired resistance greatly limits the survival benefit of TKI for NSCLC patients. Extensive efforts have been paid to find a well-tolerated drug or treatment that works before acquired resistance to EGFR-TKI with low toxicity. Focusing on clinical trials of targeted combination radiotherapy, we observed some encouraging results. Methods: Stage IV NSCLC patients with EGFR sensitive mutation (19DEL or 21L858R) have received first-line EGFR TKIs treatment and achieved stable disease or partial response have been enrolled in this prospective, multicenter, randomized controlled, phaseⅡstudy. Recruited from 4 hospitals in China, patients were divided into two groups: Stereotactic Body Radiation Therapy (SBRT) combined with TKIs group as the experimental and TKIs treatment group as an active comparator. The primary endpoint is PFS, and the secondary endpoint aims to overall survival (OS) and safety. To further confirmed these clinical observations in patients, xenograft experiments in nude mice were conducted. To examine the specific mechanism, transcriptome sequencing analysis was performed. Results: Between Mar 2015 and Mar 2018, A total of 61 patients who met the inclusion criteria were randomized to the TKI group and SBRT combined group. The median PFS of the TKI group and SBRT combined group were 9.0 vs 17.6 months (p = 0.016). Meanwhile, the median OS were 23.2 vs 33.6 months (p = 0.026). The total number of patients with T790m was 30(49.1%), and the incidence of T790M did not differ between the two groups. Toxicity data and subgroup analyses including different radiation sites will be presented at the conference. As for the xenograft experiments, data on tumor regression and time of drug resistance of early radiotherapy group was clearly superior to others. Transcriptome sequencing analysis found expression of c-Fos was the key point that led to the phenomena. Conclusions: The addition of SBRT significantly delayed the onset of EGFR TKIs acquired resistance and prolonged the PFS and OS of patients. Radiotherapy for the primary site alone might be superior to metastatic sites. Treatment-related adverse events were generally safe and controllable. The oncogenic role of c-Fos in the effect of radiotherapy on gefitinib resistance and promoting the proliferation of NSCLC cells is confirmed. Clinical trial information: NCT03595644.

EGFR mutation types and abundance were associated with the overall survival of advanced lung adenocarcinoma patients receiving first-line tyrosine kinase inhibitors.

BackgroundEpidermal growth factor receptor tyrosine kinases inhibitors (EGFR-TKIs) are currently recognized as the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. Clinically found patients with different EGFR mutational status have different prognosis.MethodsA retrospective cohort study was performed to explore the relationship between EGFR mutations and abundance with patient survival by using patient data from the Affiliated Cancer Hospital of Zhengzhou University between January 2013 and November 2016. All patients involved in the present study had sensitive EGFR mutations [either exon 19 deletion (DEL) or exon 21 L858R] and treated by EGFR-TKIs. They were followed up every three months until lost or dead. Mutation abundance was calculated as the copies of EGFR mutation divided by copies of EGFR locus, and the cut-off values for 19DEL and L858R were 4.9% and 9.5%, respectively.ResultsTotal of 236 patients were included, comprising 116 (49.2%) patients with 19DEL mutation and 120 (50.8%) patients with L858R mutation. The median follow-up duration was 23.2 months (95% CI: 14.9–26.7 months). Overall survival (OS) was significantly longer in patients with 19DEL mutation (20.9 months, 95% CI: 17.7–24.1 months versus 17.0 months, 95% CI: 14.4–19.6 months in patients with L858R; P=0.008) and in patients with high mutation abundance (20.9 months, 95% CI: 18.3–23.5 months versus 13.0 months, 95% CI: 10.3–15.7 months in patients with low mutation abundance; P<0.001). Multivariate Cox regression including age, performance status and tumor stage revealed that longer OS was independently associated with 19DEL mutation (HR: 0.48, 95% CI: 0.39–0.67, P=0.033) and high mutation abundance (HR: 0.62, 95% CI: 0.50–0.79, P=0.027).ConclusionsEGFR mutation types and abundance was associated with the patients’ survival which might be used to predict the efficacy of targeted therapy by EGFR-TKIs.

Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: A phase IIb, multicenter, single-arm, open-label study.

9098 Background: Rezivertinib (BPI-7711) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of Rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M mutated non-small cell lung cancer (NSCLC). Methods: Locally advanced or metastatic/recurrent NSCLC patients with histologic or cytologic or plasmatic confirmation of EGFR T790M mutations who progressed after first/second generation EGFR-TKIs therapy or primary EGFR T790M mutations were enrolled. Patients received Rezivertinib at 180mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review (BICR) per RECIST1.1. The efficacy for patients with central nervous system (CNS) metastases was measured by BICR according to the Response Assessment in Neuro-Oncology Brain Metastases. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Safety was assessed as per CTCAE 4.03. Results: A total of 226 patients were enrolled from Jul 5, 2019, to Jan 22, 2020. 91 (40.3%) patients had brain metastases. The tissue sample and plasma sample were positive for EGFR T790M in 120 (53.1%) and 116 (51.3%) patients, respectively. By the data cutoff date on Dec 23, 2021, the ORR by BICR was 64.6% (95%CI:58.0-70.8) and DCR was 89.8% (95%CI:85.1-93.4). The median DoR was 12.5 (95%CI:10.0-13.9) months and median PFS was 12.2 (95%CI:9.6-13.9) months. The median OS was 23.9 (95%CI:20.0-NC) months. Subgroup ORR: exon 19 deletion 72.4% (95%CI:64.4-79.5), L858R 51.9% (95%CI:40.4-63.3), tissue T790M positive 70% (95%CI:61.0-78.0), plasma T790M positive 56.9% (95%CI:47.4-66.1). Subgroup PFS: exon 19 deletion 12.4 (95%CI:8.8-15.1) months, L858R 10.3 (95%CI:8.3-13.9) months, tissue T790M positive 13.9 (95%CI:11.3-17.9) months, plasma T790M positive 9.6 (95%CI:7.0-11.0) months. Among 91 patients with CNS metastases, 29 patients had at least one brain target lesion whose CNS-ORR and CNS-DCR were 69.0% (95%CI:49.2-84.7) and 100% (95%CI:88.1-100), respectively. Time to progression of CNS was 16.5 (95%CI:9.7-NC) months. 188 of 226 (83.2%) patients had at least one adverse drug reaction, with the most common being white blood cell count decreased (27.9%), platelet count decreased (23.0%), anemia (22.6%). No interstitial lung disease was reported. Conclusions: Rezivertinib demonstrated promising efficacy and favorable safety for locally advanced or metastatic/recurrent NSCLC patients with EGFR T790M mutation. Clinical trial information: NCT003812809.

Low infiltration of CD8+ FOXP3+ T cells associated with favorable clinical outcomes after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma patients.

e21107 Background: As the standard first-line treatment for NSCLC patients with EGFR-sensitive mutation, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) were proved to be highly effective and less toxic compared to traditional chemotherapeutic regimens. But little is known about the correlation between tumor-infiltrating immune cells in the tumor microenvironment and clinical outcomes. This study was designed to investigate the association between tumor-infiltrating immune cells and the clinical outcome after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma (LUAD) patients. Methods: A total of 26 advanced LUAD patients with EGFR exon 21 mutation who received first-generation EGFR-TKIs as initial therapy between January 2017 and October 2019 were included in this study. All the patients were treated at Affiliated Dongguan Hospital, Southern Medical University, China. Patients who progressed within 12 months after first-line EGFR-TKIs therapy were defined as experiencing early progression (EP), and patients who progressed after 12 months or without progression were defined as experiencing late progression (LP). We analyzed immune markers in biopsy from these patients before treatment with EGFR-TKIs and examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD56/CD68/CD163/FOXP3/PD-L1 antibodies. Results: In this cohort, we observed that after first-line EGFR-TKIs therapy in EGFR exon 21 mutated LUAD patients, the density of CD8+ FOXP3+T cells infiltrated in tumor area of LP group was significantly lower than EP group (P = 0.038). However, the difference of the density of the other infiltrated immune cells including CD8+T cells, FOXP3+Treg cells, CD8+PD-L1+T cells, CD68+CD163+M2macrophages, etc., were not significant between LP group and EP group (P &gt; 0.05). The “optimal” cutoff value for CD8+ FOXP3+T cells infiltrated in tumor area was 5.45 (n/mm2) using the survminer package in R software according to PFS. Kaplan-Meier analysis suggested that the density of CD8+ FOXP3+T tell infiltrated in tumor area contributed to risk factor for PFS (HR = 5.56, P = 0.00054). Taking 5.45 (n/mm2) as the cutoff value, the percent of LP patients in low density of CD8+ FOXP3+T cells infiltrated in tumor area group was close to being statistically significant higher than high density of CD8+ FOXP3+T cells group (47% vs. 0%. P = 0.058). Conclusions: This study indicated that the low density of CD8+FOXP3+ T cells infiltrated in tumor area was associated with favorable clinical outcome in EGFR exon 21 mutated LUAD patients treated with first-generation EGFR-TKIs at first-line.

Platinum-free chemotherapy in the new era of immunotherapy: A phase II study of camrelizumab combined with apatinib and albumin paclitaxel in advanced non-squamous NSCLC (CAPAP-lung).

9034 Background: Cytotoxic chemotherapy and anti-angiogenic therapy may enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Platinum-containing dual-agent chemotherapy combined with ICIs is the standard first-line treatment for non-small cell lung cancer (NSCLC), however, the optimal combination regimen remains unclear. The adverse effects of platinum-based chemotherapy are relatively serious, whether platinum chemotherapy can be eliminated in the first-line treatment of non-small cell lung cancer is a hotspot and difficulty in current research. Based on these results, we initiated CAPAP-lung study, which is a single-arm, multicenter Phase II trial to evaluate the efficacy and safety of Camrelizumab in combination with apatinib and albumin paclitaxel without platinum as the first-line therapy for non-squamous non-small cell lung cancer. Methods: Patients diagnosed with ⅢB-IV non-squamous NSCLC without EGFR and ALK sensitive mutations received Camrelizumab (200mg/3w) in combination with Albumin Paclitacxel (135mg/m2, d1, d8/3w, 4-6 cycles) and Apatinib (250mg Qd po for 5 days, resting for 2 days every week). From August 2020 to February 2022, 54 of the planned 63 patients have been enrolled. The primary endpoint is progression-free survival(PFS), and secondary endpoints were overall survival (OS), duration of Response (DOR), objective response rate (ORR), and disease control rate (DCR) assessed by RECIST v1.1. This study is registered with ClinicalTrials.gov, NCT04459078 (follow-up is ongoing). Results: The data for a total of 38 patients out of 54 enrolled patients were evaluable. Median PFS was 10.97 mo (95%CI 7.1-NR).The objective response rate (ORR) and disease control rate (DCR) were 71.1% (27/38, 95%CI 53.9-84.0) and 97.4% (37/38, 95%CI 84.6-99.9), respectively. The incidence of grade 3 and worse treatment-related adverse events was acceptable, with grade 3 events in 25(46.3%) patients and grade 4 events in 3(5.6%) patients. The most common grade 3 treatment-related adverse events were decreased neutrophil count (8 [14.8%]), liver function damage (9 [16.7%]), rash (3 [5.6%]), and decreased white blood cell count (3 [5.6%]). Conclusions: Camrelizumab combined with albumin paclitaxel and apatinib showed encouraging antitumor activity with an acceptable safety profile for the first-line treatment of advanced lung adenocarcinoma. Clinical trial information: NCT04459078.

CtDNA dynamic detection reflects the clinical efficacy following treatment in NSCLC patients.

e15032 Background: EGFR is a major oncogene in non-small cell lung cancer (NSCLC) patients. Although EGFR tyrosine kinase inhibitors (TKIs) have effectively improved the survival of NSCLC patients, acquired drug resistance is a critical clinical challenge. Minimal residual disease (MRD) is the direct cause of tumor recurrence, and the abundance of circulating tumor DNA (ctDNA) can be used to reflect the status of MRD. We sought to identify the evaluation of effect of ctDNA on tumor therapeutic efficacy. Methods: Blood samples from 32 advanced NSCLC patients were dynamically collected at different timepoints (0, 4, 8, 12, months) with 1 sampling in 6 patients, 2 samplings in 15 patients, 3 samplings in 7 patients, 4 samplings in 3 patients, and 5 samplings in 1 patient. Targeted sequencing of 450 cancer-related genes were performed for genomic alteration identification at OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory in Shanghai, China. The average variant allele frequency of each sample was used to represent ctDNA abundance. Results: A total of 32 advanced NSCLC patients harboring EGFR sensitive mutations were enrolled in the study. Patients consisted of 12 (37.5%) males and 20 (62.5%) females, with a median age of 60 years old, ranged from 38 to 82 years old. These patients were randomly divided into TKI monotherapy group (N = 11) or TKI treatment combined with pemetrexed group (N = 21). The percentage of stable disease (SD) was more pronounced in patients receiving TKI combined with chemotherapy when compared to patients treated with TKI monotherapy (47.6% [10/21] vs. 36.4% [4/11], respectively). Less patients experienced the progression of disease (PD) when they were treated with TKI combined with chemotherapy than those receiving TKI monotherapy (52.4% [11/21] vs. 63.6% [7/11], respectively). For patients with PD, ctDNA abundance was progressively increased in 55.6% (10/18) during dynamic monitoring; whereas ctDNA abundance kept stable in 44.4% (8/18) patients, while 6/8 patients did not continue to perform ctDNA detection for more than half a year. In patients experienced SD, ctDNA abundance was declined in 78.6% (11/14) during dynamic monitoring, while 21.4% (3/14) patients displayed elevated ctDNA abundance. These 3 patients did not continue to perform ctDNA detection for more than 10 months. In majority of NSCLC patients (65.6% [21/32]), variation of ctDNA abundance was correlated to the treatment-induced clinical response. Conclusions: In conclusion, our results suggested that the variation of ctDNA abundance could promptly reflect the clinical response of treatment. The dynamic variation of ctDNA/MRD can possibly be considered as a biomarker of clinical efficacy following treatment in NSCLC patients.

Efficacy and safety of camrelizumab plus apatinib in previously treated patients with advanced non-small cell lung cancer harboring EGFR or ALK genetic aberration.

BackgroundCamrelizumab plus apatinib shows encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced non-small cell lung cancer (NSCLC); however, clinical benefits from this combination regimen in NSCLC patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) have not been reported. We assessed the efficacy and safety of this combined regimen in pretreated patients with advanced NSCLC and defined EGFR/ALK status (EGFR+/ALK+) in a phase 1b/2 trial.MethodsPreviously treated patients with advanced EGFR+/ALK+ NSCLC were enrolled and given camrelizumab 200 mg intravenously every 2 weeks plus apatinib at the recommended dose of 250 mg orally once daily. Patients harboring sensitive EGFR mutations or ALK fusion genes had received at least one EGFR/ALK TKI and a platinum-based chemotherapy regimen before the enrollment. The primary endpoint was objective response rate (ORR).ResultsAll 43 enrolled patients comprised the efficacy and safety analysis population. The confirmed ORR was 18.6% (95% CI: 8.4–33.4%) and the clinical benefit response rate was 27.9% (95% CI: 15.3–43.7%). Median progression-free survival (PFS) was 2.8 months (95% CI: 1.9–5.5 months) and median overall survival was not reached (95% CI: 7.3 months–not reached), with a median follow-up period of 15.7 months (range, 0.5–24.4 months). The most common grade ≥3 treatment-related adverse events (TRAEs) were hypertension (16.3%), proteinuria (11.6%) and palmar-plantar erythrodysaesthesia syndrome (9.3%). No unexpected adverse events were recorded.ConclusionsCamrelizumab plus apatinib showed moderate antitumor activity and acceptable safety profile in previously treated patients with advanced NSCLC and EGFR or ALK genetic aberrations, which warranted further validation.Trial RegistrationClinicalTrials.gov identifier: NCT03083041. Registered March 17, 2017.

Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study

IntroductionTo evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations. MethodsWe conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review. ResultsBetween January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700–1.060, 95% confidence interval: 0.531–1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm. ConclusionsThis study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.

Allele frequency and proportion defined by circulating tumor DNA profiling predict tyrosine kinase inhibitors' therapeutic outcomes for non-small cell lung cancer.

Circulating tumor DNA is more and more accessible for patients who cannot undergo biopsy. No consistent conclusion has been reached on whether frequency and proportion of mutations defined by ctDNA profiling can predict therapeutic outcomes. One hundred patients with non-small cell lung cancer harboring activating EGFR mutations (exon 19 deletion, L858R and T790M mutation) were collected in West China hospital from December 18, 2017 to December 31, 2019. We retrospectively analyzed the frequency and proportion distribution of ctDNA mutations and its relationship with tyrosine kinase inhibitors therapeutic outcomes. Patients with lower frequency of sensitizing EGFR mutations (< 3%) had a longer progression-free survival (PFS) time than those with higher frequency (15months vs. 10months, p = 0.028). Moreover, patients with the lower ratio of T790M mutation frequency and the maximum-somatic-allele-frequency (T790M/MSAF < 30%) had a less prolonged PFS than those with higher T790M/MSAF (7months vs. 15months, p = 0.013). The frequency and proportion of ctDNA mutations are worth clinical attention in the prediction of therapeutic outcomes.

Clinical Utility and Outcomes Impact of Crystal Digital PCR of Sensitizing and Resistance EGFR Mutations in Patients With Advanced Non-Small Cell Lung Cancer

BackgroundEGFRm represent 15% of advanced NSCLC in European patients. LB for molecular profiling offers a non-invasive alternative to tissue. cdPCR is a high-sensitive and low-cost LB to detect molecular alterations. We aimed to describe cdPCR clinical utility for EGFRm detection in advanced NSCLC. MethodsProspective blood sample collection in patients with advanced NSCLC harbouring EGFRm either at diagnosis, under response or at PD between January 16 and September 20 at Gustave Roussy. LB was performed by cdPCR (Stilla): sensitizing (exon19; exon21 [p.L858R]) and exon 20 p.T790M resistance EGFRm. We defined high tumour burden (high-TB) as >2 metastatic sites. We analysed EGFRm detection by cdPCR and its correlation with progression-free and overall survival (PFS, OS). ResultsA total of 252 blood samples were collected in 140 patients. At baseline (n=25), sensitizing EGFRm were detected in 64% of samples, 88% in patients with high-TB (n=8) and 40% among those with intracranial/intrathoracic isolated lesions (n=5). At PD to tyrosine-kinase inhibitors (TKI) (n=117), detection rate (sensitizing EGFRm) was 56%; 30% in patients with intracranial/thoracic isolated lesions (n=37) vs. 67% in those with high-TB (n=63). At PD to first/second generation TKI (n=81), the p.T790M mutation was found in 22% (18/81); detection rate was 9% for intracranial/thoracic (n=23) vs. 32% for high-TB (n=41) cases. The clearance of EGFRm allelic frequency was correlated with radiological response. The absence of EGFRm detection at TKI-failure was associated with longer OS (39.1 vs. 18.4 months; P=.02). ConclusionscdPCR is a sensitive LB for sensitizing and resistance EGFRm detection. cdPCR positivity was more likely observed in systemic PD cases with high-TB. It is a low-cost EGFRm detecting approach to guide treatment in NSCLC, however metastatic profile should be taken into account.

Research Progress in Immunotherapy of NSCLC With EGFR-Sensitive Mutations.

Lung cancer is a malignant tumor with high incidence and mortality across the world. The use of immune checkpoint inhibitors for lung cancer has improved the prognosis of some lung cancer patients to a greater extent and provided a new direction for the clinical treatment of lung cancer. Immunotherapy still has limitations in terms of its appropriate population and adverse reactions. Particularly for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation, there has been no major breakthrough in current immunotherapy. Whether immunotherapy can bring new benefits after drug resistance is induced by tyrosine kinase inhibitor-targeted therapy and whether the combination of immunotherapy with other treatments can improve the prognosis remain to be studied in depth. In this article, we provide a detailed review of the relevant characteristics of the tumor microenvironment of NSCLC with EGFR mutation and the current research on immunotherapy for NSCLC with EGFR mutation.

Efficacy of liquid biopsy for disease monitoring and early prediction of tumor progression in EGFR mutation-positive non-small cell lung cancer.

15–40% of non-small cell lung cancer (NSCLC) patients harbor epidermal growth factor receptor (EGFR)-sensitizing mutations. Tyrosine kinase inhibitors (TKIs) provide significant clinical benefit in this population, yet all patients will ultimately progress. Liquid biopsy can reliably identify somatic tumor-associated EGFR mutations in plasma. This study aimed to assess the feasibility and value of the quantitative assessment of EGFR driver mutations in plasma in EGFR-mutated NSCLC patients treated with EGFR-TKIs as a tool to evaluate therapeutic response to TKIs and monitor for disease progression. The study included 136 patients with tissue biopsy-confirmed EGFR-sensitizing, mutation-positive lung adenocarcinoma with plasma collected prior to TKI treatment and at least two post-initiation TKI treatment/follow-up blood samples. Plasma samples were tested with the cobas® EGFR Mutation Test v2 (cobas EGFR Test), and semi-quantitative index (SQI) values for each identified mutation were reported by the assay software. The most common baseline EGFR mutations detected in tissue were L858R (53.7%) and exon 19 deletion (39.7%). Plasma cell-free DNA analysis detected EGFR mutations in 74% of the baseline samples. Objective response rate by RECIST 1.1 was achieved in 72% of patients, while 93% had a molecular response (defined as disappearance of the EGFR mutation from plasma). 83% of patients had molecular progression (MP; 1.5X SQI increase or new T790M mutation), and 82% who had a clinical response had clinical progression. On average, MP occurred 42 days prior to clinical progression. Patients who progressed while on first-line TKI showed MP of the original EGFR-sensitizing mutations prior to the emergence of a T790M mutation, which was detected in 27% of the EGFR plasma-positive patients. Longitudinal monitoring of EGFR mutational load in plasma is feasible and can predict both response and clinical progression in EGFR-mutated NSCLC patients treated with EGFR-TKIs, as well as detect treatment-emergent EGFR mutations.

Variation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology

BackgroundGenomic alterations in 8 genes are now the targets of FDA-approved therapeutics in non-small cell lung cancer (NSCLC), but their distribution according to genetic ancestry, sex, histology, and smoking is not well established.MethodsUsing multi-institutional genetic testing data from GENIE, we characterize the distribution of targetable genomic alterations in 8 genes among 8675 patients with NSCLC (discovery cohort: DFCI, N = 3115; validation cohort: Duke, Memorial Sloan Kettering Cancer Center, Vanderbilt, N = 5560). For the discovery cohort, we impute genetic ancestry from tumor-only sequencing and identify differences in the frequency of targetable alterations across ancestral groups, smoking pack-years, and histologic subtypes.ResultsWe identified variation in the prevalence of KRASG12C, sensitizing EGFR mutations, MET alterations, ALK, and ROS1 fusions according to the number of smoking pack-years. A novel method for computing continental (African, Asian, European) and Ashkenazi Jewish ancestries from panel sequencing enables quantitative analysis of the correlation between ancestry and mutation rates. This analysis identifies a correlation between Asian ancestry and EGFR mutations and an anti-correlation between Asian ancestry and KRASG12C mutation. It uncovers 2.7-fold enrichment for MET exon 14 skipping mutations and amplifications in patients of Ashkenazi Jewish ancestry. Among never/light smokers, targetable alterations in LUAD are significantly enriched in those with Asian (80%) versus African (49%) and European (55%) ancestry. Finally, we show that 5% of patients with squamous cell carcinoma (LUSC) and 17% of patients with large cell carcinoma (LCLC) harbor targetable alterations.ConclusionsAmong patients with NSCLC, there was significant variability in the prevalence of targetable genomic alterations according to genetic ancestry, histology, and smoking. Patients with LUSC and LCLC have 5% rates of targetable alterations supporting consideration for sequencing in those subtypes.

122TiP Phase III study of durvalumab with SBRT for unresected stage I/II, lymph-node negative NSCLC (PACIFIC-4/RTOG 3515)

Stereotactic body radiation therapy (SBRT) is a standard treatment for pts with unresectable (UR) stage I/II, lymph-node negative NSCLC, with excellent safety and high rates of primary tumor control. Despite predominant regional and distant failure that increases with tumor size, no adjuvant therapy is approved for these pts. Durvalumab (D) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1/CD80. In the placebo (pbo)-controlled phase (ph) 3 PACIFIC trial of pts with stage III UR-NSCLC without progression on/after concurrent chemoradiotherapy, D improved PFS and OS with manageable safety (Antonia et al, 2017; 2018), leading to its approval in stage III UR-NSCLC. Osimertinib (O) is a 3rd-generation, irreversible CNS-active EGFR-TKI that selectively inhibits NSCLC tumors with EGFR-sensitizing mutations (EGFRm). In the recent pbo-controlled ph 3 ADAURA trial, O demonstrated statistically significant and clinically meaningful improvement in DFS (HR, 0.20 [99.12% CI, 0.14–0.30], P<0.001) in pts with resected stage IB-IIIA EGFRm NSCLC (Wu et al, 2020), leading to its approval in an adjuvant setting. Based on data for D and O in the early-stage setting, PACIFIC-4 is designed to assess the efficacy and safety of D combined with SBRT in pts with stage I/II UR-NSCLC and O after SBRT in pts with stage I/II EGFRm UR-NSCLC. PACIFIC-4 (NCT03833154) is an international ph 3 study with 2 independent cohorts. Eligible pts are ≥18 years with stage T1-T3, N0, M0 unresected NSCLC and ECOG PS 0–2. The main cohort of ∼630 pts will be randomized (1:1) in a double-blind manner, stratified by tumor size and location, to receive D (1500 mg IV) or pbo Q4W for up to 26 cycles with concurrent SoC SBRT. The primary endpoint in this cohort is PFS (BICR; RECIST v1.1); other endpoints include OS, health-related QoL and safety. The protocol was amended (v4) to exclude pts with an identified EGFRm from the main cohort and add a separate cohort of ∼60 pts with EGFRm (L858R or Ex19del) who will receive O 80 mg PO QD, following SoC SBRT, for up to 36 months. The primary endpoint in this cohort is 4-year PFS (ICR; RECIST v1.1); secondary endpoints include PFS, OS and safety. Trial recruitment is ongoing. NCT03833154. Medical writing support, under the direction of the authors, was provided by Nina Kratky of Ashfield MedComms (Manchester, UK), an Ashfield Health Company, and was funded by AstraZeneca. AstraZeneca.

7MO Oritinib (SH-1028) a third-generation EGFR tyrosine kinase inhibitor in locally advanced or metastatic NSCLC patients with positive EGFR T790M: Results of a single-arm phase II trial

Oritinib (SH-1028) is a third-generation EGFR-TKI selectively targeting both sensitive EGFR and EGFR T790M mutations. Herein, we report the efficacy and safety of oritinib in EGFR T790M-positive advanced NSCLC patients from the phase II study (NCT03823807). Eligible patients were locally advanced or metastatic NSCLC patients aged ≥ 18 years, with centrally confirmed EGFR T790M mutation. Patients with asymptomatic, stable CNS metastases were eligible into the study. Oritinib 200 mg was given orally once daily until disease progression or unacceptable toxicity. Primary efficacy endpoint was objective response rate (ORR). Secondary efficacy endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Between December 2019 and March 2021, 228 patients were enrolled and 227 patients received at least one dose of oritinib. The median age of 227 patients was 62 years old, 57.3% of patients were female and 24.7% received systemic chemotherapies. At data cutoff (September 17, 2021), 137 of 227 patients achieved confirmed partial responses with ORR of 60.4% (95% CI: 42.4%, 68.8%) by IRaC. The DCR was 92.5% (88.3%, 95.6%), the mPFS was 12.6 months (95% CI: 9.7, 15.3), the mDOR was 12.5 months (95% CI: 11.2, NA) and the mOS was immature. The most common (≥10%) treatment-emergent adverse events (TEAEs) included diarrhea (45.4%), increased blood creatine phosphokinase (26.0%), anaemia (20.3%), decreased white blood cell count (15.4%), decreased appetite (15.0%), increased blood creatine phosphokinase isoenzyme (13.2%), nausea (13.2%), vomiting (13.2%), increased serum creatine (12.8%), upper respiratory tract infection (12.3%), increased aspartate aminotransferase (11.9%), cough(11.9%), decreased platelet count (11.0%), constipation (10.6%). Grade≥3 TEAEs included increased blood creatine phosphokinase (4.0%), hypertension (3.1%), death (2.6%), diarrhea (2.2%). No interstitial lung disease were reported. Oritinib demonstrated potential clinical benefit and tolerable in advanced NSCLC patients with EGFR T790M mutation.

Rationale and design of a phase II trial of dacomitinib in advanced non-small cell lung cancer patients with uncommon epidermal growth factor receptor mutations: a prospective and single arm study (DANCE study)

BackgroundDacomitinib is a second-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). ARCHER-1050 showed that this agent can improve progression-free survival and overall survival in advanced non-small cell lung cancer patients with sensitive EGFR mutation compared to gefitinib. However, it is unclear whether dacomitinib is effective in patients with sensitizing uncommon EGFR mutations in exon 18–21. The aim of this study is to investigate the safety and efficacy of dacomitinib in these patients.MethodsThis is a single arm, prospective, open label and phase II trial. Sample size will be calculated by a minimax two-stage design method based on the following parameters: α = 0.075, 1-β = 0.9, P0 = 0.20, P1 = 0.45 and a dropout rate of 10%. A total of 30 eligible patients will be included. Patients will receive continuous oral therapy with dacomitinib (45 mg/day) until disease progression, withdrawal of consent, or unacceptable toxicity, whichever occurs first. The primary endpoint is objective response rate (ORR) per RECIST version 1.1, as assessed by investigators’ review. The second endpoint is disease control rate (DCR), PFS, OS, and safety.DiscussionWe conduct a single arm, phase II study to investigate the safety and efficacy of dacomitinib in advanced NSCLC patients with sensitizing uncommon EGFR mutations. The results of the DANCE study will provide new data regarding efficacy and safety of these patients.Trial registrationNCT04504071