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AZD9291, an irreversible inhibitor of epidermal growth factor receptor, was associated with tumor responses in the majority of patients with advanced non–small-cell lung cancer in whom T790M-mediated drug resistance to other EGFR tyrosine kinase inhibitors had developed. Somatic mutations in the gene encoding epidermal growth factor receptor ( EGFR ) are detected in approximately 30 to 40% of non–small-cell lung cancers (NSCLCs) from Asian patients and in 10% of NSCLCs from white patients. 1 – 3 EGFR mutations lead to constitutive activation of EGFR signaling and oncogenic transformation both in vitro and in vivo. 4 , 5 Cancers with EGFR mutations ( EGFR- mutated cancers) depend on EGFR signaling for growth and survival and are often sensitive to treatment with EGFR tyrosine kinase inhibitors. 6 Among patients with advanced EGFR- mutated NSCLC, treatment with EGFR tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, and . . .

Patients with non–small-cell lung cancer and mutated epidermal growth factor receptors who develop resistance to EGFR inhibitors through a particular mutation (T790M) are responsive to rociletinib. Increasingly, treatment decisions for patients with non–small-cell lung cancer (NSCLC) are based on the driver mutation rather than the histologic subtype, when such mutations are present. Mutations in the gene encoding epidermal growth factor receptor ( EGFR ) are among the most common oncogenic mutations in lung adenocarcinoma and are present in approximately 10 to 15% of Western patients and 30 to 35% of Asian patients. 1 At the time of diagnosis, approximately 90% of EGFR -mutation–positive patients have one of two activating mutations, an in-frame deletion in exon 19 or an L858R point mutation in exon 21. 1 The first-generation and . . .

Pyrotinib is an irreversible dual pan-ErbB receptor tyrosine kinase inhibitor developed for the treatment of HER2-positive advanced solid tumours. Based on positive results in a phase II trial, the drug recently received conditional approval in China for use in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer in patients previously treated with anthracycline or taxane chemotherapy. This article summarizes the milestones in the development of pyrotinib leading to this first global approval for the treatment of HER2-positive advanced breast cancer.

Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand–foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. Jiangsu Hengrui Medicine and National Key R&D Program of China. For the Chinese translation of the abstract see Supplementary Materials section.

Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466. Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39–56) patients in part B and 23 (64%; 46–79) in part D. The combination of osimertinib and savolitinib has acceptable risk–benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. AstraZeneca.

Background Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4–12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations. Methods Tumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib. Results EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0–12.9 months; range 4.9–14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented. Conclusions This study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

A mutation conferring resistance to novel irreversible EGFR inhibitors is identified in cell-free plasma DNA from lung cancer patients. Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.

Abstract Importance THP (trastuzumab + paclitaxel + pertuzumab) and THPy (trastuzumab + paclitaxel + pyrotinib) are widely used as first-line regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in China. However, direct comparative data on their efficacy and safety remain scarce. Objective To evaluate and compare the clinical outcomes of THPy and THP in the first-line treatment of HER2-positive MBC to guide clinical decision-making. Design Real-world, multicenter retrospective study conducted from 2020 to 2024. Setting Five large breast cancer centers in China. Participants A total of 145 patients with HER2-positive MBC were included before propensity score matching (PSM). After PSM, 76 patients (38 in each group) were analyzed. Intervention(s) or Exposure(s) Patients received either THP (trastuzumab + paclitaxel + pertuzumab) or THPy (trastuzumab + paclitaxel + pyrotinib) as first-line treatment. Main Outcome(s) and Measure(s) The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate, and safety profile. Results Before PSM, 145 patients were included, with the median follow-up of 9.4 months. The ORR was significantly higher in the THPy group (75.0%) compared to the THP group (56.8%; P = .023). Median PFS showed a trend favoring THPy (19.80 months vs 15.57 months; Log-rank P = .343). After PSM, 76 patients were matched, with the median PFS of 24.33 months versus 14.50 months for THPy and THP groups, respectively. Though the difference in PFS was not statistically significant (Log-rank P = .309), THPy demonstrated a higher ORR compared to THP (78.9% vs 57.9%; P = .048). Further subgroup analysis revealed greater benefits of THPy, particularly in patients with prior neoadjuvant therapy (hazard ratio [HR] = 0.261; 95% CI: 0.072-0.940). Regarding safety, THPy was associated with a higher incidence of grade 3/4 diarrhea (26.6% vs 3.1%) as well as increased rates of neutropenia, anemia, alanine aminotransferase elevation, fatigue, and peripheral neuropathy compared to THP. Conclusion and Relevance Both THP and THPy are effective first-line options for HER2-positive MBC. While THPy demonstrates a higher ORR and a trend toward longer PFS, it also carries a higher incidence of adverse events, particularly diarrhea. These findings offer preliminary insights that may help inform treatment decisions, pending further validation in prospective studies.

Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR -mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting. Osimertinib and dacomitinib are approved as first-line treatment of EGFR -mutant NSCLC but resistance can arise. Here, the authors use a computational model to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy that was confirmed tolerable and effective in an ongoing phase I clinical trial.

To evaluate the efficacy and safety of aumolertinib combined with pemetrexed and carboplatin as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation (exon 19 deletion or exon 21 L858R). In phase II trial (NCT04646824), patients received aumolertinib 110 mg once daily plus pemetrexed (500 mg/m2) and carboplatin (area under curve = 5) once every 3 weeks for 4 cycles, followed by maintenance aumolertinib (110 mg once daily) and pemetrexed (500 mg/m2 once every 4 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From November 2020 to October 2021, 34 patients were included for analysis. The median PFS was 28.0 months (95% CI, 18.7-36.9). The ORR was 91.2% (31/34), and the DCR was 100%. The median OS was not reached. Of 28 patients with circulating tumor DNA (ctDNA) testing, 22 (78.6%) showed clearance of EGFR mutation after 2 or 4 cycles. The median PFS was 31 months in patients with EGFR mutation clearance in ctDNA, and the ORR of them was higher than those without EGFR mutation clearance in ctDNA (90.9% vs 33.3%). The most common grade ≥ 3 treatment-related adverse event was decreased neutrophil count (22 [64.7%]). Aumolertinib plus chemotherapy shows potential as first-line treatment for patients with EGFR-mutant advanced NSCLC, which deserves to be investigated in randomized controlled trials. CtDNA clearance may be a prognostic marker.