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.

Penpulimab is a novel humanized IgG1 mAb that blocks PD-1 binding to PD-L1, engineered to eliminate FcγR binding and ADCC/ADCP completely. AK105-302 is a 1:1 randomized, double-blind, placebo-controlled, multicenter, phase III trial to compare penpulimab or placebo plus carboplatin and paclitaxel as first-line treatment for locally advanced or metastatic squamous NSCLC. The stratification factors included PD-L1 and gender. Eligible pts were randomized 1:1 to receive penpulimab 200 mg or placebo plus chemotherapy every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy until disease progression or 24 months, subjects in placebo group may choose to cross over to open-label penpulimab monotherapy for up to 24 months. The primary endpoints were PFS in the ITT population and in the PD-L1-positive population (TPS of PD-L1≥1%), assessed by an IRRC. The secondary endpoints were OS, ORR, DoR, DCR and TTR. 175 pts were assigned to penpulimab plus chemotherapy (P+C) and 175 to placebo plus chemotherapy (C). At data cutoff (Jun 1, 2022), the median follow-up was 23.56m. The mPFS by IRRC was significantly longer with P+C than with C (7.6m vs. 4.2m; HR 0.44, 95%CI: 0.34-0.56; p < 0.0001), 12m-PFS rate (37.1% vs. 9.2%) and 24m-PFS rate (23.8% vs. 5.9%) were significantly higher in P+C than C. In the PD-L1-positive population, the mPFS by IRRC was also significantly longer with P+C than with C (8.1m vs. 4.2m; HR 0.37, 95%CI: 0.27-0.51; p < 0.0001). The mOS of P+C was not reached, but the benefit trend was obvious (NR vs. 19.8m; HR 0.55, 95%CI: 0.40-0.75; p = 0.0002), 24m-OS rate (61.1% vs. 41.6%) were significantly higher in P+C than C. ORR by IRRC was 71.4% in P+C and 44.0% in C. Treatment with P+C was associated with more durable response (mDoR by IRRC: 8.25m vs 2.96m) than C. Grade ≥3 TRAEs occurred in 63.6% (P+C) vs. 62.9% (C). Serious TRAEs occurred in 28.3% (P+C) vs. 26.9% (C). TRAEs led to treatment discontinuation were 5.2% in P+C and 3.4% in C. These positive data will support penpulimab plus chemotherapy may be a promising and safe first-line treatment for locally advanced or metastatic squamous NSCLC.

Large-scale screening was needed to identify rare genetic mutations. However, overly restrictive inclusion and exclusion criteria limit patients for trial participation. Here, we reported a patient-centric study with parallel, multi-center, multi-cohort for the enrollment of untreated, advanced non-small cell lung cancer (NSCLC) with HER2 mutations.

Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), was shown in a global Phase 2 study to have potent overall and intracranial (IC) anti-tumor activity in patients with ALK-positive advanced non-small cell lung cancer (NSCLC) after progression on first- and/or second-generation ALK inhibitors (NCT01970865). Here we report primary data from a multicenter Phase 2 study conducted in China that investigated lorlatinib in ALK inhibitor-treated patients with ALK-positive NSCLC (NCT03909971).

Camrelizumab, a fully humanized monoclonal antibody against PD-1,has been approved in the treatment of advanced esophageal squamous carcinoma in China.The purpose of this study was to observe the efficacy and safety of Camrelizumab in the treatment of esophageal cancer in the real world. This is an open-label,prospective,multicenter, observational study. Eligible patients (pts) who received camrelizumab had esophageal cancer; age≥18, ECOG PS of 0-2; and measurable disease. From August 1, 2019 to May 1, 2020. 100 pts were enrolled. There are 80 (80.0%) males. The median age was 65.0 yrs. The majority pts were at stage IV 74(74.0%), had prior surgery 47(47.0%) and radiotherapy 61(61.0%). Pts with ECOG PS 1-2 were 85 (85.0%). Metastases were detected in 88 (88.0%) pts, which mainly were lymphatic metastasis.Pts received first-line treatment, second-line, third-line or above, respectively were 20.0%, 31.0%, 48.0%. Before immunotherapy, only one patient was tested for PD-L1. Pts received apatinib monotherapy or in combination with chemotherapy or antiangiogenictherapy,respectively were 9.0%, 39.0%, 36.0%. There were 49 patients eligible for efficacy evaluation .9 achieved partial response, 30 had stable disease and 10 got progressive disease. Thus, the objective response rate (ORR) and disease control rate (DCR) were 18.4% and 79.6%. The incidence of AEs was 55 (55.0%) and the grade 3/4 treatment-related AEs was 3 (3.0) %. Main AEs were RCCEP (18.0%), and fatigue (17.0%), anorexia (11.0%). The grade 3/4 treatment-related AEs were RCCEP (1.0%), hypothyroidism (1.0%) and anemia(1.0%). In real clinical applications, Camrelizumab is mostly used in patients with poor physical condition, metastatic and late stage, and most patients had front-line treatment.PD-L-1 detection is rarely performed in patients before medication, and most patients are treated with combination therapy of Camrelizumab.Camrelizumab is confirmed to be effective and safe in patients with esophageal cancer.Further analysis is needed to determine which factors are the positive factors in the treatment of Camrelizumab.

Epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism for resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKI). Osimertinib has been demonstrated to overcome EGFR T790M non-small cell lung cancer (NSCLC). However, most of these patients eventually developed resistance after 10 months. Here we performed a comprehensive next generation sequencing (NGS) using circulating tumor DNA (ctDNA) to study resistance mechanisms in patients with advanced NSCLC who had developed resistance to osimertinib, and to provide potential opportunities for treatment. 10 advanced NSCLC patients were enrolled in this study after progression from first-generation EGFR-TKI treatment. Patients received osimertinib with 80mg daily, the response rate and progression-free survival (PFS) was assessed during treatment. 10ml peripheral blood was collected from patients after progression from osimertinib, and ctDNA genotyping was performed by next-generation sequence (NGS). There were 3 patients received gefitinib and 7 patients received erlotinib before osimertinib therapy. All patients confirmed a partial response (PR) on osimertinib, the median PFS was 13.3 months. The initial gene mutation patterns before osimertinib therapy could be classified into two groups: L858R/Exon 19 Deletion (19Del) +T790M, and L858R/19Del+T790M unknown or wild-type. However, after progression from osimertinib, mutation patterns varied from groups. In the L858R/19Del+T790M group, two of six patients detected with L858R/19Del+T790M+C797S, two patients with L858R (+T790M) +HER2 amplification, and two patients with only 19Del+T790M; In the L858R/19Del+T790M unknown or wild-type group, there was only one patient detected with L858R/19Del+C797S mutation, the other three patients detected with only L858R mutation. For the C797S-mutated patients, it showed that T790M and C797S mutation presented in the same allele (cis) in two patients, while in both trans and cis in one patient. Other EGFR mutations were also detected, such as A750P, L792F, E709K, A1013V, L718V, and EGFR amplification. Genotyping of ctDNA in osimertinib resistant patients showed that the resistance might be related to specific gene mutation, e.g., EGFR C797S and HER2 amplification. Our findings provide insight that resistance to osimertinib might be different between T790M-mutated patients and T790M wilt-type patients. Combination therapy of osimertinib with other agents may be candidate to overcome the acquired mutation.