At present, the state has accelerated the accessibility of innovative overseas new drugs, but there is still a certain amount of time to wait for new drugs listed abroad to be listed in China, and overseas available drugs have always been a hot spot for the majority of cancer patients and their families. With reference to the official information of the FDA and CFDA, we have summarized the most comprehensive domestic unlisted tumor drug series for everyone, according to different cancer species, to provide reference for all oncologists and patients and their families! This article is a lung cancer article.
1. Sotorasib (Sotolasibu AMG510)
Product name: Lumakras
Manufacturer: Amgen
Listing time: February 2020 (Hong Kong)
Packing specification: 100mg× 240 tablets
Indications: For the treatment of patients with KRAS G12c mutation who have undergone at least one systemic therapy in patients with non-small cell lung cancer (NSCLC).
Application: 960 mg once a day.
KRAS is a common driver gene for tumors, occurring in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and more than 30% of lung adenocarcinomas. However, because there is no pocket on the surface of the KRAS protein suitable for small molecule inhibitor binding, the development of small molecule drugs that target KRAS has not had a major breakthrough in nearly 40 years. At the 2019 ASCO Conference, AMG510 successfully broke the ice, and the Phase I study results surprised the audience, bringing a historic moment to KRAS targeted therapy.
In August 2018, the drug was registered in ClinicalTrials in clinical phase I trial (NCT03600883) and achieved good results in less than a year, disclosing gratifying data at the 2019 American Association for Cancer Research Annual Meeting (AACR) and the American Clinical Oncology Annual Conference (ASCO);
Obtained FDA approval for orphan drugs for the treatment of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) on May 1, 2019 and May 23, 2019, respectively;
On March 9, 2020, the official website of the CDE (State Food and Drug Administration) was updated, and the clinical application for the KRAS G12C inhibitor AMG 510 developed by Amgen was undertaken by the Drug Review Center;
On December 9, 2020, AMG510 2-line treatment KRAS G12C mutation NSCLC was recognized by the FDA as a breakthrough therapy and submitted a marketing application on the 16th of that month.
The AMG510 was unveiled at the 2020 ASCO, WCLC and ESMO Conferences. The results of the Phase I study showed that the total ORR (objective response rate) and DCR (disease control rate) of 96% were 48% in patients treated with NSCLC (non-small cell lung cancer) with KRAS mutations. In 13 patients with NSCLC who received the dose of 960 mg of AMG 510, the ORR was 54% and the DCR was 100%. The CRR in patients with KRAS mutant colorectal cancer reached 79%.
On May 29, 2021, Sotorasib (AMG-510, trade name: Lumakras) received accelerated FDA approval for the treatment of patients with KRAS G12c mutation who have undergone at least one systemic therapy in patients with non-small cell lung cancer (NSCLC). This is the world's first targeted drug for KRAS, which is of landmark significance!
The approval is based on CodeBreak 100 research data. The latest data from the CodeBreaK 100 study showed that after a median follow-up of 12.2 months, a total of 46 participants in 124 patients with previously received chemotherapy and/or immunotherapy disease progression KRASG12C mutation NSCLC who had previously received chemotherapy and/or immunotherapy achieved confirmed response, including 3 complete responses and 43 partial responses, and the sotorasib group achieved an objective response rate (ORR) of 37.1%. The objective median response time was 1.4 months, the median duration of response was 10 months, and 43% of patients who responded received continued treatment and did not progress to the disease. The disease control rate was 80.6% and the median progression-free survival (PFS) was 6.8 months.
About 3% of bowel cancer patients are accompanied by KRAS mutations, and data presented at the 2021 ESMO World GI conference show that AMG510 (Sotorasib) treats bowel cancer patients with KRAS G12C mutations, with an ORR of 7.1%, a DCR of 73.8%, and a median PFS of 4 months, both secondary and primary resistance.
2. Capmatinib (carmatinib)
Product name: Tabrecta
Manufacturer: Novartis
Listing time: May 2020 (US)
Packing specification: 56 tablets/bottle
Indications: LUNG CANCER WITH MET14 mutation is currently one of the most effective drugs with MET14 mutation.
Application: 400 mg 2 times a day.
Carmatinib (INC280) is a highly selective type Ia MET inhibitor orally and the first FDA-approved targeted therapy drug (2020.5) for METex14 metastatic NSCLC approved for the treatment of metastatic NSCLC patients with MET exon 14 jump mutations, including first-line (initial) patients and patients who have previously received treatment (treatment). The approval is based on the results of the Phase II GEOMETRY mono-1 study. The study was a prospective, non-randomized, open-label Phase II study enrolling a total of 94 adults with advanced or metastatic NSCLC carrying a META exon 14-jump mutation, with an overall response rate of 68% for first-line treatment with cabatinib assessed by a double-blind Independent Review Committee (BIRC), an ORR of 48% for patients who had previously received one treatment regimen, and ANR of 41% for METex14 patients who had previously undergone more than two regimens. The median duration of response was 12.6 months and 9.7 months, respectively. The results showed that Capmatinib delivered significant therapeutic effects regardless of whether the patient had previously received treatment (first- and posterior). But progression-free survival (PFS) is not particularly long, only about 4 months, so we are also looking forward to more data on the drug.
The 2021 ASCO Conference reported 160 NSCLC patients including untreated METex14NSCLC patients (groups 5b and 7) and patients who had previously received 1L or 2L treatment (extended groups 6 and cohort 4). The ORR of the extended queue 7 is 65.6%, the median PFS is 10.8 months, and the median OS is not yet mature. Cohort 5b group, ORR was 67.9%, OS was 20.8 months, and median PFS was 12.4 months. Carmatinib was treated with a treated MET14 jump mutation with an ORR of 40.6% and an OS of 13.6 months. Therefore, first-line treatment with carmatinib can be more beneficial.
In addition, carmatinib also shows a good intracranial response. In the GEOMETRY mono-1 trial, 13 patients with neuroradiological data, 92% had intracranial metastases, and 54% showed a good intracranial response (31% showed complete remission). In all patients receiving carmatinib treatment, the most common AE (any cause; ≥20%) is peripheral edema, nausea, vomiting, increased serum creatinine, dyspnea, fatigue and loss of appetite.
3. Tepotinib Tepotinib (TEPMETKO®)
Product name: Takeda
Manufacturer: Merck
Time to Market: February 3, 2020 (FDA)
Packing specification: 250mg×60
Indications: For the treatment of patients with unresectable, advanced MET exon 14 jump mutation, or recurrent non-small cell lung cancer.
Application: 500 mg once a day, orally after a meal
Tepotinib (tepotinib) is an oral, highly selective IB-type MET inhibitor that has been approved in the United States and Japan. On February 3, 2021, the FDA accelerated approval of Tepotinib for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) carrying METAtomon 14 (METex14) jump mutations. The NCCN V4 guidelines also upgrade Tepotinib to a first-line priority recommendation for late-stage MET14 mutation NSCLC.
The approval of the drug was based on the results of the Phase II VISION trial, a prospective, non-randomized, open-label Phase II study that included a total of 152 patients with advanced or metastatic NSCLC with MET exon 14-hop reading, given Tepotinib (500 mg/day) per day. The Independent Review Committee (BIRC) identified 43% (95% CI, 32-56) of meTex14NSCLC patients with untreated ORR and mDOR of 10.8 months (95% CI, 6.9 months - NE); treated METex14NSCLC patients with ORR of 43% (95% CI, 33-55%) and mDOR 11.1 months (95% CI, 9.5-18.5 months). The most common adverse reactions (any cause; ≥20%) are edema, fatigue, nausea, diarrhea, increased serum creatinine, musculoskeletal pain and difficulty breathing.
The 2021 ELCC Conference updated efficacy data for cohort A (MET14 exon-jumping mutation population) in the VISION Phase II study. Among the 152 patients, the ORR treated with tepotinib reached 44.7%, of which the ORR of the initial and treated patients was similar (both 44.9%). The median DOR of the total population was 11.1 months, and the data were similar for the initial and treated populations (10.8 months and 11.1 months), and the median PFS was 8.9 months (8.5 months for treatment and 10.9 months for treatment). Patients with intracranial metastases had an ORR of 47.8%, a median DOR of 9.5 months, and a median PFS of 9.5 months. In terms of safety, it is important to note that Tepotinib also reported interstitial lung disease in about 4% of patients.
4、Rybrevant（amivantamab-vmjw）
Common name: amivantamab-vmjw
Product Name:Rybrevant
Full name: Rybrevant, amivantamab-vmjw
Manufacturer: Janssen Biotech, Inc.
Package size: 350 mg/7 mL (50 mg/mL)/bottle/box, a sterile, preservative-free, colorless to pale yellow IV solution.
Indications:
RYBREVANT is a bispecific antibody that directly targets the EGF receptor and the MET receptor for the treatment of adult patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutations in locally advanced or metastatic non-small cell lung cancer (NSCLC), whose disease has been tested with FDA approval and whose disease has developed chemotherapy on or after platinum drugs.
Dosage:
The recommended dose of RYBREVANT is based on baseline body weight, diluted and administered as an intravenous infusion.
Administer prescription drugs as recommended. It is managed via the peripheral line in weeks 1 and 2. RYBREVANT is administered weekly for 4 weeks, with a large-dose infusion of the initial dose starting at the 1st week of day 1 and day 2, followed by every 2 days, and several weeks thereafter. Diluted RYBREVANT is injected intravenously according to the infusion.
Adverse reactions:
The most common adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation and vomiting. The most common grade 3 or 4 laboratory abnormalities (≥2%) are lymphopenia, albumin reduction, phosphate reduction, potassium reduction, alkaline phosphatase increase, increased glucose, γ-glutamyl transferase increase, and sodium decrease.
Contraindications: None.
Notes:
Infusion-related reaction (IRR): Interrupt the infusion at the first sign of IRR. Reduce the infusion speed or permanently terminate RYBREVANT depending on the severity.
Interstitial lung disease (ILD)/pneumonia: monitoring indicates new or worsening symptoms of ILD. Immediately stop hospitalized patients with RYBREVANT suspected of having ILD/pneumonia, and permanently terminate treatment if ILD/pneumonia is confirmed.
Skin adverse reactions: may cause a rash, including acne-like dermatitis and toxic epidermal necrolysis. Discontinuation of the drug, reduction or permanent termination of RYBREVANT depending on the severity.
Ophthalmic toxicity: patients with worsening ocular symptoms are promptly referred to an ophthalmologist. Discontinue, reduce the dose or discontinue RYBREVANT permanently depending on the severity.
Embryonic-fetal toxicity: can cause fetal injury. Women at risk of potential fetal reproduction are recommended and use effective contraceptive methods.
Use in specific populations
Lactation: breastfeeding is not recommended.
Storage:
Place it in a refrigerator of 2 °C to 8 °C (36 °F to 46 °F) in the original carton to store away from light.
Mechanism of action:
Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET.
In in vitro and in vivo studies, amivantamab-vmjw is able to disrupt EGFR and MET signaling functions by blocking ligand binding and disrupting EGFR and MET in exon 20 insertion mutation models. The presence of EGFR and MET on the surface of tumor cells also allows these cells to be destroyed by immune effector cells (e.g., natural killer cells and macrophages) by antibody-dependent cytotoxicity (ADCC) and phototoptytic mechanisms, respectively.
Safety & Efficacy:
In a study of 81 patients with non-small cell lung cancer and EGFR exon 20 insertion mutations, the researchers evaluated the efficacy of Rybrevant, all of whom were advanced patients who progressed after platinum-based chemotherapy. The findings showed: the overall response rate was 40%; the median response time was 11.1 months; 63% of these patients had a response time of 6 months or more.
Clinical data:
1. On May 21, 2021, the FDA accelerated the approval of EGFR/c-Met double antibody Rybrevant (amivantamab-vmjw, JNJ-6732) developed and produced by Johnson & Johnson for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations that progress after platinum chemotherapy. This is the first FDA-approved drug to target this type of mutation. In addition to treating 20ins, amivantamab is also superior in addressing osimertinib resistance as well as covering EGFR targets across the board!
The approval is based on positive results from the amivantamab monotherapy cohort of the Phase I CHRYSALIS study, which included a total of 81 lung cancer patients with EGFR 20ins who had previously received first-line platinum-based chemotherapy, all of whom received Amivantamab after disease progression. Patients with a body weight < 80 kg received a dose of 1050 mg, and patients with a body weight ≥ 80 kg received a dose of 1400 mg. After a median follow-up of 9.7 months, the objective response rate (ORR) was 40%, of which the complete response rate was 4%, the partial response rate PR was 36%, and the median response time DoR was 11.1 months. The clinical benefit rate (defined as complete or partial remission or disease stabilization in at least two disease evaluations) was 74%.
2. Launch a Phase 3 clinical trial of EGFR/MET double anti-amivantamab (R&D code: JNJ-61186372) in China to evaluate the efficacy of amifantamab and the third-generation EGFR-TKI drug laziertinib in the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations.
In March 2020, Janssen Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) granted JNJ-61186372 (JNJ-6372) breakthrough therapy designation for the treatment of patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutations in metastatic non-small cell lung cancer (NSCLC) whose disease progressed in platinum chemotherapy or after). It is a milestone in the field of lung cancer treatment.
The breakthrough therapy designation is based on data from a Phase 1, first-of-its-kind, non-blind, multicenter trial (NCT02609776). The trial evaluated the safety, pharmacokinetics and preliminary efficacy of JNJ-6372 monotherapy and combination with lazirtib (a novel third-generation EGFR TKI) in the treatment of advanced NSCLC in adults.
5. Necitumumab (nexitozumab)
Product name: Portrazza
Manufacturer: Eli Lilly
Time to Market: November 24, 2015 (FDA)
Packing specification: 800mg/50ml
Indications: in combination with gemcitabine and cisplatin, for first-line treatment in patients with metastatic squamous non-small cell lung cancer. Not suitable for the treatment of non-squamous non-small cell lung cancer.
Directions of use: The recommended dose is 800 mg (absolute dose) every 3 weeks for 1 course of intravenous infusion for more than 60 minutes on days 1 and 8, before gemcitabine and cisplatin, until the disease progresses or an unacceptable toxic reaction occurs.
The most common form of lung cancer is non-small cell lung cancer (NSCLC), of which squamous NSCLC accounts for about 30% of NSCLC. Lung squamous cell carcinoma is currently dominated by chemoradiation and chemotherapy, and there are few targeted drugs. Portrazza (Necitumumab) is a recombinant human lgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR), thereby blocking the binding of EGFR to its ligands.
In vitro assays, Necitumumab induces internalization and degradation of EGFR and triggers antibody-dependent cytotoxicity (ADCC) effects in EGFR-expressing cells. In vivo studies, using human tumor xenograft models, including non-small cell lung cancer models, it was found that giving Necitumumab to mice increased the antitumor activity of gemcitabine and cisplatin combined with gemcitabine and cisplatin alone.
Eli Lilly initially conducted 2 phase III clinical trials of necitumumab in non-small cell lung cancer (NSCLC), including one phase III SQUIRE trial in the squamous NSCLC population and another phase III INSPIRE trial in the nonsquamous NSCLC population. In early 2011, Lilly and BMS discontinued the INSPIRE trial because some patients in the necitumumab treatment group experienced thromboembolism. The trial in patients with squamous NSCLC was allowed to proceed, and later, the BMS terminated the necitumumab collaboration and returned full rights to Lilly.
On November 24, 2015, the U.S. Food and Drug Administration (FDA) approved Portrazza (necitumumab) in combination with gemcitabine and cisplatin for the treatment of advanced squamous non-small cell lung cancer (NSCLC).
Portrazza was approved based on a randomized phase III study, SQUIRE, conducted specifically in a population of metastatic squamous lung cancer, in which patients were randomized to receive gemcitabine plus cisplatin + NECITU monoclonal antibody (study group, n=545)/placebo (control group, n=548). The NECITU dosing regimen is 800 mg every 1 and 8 days of 3 weeks. Gemcitabine administration regimens of 1250 mg/m2 on days 1 and 8 and 75 mg/m2 for cisplatin on day 1 were administered in both groups. Patients who responded in the study group continued to receive the monotherapy NECITU monoclonal antibody.
The basic characteristics of patients are similar between the two groups. The median age was 62 years, the main patient was white (84%), the vast majority had a history of smoking (91%), and the most common metastase was the lungs (83%). The primary endpoint of the study was OS, and the secondary endpoint was PFS and objective response rate (ORR).
The results showed that after nearly 25 months of follow-up, the median OS study group vs. control group (the same below) was 11.5 months vs. 9.9 months (HR=0.84; 95% CI 0.74-0.96; P=0.012). 1-year OS rate: 48% vs. 43%; 2-year OS rate: 20% vs. 17%.
Median PFS: 5.7 months vs. 5.5 months (HR=0.85; 95%CI 0.74-0.98; P=0.02); 6-month PFS rate: 45% vs. 37%.
ORR: 31% vs. 29% (P=0.40); disease control rate (ORR + disease stabilization): 82% vs. 77% (P=0.043); median treatment failure time: 4.3 months vs. 3.6 months.
The incidence of adverse events (AE) of grade 3 and above was 72% vs. 62%. The study group had significant increases in grade 3 or above AE: hypomagnesemia (9% vs. 1%), rash (4% vs. <1%), and venous thrombosis (5% vs. 3%).
Incidence of severe AE: 48% vs. 38%. AE leads to a 31% vs. 25% incidence of treatment interruption. Mortality after AE: 12% vs. 11%.
The results of the SQUIRE study of molecular marker exploration showed that patients with stage IV lung squamous cell carcinoma with EGFR expression (immunohistochemical method check for at least one positive cell, EGFR>0) could benefit from necitumumab, while patients without EGFR expression (EGFR=0) subgroup did not have a significant clinical benefit.
At present, the treatment options for advanced squamous cell carcinoma are very limited, and the combined application of necitumumab therapy can improve the survival rate of patients with squamous cell carcinoma, which is of great significance for the treatment of tumors in the future.
Disclaimer: The information contained in this material is for informational purposes only, please follow the advice or guidance of a doctor or other healthcare professional.