Erlotinib Hydrochloride

Median overall survival not yet reached with projected improvement of more than one year versus osimertinib RARITAN, N.J., March 26, 2025 /PRNewswire/ -- Johnson & Johnson (NYSE:JNJ) today announced results for the gold standard endpoint in cancer treatment of overall survival (OS) from the Phase 3 MARIPOSA study. Head-to-head comparison data versus osimertinib showed RYBREVANT® (amivantamab-vmjw) plus LAZCLUZE™ (lazertinib) significantly extended OS in the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution mutations. Median OS is projected to exceed one year beyond the median of three years observed with osimertinib and has not yet been reached. This is the first and only study to show a statistically significant and clinically meaningful OS improvement over osimertinib. New compelling data were presented during a proffered paper session at the 2025 European Lung Cancer Congress (ELCC) (Abstract #4O).1 "The survival curve tells a clear story. RYBREVANT plus LAZCLUZE helps patients live longer, and the benefit keeps growing over time," said trial investigator Professor Nicolas Girard*, M.D., Ph.D., Head of Medical Oncology, Institut Curie, and Professor of Thoracic Oncology and Respiratory Medicine at the Paris-Saclay University, France. "We see the gap between the survival curves continue to widen, which is exactly what we want to see in lung cancer treatment to improve outcomes for patients. These results reinforce that we are entering a new era for EGFR-mutated non-small cell lung cancer; with this evidence in hand, we need to ensure every patient gets the most effective treatment in the first line for the best possible chance at longer survival." Unlike progression-free survival (PFS), which tracks the time a treatment keeps a patient's cancer from progressing, OS helps patients understand the impact therapy could have on the ability to live longer from the start of treatment. Extending life expectancy is the most meaningful indicator of a treatment's impact. At a median follow-up of 37.8 months, patients treated with the chemotherapy-free regimen of first-line RYBREVANT® plus LAZCLUZE™ had a significantly longer OS compared to those receiving osimertinib (hazard ratio [HR], 0.75; 95 percent confidence interval [CI], 0.61-0.92; nominal P<0.005). Median OS for RYBREVANT® plus LAZCLUZE™ has not yet been reached, indicating that survival benefits continue to extend beyond the measured follow-up period (not reached [NR]; 95 percent CI, 42.9-NR). Comparatively, median OS for osimertinib-treated patients was 36.7 months (95 percent CI, 33.4-41.0) and consistent with prior studies with osimertinib. Fifty-six percent of patients treated with RYBREVANT® and LAZCLUZE™ were alive at three and a half years compared to 44 percent of patients on osimertinib. Projections based on survival data suggest RYBREVANT® plus LAZCLUZE™ could extend median OS by at least 12 months compared to osimertinib.1 The RYBREVANT® combination also prolonged multiple secondary endpoints vs osimertinib, including intracranial PFS, intracranial duration of response (DOR) and intracranial overall response rate (ORR). Notably, RYBREVANT® plus LAZCLUZE™ prolonged time to symptomatic progression (TTSP) – the time from treatment randomization to the onset of lung cancer symptoms – by more than 14 months compared to osimertinib (43.6 months vs 29.3 months; HR, 0.69; 95 percent CI, 0.57–0.83; nominal P<0.001). This is a key patient-centered measure, highlighting how long quality of life can be preserved before lung cancer symptoms emerge.1 "Right now, only twenty percent of patients with EGFR-positive NSCLC survive beyond five years. These MARIPOSA results suggest that RYBREVANT plus LAZCLUZE can change this dire statistic that has been stagnant for far too long," said Joshua Bauml, M.D., Vice President, Lung Cancer Disease Area Stronghold Leader, Johnson & Johnson Innovative Medicine. "This regimen isn't just extending survival, it's offering hope. By using RYBREVANT plus LAZCLUZE first, we're delaying the need for chemotherapy and giving patients and their families more time." The safety profile of RYBREVANT® plus LAZCLUZE™ was consistent with the primary analysis, with adverse event (AE) rates comparable to other RYBREVANT® regimens. No new safety signals were identified with the additional longer-term follow-up. Most AEs occurred early during RYBREVANT® and LAZCLUZE™ treatment.1 RYBREVANT® research findings suggest that implementing prophylactic measures during the first four months of RYBREVANT® and LAZCLUZE™ treatment may significantly reduce the risk of skin reactions, infusion-related reactions and venous thromboembolic events.2,3,4 The MARIPOSA study met its primary endpoint in October 2023, showing a statistically significant and clinically meaningful improvement in PFS compared to osimertinib. RYBREVANT® plus LAZCLUZE™ is approved in the United States, Europe and other markets around the world for patients with first-line EGFR-mutated NSCLC. These OS results will be shared with health authorities globally. About the MARIPOSA Study MARIPOSA (NCT04487080), which enrolled 1,074 patients, is a randomized, Phase 3 study evaluating RYBREVANT® in combination with LAZCLUZE™ versus osimertinib and versus LAZCLUZE™ alone in first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or substitution mutations. The primary endpoint of the study is PFS (using RECIST v1.1 guidelines**) as assessed by BICR. Secondary endpoints include OS, ORR, DOR, PFS2 and intracranial PFS.5 About RYBREVANT® RYBREVANT® (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S., Europe and other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.6 RYBREVANT® is approved in the U.S., Europe and other markets around the world in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. RYBREVANT® is approved in the U.S., Europe and other markets around the world in combination with LAZCLUZE™ (lazertinib) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. RYBREVANT® is approved in the U.S., Europe and other markets around the world in combination with chemotherapy (carboplatin-pemetrexed) for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR TKI. In February 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of SC amivantamab and LAZCLUZE™ in Europe for the first-line treatment of adult patients with advanced NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, and as a monotherapy for the treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy. The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC§ prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include: Amivantamab-vmjw (RYBREVANT®) plus lazertinib (LAZCLUZE™) as a Category 1 recommendation for first-line therapy in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.7†‡ Amivantamab-vmjw (RYBREVANT®) plus chemotherapy as a Category 1 recommendation for patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.7†‡ Amivantamab-vmjw (RYBREVANT®) plus chemotherapy as a Category 1 recommendation for first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC.7†‡ Amivantamab-vmjw (RYBREVANT®) as a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.7†‡ In addition to the Phase 3 MARIPOSA Study, RYBREVANT® is being studied in multiple clinical trials in NSCLC, including: The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT® (with or without LAZCLUZE™) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations after disease progression on or after osimertinib.8 The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT® in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.9 The Phase 3 PALOMA-3 (NCT05388669) study assessing LAZCLUZE™ with subcutaneous (SC) amivantamab compared to RYBREVANT® in patients with EGFR-mutated advanced or metastatic NSCLC.10 The Phase 2 PALOMA-2 (NCT05498428) study assessing SC amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.11 The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of SC amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for SC amivantamab delivery.12 The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT® in patients with advanced NSCLC.13 The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT® in combination with LAZCLUZE™ and LAZCLUZE™ as a monotherapy in patients with advanced NSCLC with EGFR mutations.14 The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT® and capmatinib combination therapy in locally advanced or metastatic NSCLC.15 The Phase 1/2 swalloWTail (NCT06532032) study assessing RYBREVANT® and docetaxel combination therapy in patients with metastatic NSCLC.16 The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT® and cetrelimab combination therapy in locally advanced or metastatic NSCLC.17 The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT® in combination with LAZCLUZE™ in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.18 The Phase 2 COPERNICUS (NCT06667076) study combining developments in treatment administration and prophylactic supportive care in representative US patients with common EGFR-mutated NSCLC treated with SC amivantamab in combination with LAZCLUZE™ or chemotherapy.19 The Phase 2 COCOON (NCT06120140) study assessing the effectiveness of a proactive dermatologic management regimen given with first-line RYBREVANT® and LAZCLUZE™ in patients with EGFR-mutated advanced NSCLC.20 For more information, visit: https://www.RYBREVANT.com. About LAZCLUZE™ In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of LAZCLUZE™ (marketed as LECLAZA in South Korea). LAZCLUZE™ is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild-type EGFR. An analysis of the efficacy and safety of LAZCLUZE™ from the Phase 3 LASER301 study was published in The Journal of Clinical Oncology in 2023.21 About Non-Small Cell Lung Cancer Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.22,23 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.24 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.25 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.22,23,26,27,28,29 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.30 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent.31,32 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.33 Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.34 IMPORTANT SAFETY INFORMATION6,35 WARNINGS AND PRECAUTIONS Infusion-Related Reactions RYBREVANT® can cause infusion-related reactions (IRR) including anaphylaxis; signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The median time to IRR onset is approximately 1 hour. RYBREVANT® with LAZCLUZE™ RYBREVANT® in combination with LAZCLUZE™ can cause infusion-related reactions. In MARIPOSA (n=421), IRRs occurred in 63% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 5% and Grade 4 in 1% of patients. The incidence of infusion modifications due to IRR was 54% of patients, and IRRs leading to dose reduction of RYBREVANT® occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT® occurred in 4.5% of patients receiving RYBREVANT® in combination with LAZCLUZE™. RYBREVANT® with Carboplatin and Pemetrexed Based on the pooled safety population (n=281), IRR occurred in 50% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed, including Grade 3 (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT® due to IRR. RYBREVANT® as a Single Agent In CHRYSALIS (n=302), IRR occurred in 66% of patients treated with RYBREVANT®. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT® due to IRR. Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT® as recommended. Administer RYBREVANT® via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. Monitor patients for signs and symptoms of infusion reactions during RYBREVANT® infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT® based on severity. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT®. Interstitial Lung Disease/Pneumonitis RYBREVANT® can cause severe and fatal interstitial lung disease (ILD)/pneumonitis. RYBREVANT® with LAZCLUZE™ In MARIPOSA, ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was one fatal case (0.2%) of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT® and LAZCLUZE™ due to ILD/pneumonitis. RYBREVANT® with Carboplatin and Pemetrexed Based on the pooled safety population, ILD/pneumonitis occurred in 2.1% treated with RYBREVANT® in combination with carboplatin and pemetrexed with 1.8% of patients experiencing Grade 3 ILD/pneumonitis. 2.1% discontinued RYBREVANT® due to ILD/pneumonitis. RYBREVANT® as a Single Agent In CHRYSALIS, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT®, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) permanently discontinued RYBREVANT® due to ILD/pneumonitis. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). For patients receiving RYBREVANT® in combination with LAZCLUZE™, immediately withhold both drugs in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. For patients receiving RYBREVANT® as a single agent or in combination with carboplatin and pemetrexed, immediately withhold RYBREVANT® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT® and LAZCLUZE™ RYBREVANT® in combination with LAZCLUZE™ can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of therapy. In MARIPOSA, VTEs occurred in 36% of patients receiving RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT®, and 7% of patients had VTE leading to dose interruptions of LAZCLUZE™; 1% of patients had VTE leading to dose reductions of RYBREVANT®, and 0.5% of patients had VTE leading to dose reductions of LAZCLUZE™; 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT®, and 1.9% of patients had VTE leading to permanent discontinuation of LAZCLUZE™. The median time to onset of VTEs was 84 days (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate. Withhold RYBREVANT® and LAZCLUZE™ based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT® and LAZCLUZE™ at the same dose level at the discretion of the healthcare provider. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT® and continue treatment with LAZCLUZE™ at the same dose level at the discretion of the healthcare provider. Dermatologic Adverse Reactions RYBREVANT® can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin. RYBREVANT® with LAZCLUZE™ In MARIPOSA, rash occurred in 86% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions occurred in 37% of patients for RYBREVANT® and 30% for LAZCLUZE™, rash leading to dose reductions occurred in 23% of patients for RYBREVANT® and 19% for LAZCLUZE™, and rash leading to permanent discontinuation occurred in 5% of patients for RYBREVANT® and 1.7% for LAZCLUZE™. RYBREVANT® with Carboplatin and Pemetrexed Based on the pooled safety population, rash occurred in 82% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT® and 3.1% discontinued pemetrexed. RYBREVANT® as a Single Agent In CHRYSALIS, rash occurred in 74% of patients treated with RYBREVANT® as a single agent, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT® was permanently discontinued due to rash in 0.7% of patients. Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT® as a single agent. Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT® or LAZCLUZE™ in combination with RYBREVANT®. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin. When initiating RYBREVANT® treatment with or without LAZCLUZE™, administer alcohol-free emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g. use of oral antibiotics) to reduce the risk of dermatologic reactions. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. For patients receiving RYBREVANT® in combination with LAZCLUZE™, withhold, reduce the dose, or permanently discontinue both drugs based on severity. For patients receiving RYBREVANT® as a single agent or in combination with carboplatin and pemetrexed, withhold, dose reduce or permanently discontinue RYBREVANT® based on severity. Ocular Toxicity RYBREVANT® can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis. RYBREVANT® with LAZCLUZE™ In MARIPOSA, ocular toxicity occurred in 16% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT® and continue LAZCLUZE™ based on severity. RYBREVANT® with Carboplatin and Pemetrexed Based on the pooled safety population, ocular toxicity occurred in 16% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed. All events were Grade 1 or 2. RYBREVANT® as a Single Agent In CHRYSALIS, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT®. All events were Grade 1-2. Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT® based on severity. Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal models, RYBREVANT® and LAZCLUZE™ can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT®. Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose. Adverse Reactions RYBREVANT® with LAZCLUZE™ For the 421 patients in the MARIPOSA clinical trial who received RYBREVANT® in combination with LAZCLUZE™, the most common adverse reactions (≥20%) were rash (86%), nail toxicity (71%), infusion-related reactions (RYBREVANT®, 63%), musculoskeletal pain (47%), stomatitis (43%), edema (43%), VTE (36%), paresthesia (35%), fatigue (32%), diarrhea (31%), constipation (29%), COVID-19 (26%), hemorrhage (25%), dry skin (25%), decreased appetite (24%), pruritus (24%), nausea (21%), and ocular toxicity (16%). The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased albumin (8%), decreased sodium (7%), increased ALT (7%), decreased potassium (5%), decreased hemoglobin (3.8%), increased AST (3.8%), increased GGT (2.6%), and increased magnesium (2.6%). Serious adverse reactions occurred in 49% of patients who received RYBREVANT® in combination with LAZCLUZE™. Serious adverse reactions occurring in ≥2% of patients included VTE (11%), pneumonia (4%), ILD/pneumonitis and rash (2.9% each), COVID-19 (2.4%), and pleural effusion and infusion-related reaction (RYBREVANT®) (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT® in combination with LAZCLUZE™ due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction, and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each). RYBREVANT® with Carboplatin and Pemetrexed For the 130 patients in the MARIPOSA-2 clinical trial who received RYBREVANT® in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (72%), infusion-related reactions (59%), fatigue (51%), nail toxicity (45%), nausea (45%), constipation (39%), edema (36%), stomatitis (35%), decreased appetite (31%), musculoskeletal pain (30%), vomiting (25%), and COVID-19 (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased neutrophils (49%), decreased white blood cells (42%), decreased lymphocytes (28%), decreased platelets (17%), decreased hemoglobin (12%), decreased potassium (11%), decreased sodium (11%), increased alanine aminotransferase (3.9%), decreased albumin (3.8%), and increased gamma-glutamyl transferase (3.1%). In MARIPOSA-2, serious adverse reactions occurred in 32% of patients who received RYBREVANT® in combination with carboplatin and pemetrexed. Serious adverse reactions in >2% of patients included dyspnea (3.1%), thrombocytopenia (3.1%), sepsis (2.3%), and pulmonary embolism (2.3%). Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT® in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each). For the 151 patients in the PAPILLON clinical trial who received RYBREVANT® in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (90%), nail toxicity (62%), stomatitis (43%), infusion-related reaction (42%), fatigue (42%), edema (40%), constipation (40%), decreased appetite (36%), nausea (36%), COVID-19 (24%), diarrhea (21%), and vomiting (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin (7%), increased alanine aminotransferase (4%), increased gamma-glutamyl transferase (4%), decreased sodium (7%), decreased potassium (11%), decreased magnesium (2%), and decreases in white blood cells (17%), hemoglobin (11%), neutrophils (36%), platelets (10%), and lymphocytes (11%). In PAPILLON, serious adverse reactions occurred in 37% of patients who received RYBREVANT® in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥2% of patients included rash, pneumonia, ILD, pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified. RYBREVANT® as a Single Agent For the 129 patients in the CHRYSALIS clinical trial who received RYBREVANT® as a single agent, the most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%). Serious adverse reactions occurred in 30% of patients who received RYBREVANT®. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death. LAZCLUZE™ Drug Interactions Avoid concomitant use of LAZCLUZE™ with strong and moderate CYP3A4 inducers. Consider an alternate concomitant medication with no potential to induce CYP3A4. Monitor for adverse reactions associated with a CYP3A4 or BCRP substrate where minimal concentration changes may lead to serious adverse reactions, as recommended in the approved product labeling for the CYP3A4 or BCRP substrate. Please read full Prescribing Information for RYBREVANT®. Please read full Prescribing Information for LAZCLUZE™. About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at https://www.jnj.com or at http://www.innovativemedicine.jnj.com/. Follow us at @JNJInnovMed. Janssen-Cilag International NV, Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen Global Services, LLC and Janssen-Cilag, S.A. are Johnson & Johnson companies. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of RYBREVANT® and LAZCLUZE™. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV, Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen Global Services, LLC, Janssen-Cilag, S.A. and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's most recent Annual Report on Form 10-K, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at http://www.sec.gov, http://www.jnj.com, or on request from Johnson & Johnson. None of Janssen-Cilag International NV, Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen Global Services, LLC, Janssen-Cilag, S.A. nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. ### *Nicolas Girard, M.D., Ph.D., has served as a consultant to Johnson & Johnson; he has not been paid for any media work. **RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumors, which is a standard way to measure how well solid tumors respond to treatment and is based on whether tumors shrink, stay the same or get bigger. †See the NCCN Guidelines for detailed recommendations, including other treatment options. ‡The NCCN Guidelines for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories. §The NCCN Content does not constitute medical advice and should not be used in place of seeking professional medical advice, diagnosis or treatment by licensed practitioners. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. _________________________ 1 Yang J, et al. Amivantamab Plus Lazertinib vs Osimertinib in First-line (1L) EGFR-mutant (EGFRm) Advanced NSCLC: Final Overall Survival (OS) from the Phase 3 MARIPOSA Study. 2025 European Lung Cancer Congress. March 26, 2025. 2 Johnson & Johnson. COCOON study meets primary endpoint demonstrating statistically significant and clinically meaningful reduction in dermatologic reactions with easy-to-use prophylactic regimen for patients with EGFR-mutated NSCLC. January 14, 2025. Accessed February 13, 2025. 3 Spira AI, et al. J Thorac Oncol. 2025. In press. 4 Leighl N, et al. J Clin Oncol. 2024;42(30):3593-3605. 5 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). https://classic.clinicaltrials.gov/ct2/show/NCT04487080. Accessed March 2025. 6 RYBREVANT® Prescribing Information. Horsham, PA: Janssen Biotech, Inc. 7 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2025 © National Comprehensive Cancer Network, Inc. All rights reserved. To view the most recent and complete version of the guideline, go online to NCCN.org. Accessed March 2025. 8 ClinicalTrials.gov. A Study of Amivantamab and LAZCLUZE™ in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer After Osimertinib Failure (MARIPOSA-2). Available at: https://classic.clinicaltrials.gov/ct2/show/study/NCT04988295. Accessed March 2025. 9 ClinicalTrials.gov. A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions (PAPILLON). Available at: https://clinicaltrials.gov/ct2/show/NCT04538664. Accessed March 2025. 10 ClinicalTrials.gov. A Study of LAZCLUZE™ With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Participants With Epidermal Growth Factor Receptor (EGFR)-Mutated Advanced or Metastatic Non-small Cell Lung Cancer (PALOMA-3). https://clinicaltrials.gov/ct2/show/NCT05388669. Accessed March 2025. 11 ClinicalTrials.gov. A Study of Amivantamab in Participants With Advanced or Metastatic Solid Tumors Including Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small Cell Lung Cancer (PALOMA-2). https://clinicaltrials.gov/ct2/show/NCT05498428. Accessed March 2025. 12 ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). Available at: https://clinicaltrials.gov/study/NCT04606381. Accessed March 2025. 13 ClinicalTrials.gov. A Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). https://clinicaltrials.gov/ct2/show/NCT02609776. Accessed March 2025. 14 ClinicalTrials.gov. A Study of LAZCLUZE™ as Monotherapy or in Combination With Amivantamab in Participants With Advanced Non-small Cell Lung Cancer (CHRYSALIS-2). https://clinicaltrials.gov/ct2/show/NCT04077463. Accessed March 2025. 15 ClinicalTrials.gov. A Study of Amivantamab and Capmatinib Combination Therapy in Unresectable Metastatic Non-small Cell Lung Cancer (METalmark). https://clinicaltrials.gov/ct2/show/NCT05488314. Accessed March 2025. 16 ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Docetaxel in Participants With Metastatic Non-small Cell Lung Cancer (swalloWTail). https://www.clinicaltrials.gov/study/NCT06532032. Accessed March 2025. 17 ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Cetrelimab in Participants With Metastatic Non-small Cell Lung Cancer (PolyDamas). https://www.clinicaltrials.gov/study/NCT05908734. Accessed March 2025. 18 ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). https://classic.clinicaltrials.gov/ct2/show/NCT05663866. Accessed March 2025. 19 ClinicalTrials.gov. A Study of Amivantamab in Combination With Lazertinib, or Amivantamab in Combination With Platinum-Based Chemotherapy, for Common Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (COPERNICUS). https://www.clinicaltrials.gov/study/NCT06667076. Accessed March 2025. 20 ClinicalTrials.gov. Enhanced Dermatological Care to Reduce Rash and Paronychia in Epidermal Growth Factor Receptor (EGRF)-Mutated Non-Small Cell Lung Cancer (NSCLC) Treated First-line With Amivantamab Plus Lazertinib (COCOON). https://www.clinicaltrials.gov/study/NCT06120140. Accessed March 2025. 21 Cho BC, et al. Lazertinib versus gefitinib as first-line treatment in patients with EGFR-mutated advanced non-small-cell lung cancer: Results From LASER301. J Clin Oncol. 2023;41(26):4208-4217. 22 The World Health Organization. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed March 2025. 23 American Cancer Society. What is Lung Cancer? https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html. Accessed March 2025. 24 Oxnard JR, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013 Feb;8(2):179-84. doi: 10.1097/JTO.0b013e3182779d18. 25 Bauml JM, et al. Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real World Datasets. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 26 Pennell NA, et al. A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol. 37:97-104. 27 Burnett H, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 28 Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. 29 Midha A, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity. Am J Cancer Res. 2015;5(9):2892-2911. 30 American Lung Association. EGFR and Lung Cancer. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/egfr. Accessed March 2025. 31 Howlader N, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site. 32 Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 2016 Apr;11(4):556-65. 33 Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013 Feb; 12(2):220-9. 34 Girard N, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 35 LAZCLUZE™ Prescribing Information. Horsham, PA: Janssen Biotech, Inc. Media contact: Investor contact: Oncology Media Relations Lauren Johnson oncology_media_relations@its.jnj.com investor-relations@its.jnj.com U.S. Medical Inquiries: +1 800 526-7736 View original content to download multimedia:https://www.prnewswire.com/news-releases/rybrevant-amivantamab-vmjw-plus-lazcluze-lazertinib-outperforms-osimertinib-with-a-significant-and-unprecedented-overall-survival-benefit-in-patients-with-egfr-mutated-non-small-cell-lung-cancer-302412036.html SOURCE Johnson & Johnson

点击上方的 行舟Drug ▲ 添加关注 药物相互作用临床研究进展 来源 《药物评价研究》 2025年3月 第48卷第3期 作者 翟天野，吕炯贤，井源浩，杨天绎，黄一欢，刘岩，苏钰文，张力 南京医科大学药学院； 南京医科大学附属逸夫医院临床药理研究中心； 罗格斯大学； 北京中医药大学东直门医院； 北京中医药大学东方医院 摘要 药物相互作用（DDI）临床研究的目的在于确认人体内是否会发生DDI并对其严重程度进行评估，为临床DDI防控策略制定提供科学依据。通过结合多项DDI临床研究具体案例，从独立或嵌套设计的DDI随机对照临床试验（RCT）及其事后分析，基于健康医疗数据或自发呈报不良反应报告的DDI真实世界研究，包括模型引导药物研发、机器学习和人工智能在内DDI计算机模拟研究、DDI文献研究，以及DDI临床研究内容与类型等方面，综述了DDI的临床研究现状。DDI相关真实世界数据和随机对照临床试验数据的链接和共享，将更有助于其计算机模拟研究的开展，以全面评估DDI临床效应与患者获益风险，从而为指导临床合理用药、保障公众用药安全提供科学的依据。 关键词 药物相互作用；临床研究；临床试验；真实世界研究；模型引导药物研发；人工智能 _ 正文 _ 人体对药物的处置过程复杂，一般包括吸收、分布、代谢和排泄。当多种药物合并使用时，可能会由于药物自身理化性质、药物作用靶点、机体疾病状态，或存在药物及其代谢产物与代谢酶或转运体之间发生抑制或诱导作用即药物相互作用（DDI），进而影响药物代谢速率及药物效应浓度，最终导致预期的药物安全性或治疗效果发生变化。20世纪后期，美国食品药品管理局（FDA）有多个药品撤市是基于DDI引起严重不良反应的依据。如特非那丁（CYP3A4底物）于1985年在美国上市，在合并使用酮康唑或红霉素等CYP3A4抑制剂时，由于其代谢受到明显抑制，原药的血药浓度增高，显著增加了发生尖端扭转型室性心动过速等心血管事件的风险，FDA于1998年将其撤出市场；作为CYP3A4抑制剂的钙通道阻滞剂米贝拉地尔于1997年在美国上市，鉴于与二氢吡啶类钙拮抗剂合用引起死亡、心源性休克、心肌梗死等严重不良反应，也于1998年撤市；阿司咪唑、西沙必利和西立伐他汀也由于DDI相关原因分别在1999年、2000年和2001年撤出美国市场。由此可见，在药品上市许可之前，科学评估DDI发生的可能性、严重性及其风险获益影响程度，依据评估结果制定合理的用药方案，并在说明书中对临床合理用药提出建议和指导，从而保障患者用药安全，这些药品风险控制措施对各利益攸关方都具有十分重要的意义。 DDI研究通常从体外实验入手，确定可能影响药物处置的因素以阐明潜在的DDI机制及影响程度，并获得用于进一步研究的动力学参数，其主要内容包括确定药物的主要消除途径、评估相关代谢酶和转运体对药物处置的贡献，考察药物对代谢酶和转运体的影响。DDI临床研究的目的在于确认人体内是否会发生DDI并对其严重程度进行评估，为临床DDI防控策略制定提供科学依据。本文基于DDI相关国内外文献与制药行业指南的调研分析，结合具体临床案例，综述DDI临床研究最新进展。 1 DDI的概念及其临床研究 在临床应用中，DDI是指患者同时或序贯使用多种药物后所产生的临床效应，包括导致不良反应或改变治疗效果等用药预期获益风险的变化。药品说明书及标签中的DDI相关信息，主要来源于体外实验、临床研究、文献研究，以及近年来发展并逐渐成熟的计算机模拟研究。 DDI临床研究的主要内容包括但不限于：在研药物或其他药物的药动学特征或参数的改变及其变化程度，评估在研药物DDI的临床意义、临床严重DDI的防控策略。根据临床研究设计，DDI临床研究一般可分为随机对照临床试验（RCT）和真实世界研究（RWS）；根据研究方法，DDI临床研究一般可分为基于指针药物（index drug）的DDI临床研究、基于临床常见合并用药品种的DDI临床研究及DDI计算机模拟研究。 文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。 2 基于RCT的DDI临床研究 RCT由于其循证医学证据级别高、偏倚风险小和样本量要求有限等特点，被全球药品监管机构和药品上市许可持有人（MAH）广泛接受，并作为金标准应用于药品上市前的临床有效性和安全性评价。在DDI临床研究中，RCT用于确证是否发生DDI及DDI影响临床效应的程度。基于RCT的DDI临床研究所获得的数据和结论，是MAH进行品种开发决策和药品监管机构进行监管决策的首选证据；RWS和计算机模拟研究一般不能为DDI提供足够充分的评价证据。DDI临床试验可以设计为专门进行DDI评价的独立Ⅰ期临床试验，也可以设计为Ⅲ期临床试验中的一个嵌套研究或一个扩展队列。 2.1 独立的DDI相关RCT 基于RCT的DDI临床研究通常设计为Ⅰ期试验，评估指针药物或常见联合用药与在研药物的DDI。研究应选择合适的指针药物或上市药品，并根据相互作用机制、药动学（PK）、药效动力学及安全性特征设计，确保能够观察到最大DDI效应。同时，DDI临床研究还应该考虑是否有与暴露相关的底物安全性问题，以及评价抑制或诱导作用的可行性。Zheng等通过开展1项奥美拉唑与吡咯替尼餐后DDI临床研究，分析奥美拉唑对吡咯替尼体内PK的影响，结果表明两药联用和单独使用吡咯替尼后体内暴露量相同，证明联用奥美拉唑不会对吡咯替尼体内PK参数产生影响。Ren等通过4项独立DDI临床试验的开展，研究赛沃替尼单独或与强CYP3A4诱导剂利福平、强CYP3A4抑制剂伊曲康唑、胃pH值调节剂法莫替丁以及CYP3A4底物咪达唑仑联合给药时的PK。结果显示，法莫替丁和伊曲康唑与赛沃替尼的联合使用，对赛沃替尼PK无显著影响，而利福平则显著降低其体内暴露，因此应避免赛沃替尼与强效CYP3A4诱导剂联合使用。而赛沃替尼与咪达唑仑联合使用时，咪达唑仑的PK未发生有临床意义的改变，提示赛沃替尼可与CYP3A底物联合使用。Laura等进行1项随机、平行组的研究，分析了右美沙芬（DMQ）和美金刚在健康志愿者体内发生DDI的可能性以及联合用药引起的药效学相互作用。结果表明，无论药物添加顺序如何，药效学变量指标未显示明显的负面作用。证明在临床用药过程中，两种药物可以安全地联合用药，且不会引起药物浓度的显著变化或增强不良反应。 2.2 嵌套的DDI相关RCT 除了开展独立的Ⅰ期临床试验评价DDI以外，还可在Ⅲ期临床试验中，通过收集稀疏采集的药动学样本，同期评价DDI的发生情况。因此，需要有针对性地收集影响评价DDI的信息（如给药剂量、给药时间、终止给药时间、合并用药以及可显著影响药物暴露等临床因素），有时需要提前进行模拟（如群体PK模型或生理PK模型）来支持采样点选择，以达到能充分观察到潜在DDI的目的，也可通过群体PK模型方法评价在研药物为底物时的DDI。当在研药物为促变药物时，应提前设计并收集足以支持DDI研究的必要信息，也可应用群体PK方法进行DDI评价，否则（如未测定底物药物浓度）不适用。Tran等开展的1项紫杉醇和卡铂联合厄洛替尼或安慰剂治疗晚期非小细胞肺癌（NSCLC）患者的III期、随机、双盲、多中心试验纳入了1079例未经治疗的晚期NSCLC患者，随机分为接受厄洛替尼治疗组和安慰剂组，同时联合紫杉醇和卡铂。为了探讨DDI，该研究设置了1个24例患者的DDI研究亚组，最终发现厄洛替尼与这两种化疗药物之间未发生显著DDI。Sabo等进行1项双盲、多中心的研究，目的是表征奈韦拉平和拉米夫定联合用于HIV-1感染患者的PK，该研究嵌套在1项更大的III期临床试验中。研究结果显示，奈韦拉平对拉米夫定的PK没有显著影响。但当拉米夫定与复方新诺明联合应用时，产生的DDI会导致拉米夫定表观口服清除率显著降低31%，且平均稳态浓度增加约43%，提示临床医师在为HIV患者开具处方时，可能需要调整拉米夫定的剂量或采用其他药物替代复方新诺明，合理调整治疗方案。 2.3 DDI相关的RCT事后分析 事后分析是指在临床试验方案中没有预先计划，在完成临床试验后进行的额外分析。在进行事后分析时，临床研究已经结束，所有受试者的数据已经收集完毕。相较于临床研究方案中预先设计的分析方案，事后分析是看到受试者数据后以数据驱动的分析，根据已经收集到的数据提出研究假设，通过统计分析来回答临床试验方案之外的问题。Sechaud等基于1项柔红霉素、阿糖胞苷和米哚妥林治疗新诊断的急性髓性白血病患者的III期临床试验所得数据，事后分析了在联合使用强效CYP3A4抑制剂泊沙康唑时，米哚妥林的暴露情况和DDI严重程度，以及这类强效CYP3A4抑制剂对米哚妥林用药安全性的影响。研究结果表明，当联合用药时，米哚妥林的暴露量会增加1.44倍。尽管未观察到临床安全性方面的差异，研究团队建议在使用米哚妥林治疗急性髓性白血病患者时，应该尽量避免合并使用强效CYP3A4抑制剂，如无法避免联用，应对患者进行密切监测，确保联合用药安全性。 3 基于真实世界数据（RWD）的DDI临床研究 药品上市前的前瞻性RCT由于试验参与者的入选排除标准和禁用药品的限制，对多种药物合并或序贯使用的研究数据较难获得，难以发现或评价潜在的DDI。RWD记录了在临床实践过程中与药品使用相关的诊疗信息或不良反应信息。基于RWD可开展回顾性临床DDI潜在风险的初步评价和研究，但是相关DDI临床效应的确证，目前主要还依赖于前瞻性RCT。根据数据获取方式的不同，基于RWD的回顾性DDI临床研究可分为主动监测研究和被动监测研究。 3.1 基于健康医疗数据的DDI主动监测研究 DDI主动监测研究一般利用主动收集的一种或多种来源相关数据评价目标药物的DDI情况。这是一种有组织、有计划的监测活动，信息采集者主动从患者和医务人员中获取信息，并通过预先制定的方案使信息尽可能全面而准确。医院电子病历系统数据（EMR）、医保数据、区域健康医疗数据等均为常规诊疗过程形成的数据，可用于支持主动监测。还有因其他研究/管理目的形成的RWD，如出生/死亡登记数据库、公共卫生监测数据库、自然人群队列数据等。魏安华等采用回顾性研究方法，分析了某三甲医院2020年1月1日—2022年6月30日间住院患者使用达比加群酯的潜在DDI情况。研究发现，在临床应用中，达比加群酯普遍存在DDI，提醒临床医师在用药时需权衡利弊，以保障患者用药的安全性。研究共纳入1965份使用达比加群酯的病历，共发生736例潜在DDI，发生率37.46%。涉及41种药物，主要为抗心律失常药、抗血小板药、抗凝药、非甾体抗炎药等，其中高风险DDI共879例次，占80.79%。另外这41种药物中有13种药物未在药品说明书中DDI部分被提及，该研究表明回顾性研究可以发现并关注被忽视但存在DDI的药物，从而优化治疗方案。刘璐等进行了1项对住院老年患者具有临床意义的药物相互作用（pcsDDI）的横断面研究，收集了淮北市人民医院电子病历系统2022年5月1日—2022年5月20日期间出院的老年患者的病历，并对患者用药进行评估。结果显示，在入院的856例患者中，413例（48.2%）患者在用药史中至少有1种可能导致pcsDDI的药物组合。表明在老年患者用药中pcsDDI发生率较高，应警惕潜在用药风险，加强合理用药的监测。 3.2 基于不良反应报告的DDI被动监测 DDI被动监测研究多基于涵盖已上市的各类药品及用药人群的不良反应数据库分析，评价目标药物的DDI情况。但此类数据来源于自发报告，存在低报、漏报、无法统计发生率、报告偏倚、信号发现迟滞等局限性。DDI主动监测研究可以弥补被动监测研究的以上不足，但研究成本相对较高。利用互为补充的2类研究，可产生用于支撑监管决策的重要证据。林艳花等收集了2011年1月—2020年12月期间上报至国家药品不良反应监测中心的严重药物不良反应报告，利用DDI分析软件评估潜在的DDI。研究表明在150例老年人严重不良反应中有64例存在潜在DDI，占比42.67%，实际发生DDI有42例，占比28%。可以得出应特别关注DDI导致严重药物不良反应对老年人这一特殊人群的影响，并加强对特殊人群的用药监测以保障用药安全。Ma等基于FDA不良事件报告系统（FAERS）中2013—2023年的数据，采用比例失衡分析与Logistic回归分析的方法评估了吸入性皮质类固醇与苯二氮卓类药物联合用药的肺炎风险。结果表明两药联合使用可显著增加发生肺炎事件的风险。此外，Mohammedt等基于2009—2019年FAERS数据库中与直接口服抗凝剂（DOACs）阿哌沙班等联合使用左乙拉西坦相关的缺血性脑卒中报告，以评估两者之间的潜在DDI。结果显示，左乙拉西坦与DOACs联合使用时，调整报告赔率比为3.57[95%置信区间（CI）2.81~4.58]，提示存在强烈的DDI信号，具有显著的相互作用风险，并建议在临床实践中实施药物监测策略，以提高左乙拉西坦的用药安全性。 4 DDI模拟研究 在新药临床研发过程中，DDI临床研究的预测有助于临床试验设计，并可根据预测结果评估DDI的临床效应。研究的主要目的是评估系统特异性参数或药物特异性参数变化对PK特征的影响。某些情况下，选择健康的虚拟人群进行模拟可能无法充分体现患者特性，因此分析时有必要把这些特性考虑在模型结构中。在过去的20年，药品监管机构对模型引导的药物研发（MIDD）认可度不断提升。近年来，多项指导原则介绍了MIDD及其在药品全生命周期管理应用中涉及的范畴，涵盖从非临床研究、临床研究及上市后临床再评价的各个阶段，其中常见的方法有：基于生理的药动学（PBPK）模型、群体药动学（PopPK）模型、药动学/药效动力学（PK/PD）模型等。随着人工智能和机器学习的快速发展，定量药理学模型在DDI研究中将发挥重要作用。 4.1 PBPK模型 PBPK模型基于机体的解剖结构、生理特征、生化反应及药物的理化性质构建，能够模拟药物在体内的动态分布过程，预测药物及其代谢产物在不同组织器官中的浓度变化，并定量评估病理和生理参数变化对药物处置的影响。近10年来，PBPK模型在DDI研究中的应用显著增加，逐渐成为评估DDI风险、制定剂量建议和辅助临床决策的重要工具，多个指导原则推荐PBPK模型在DDI研究中的应用，旨在提高临床应用的准确性与安全性。这一模型的广泛应用为DDI临床研究的评估提供了更为精确、充分的科学依据，进而提高临床用药的安全性和有效性，更好地为患者健康服务。 Xiang等通过建立PBPK模型预测安罗替尼介导的DDI，并通过收集肿瘤患者的文献数据进行外部验证，验证结果显示观测值与模型预测值差异不显著，该模型科学可靠，结合模型预测提示安罗替尼通过抑制几种主要细胞色素酶引起有临床意义DDI的可能性非常低。根据FDA最新的DDI指南，基于模拟结果的PBPK模型可作为修订安罗替尼说明书的依据，无需进一步的临床试验验证。此外，多项研究报道了PBPK模型在多种机制DDI应用中模型表现稳定，其预测结果与实际观察数据高度吻合，为各类药物DDI的研究提供了有力支持。进一步的研究也证实，PBPK模型在DDI临床研究中不仅能够减少受试者的纳入数量，还显著降低了研究成本。同时随着PBPK模型技术的成熟，监管机构已经批准了应用PBPK模型的DDI研究案例，如卡巴他赛的应用。 4.2 PopPK模型 PopPK模型将经典PK房室模型与统计学方法相结合，用于研究患者或健康受试者群体在接受特定剂量药物后的体内药物分布规律。该模型不仅能够深入分析个体间药物浓度差异的来源及其相关性，还能揭示群体的整体PK特性。多项指导原则提及PopPK模型已经成为DDI研究中重要的分析工具之一。在使用PopPK模型研究DDI中，药物联用常作为协变量之一分析DDI对药物PK/PD的影响。例如，Barcel等通过开发PopPK模型分析多替拉韦的PK特征及变异性，研究将联合用药作为协变量探索影响多替拉韦药效的个体因素和联合用药效应，结果表明该模型能够准确可靠地模拟两药联用时的PK特征，从而预测DDI的发生并优化治疗方案。 4.3 机器学习（ML）和人工智能（AI） ML和AI的应用拓展了传统DDI预测的能力。近年来，研究人员提出了基于ML和AI的计算方法，在公开的生物医学数据源（如数据库和相关文献）中收集可用数据，包括DDI、靶点、基因和蛋白质等信息，开发出能高效预测DDI的模型。Lee等提出了一种新的深度学习模型，使用自编码器和深度前馈网络，用已知药物对的结构相似谱、基因本体术语相似谱和靶基因相似谱进行训练，以预测DDI发生的概率和潜在影响。此外，图神经网络（GNN）和深度神经网络（DNN）在DDI预测中的应用显著提升了模型的准确性和可解释性。Abramson等开发了最新的人工智能模型Alphafold3，该模型可高效准确预测蛋白质与其他各种生物分子相互作用的结构。这类技术为DDI研究提供了全新视角，展示了AI与深度学习在未来应用中的广阔潜力。 4.4 多模型结合在DDI研究中的应用 近年来，计算机模型尤其是PBPK模型在DDI领域的应用越来越多，但是单一模型的应用仍存在如参数准确性、数据质量和数据来源的限制。因此，多模型结合已逐渐成为DDI研究中的新趋势。PBPK模型因其对药物在体内动态分布的精确模拟而具优势，而PopPK模型则通过分析个体差异，识别影响药物浓度和疗效的关键协变量，在解释个体差异的成因和机制方面存在一定不足。将PBPK与PopPK模型结合使用，能够在DDI研究中实现优势互补，从而提高预测精度和临床应用的可靠性。例如，Andre等先建立米达唑仑和酮康唑的PBPK模型生成所需数据集，随后构建两药联用的PopPK模型，将药物联用作为协变量纳入以模拟不同药物联用的情况。将2个模型独立构建后再结合使用，可以有效弥补各自的局限性。 AI/ML研究方法除了可以通过药物结构预测DDI，还可以结合常见的DDI研究模型（PBPK模型）预测药物PK特征，能更准确地预测DDI的发生和严重程度。前文提到建立新药的PBPK模型来预测DDI是耗时且消耗大量资源的，很多输入参数需要通过将模型与动物研究的观察数据进行拟合来估计。因此，将AI/ML与PBPK模型相结合的新方法，不仅在很大程度上加快了药物PBPK模型的构建，并且节省了大量的资源。Ryu等提出了DeepDDI计算框架，通过输入药物名称及其化学结构，能够准确预测药物与药物之间或药物与食物之间的DDI类型。除此之外，AL/ML也可以帮助筛选具有高DDI风险的药物，在使用更耗时的PBPK模型之前，可以将实验后得到的额外的PK参数和给药数据应用于基于回归的AL/ML模型，这样更准确地估计DDI风险。不同的机器学习算法都有各自的优缺点，哪种算法的预测性能最佳目前尚无定论。此外，现有报道的算法仍缺乏严格的临床验证。 4.5 DDI分析软件的选择与性能评估 随着DDI研究的深入，国外相继开发出多款DDI分析软件，为临床和科研人员提供了预测和管理DDI风险的有力工具。目前常用的DDI分析软件包括Micromedex、Lexicomp Interactions、Drugs. com和Medscape等，这些软件在准确性、全面性、易用性和可靠性等方面表现各异。然而，这些软件在草药-药物相互作用（HDI）检测方面仍存在不足，主要原因在于草药相互作用信息的缺乏和不确定性。 针对不同DDI分析软件的准确性，不同研究得出的结论并不完全一致。Barrons的研究表明Micromedex在准确性方面优于Lexicomp Interactions和Epocrates；而Bossaer等的研究则发现Lexicomp Interactions的准确性更高。这种差异可能源于不同研究的人群特征、用药剂量、DDI类型，以及检测金标准的差异；同时，软件版本的不断更新也可能导致研究结果的不同。此外，各软件在严重程度分级、证据等级和参考文献等方面存在信息不一致的情况，缺乏统一的标准。这种信息来源的差异性影响了DDI分析软件的可靠性，提示未来应在证据等级和参考文献的规范性上加强改进，以进一步提升信息的准确性和权威性。 目前，我国在DDI分析软件的开发和研究上仍处于初级阶段，尚未形成基于我国临床数据和用药特点的高质量DDI分析软件。国内多依赖国外开发的DDI软件，但这些软件未能充分涵盖我国特有的药物使用习惯和HDI特征。因此，未来国内DDI分析软件的开发应注重提高本地化适应性，增强对HDI的识别能力。同时，需进一步优化软件的易用性和信息可靠性，以满足不同层次临床和科研工作的需求，为合理用药提供更有力的支持。 5 文献研究 随着生物医学文献数量的迅速增长，研究人员可以从大量的文献中提取并分析潜在的DDI、当前的研究热点与方法等相关信息，为临床合理用药提供科学依据，从而保障患者用药安全。Schwier等为了探究他汀类药物与秋水仙碱是否会发生DDI并对患者造成伤害，对已发表的文献进行了检索，结果表明需要针对他汀类药物引起的肌肉症状采用风险缓解策略。 Meta分析作为一种系统性定量总结和分析的方法，能够将多个独立研究的结果进行综合分析。利用Meta分析进行DDI研究，可以提高研究的统计效能，强化证据水平，在显著提高结论的可靠性的同时，也可以发现研究结果的不一致性，提供新的研究思路。Villa Zapata等进行了1项华法林与非甾体抗炎药联合使用引起出血风险的Meta分析。结果表明与单独使用华法林相比，华法林与非甾体类抗炎药或环氧化酶-2（COX-2）抑制剂联合使用其出血风险显著增加，此项研究为规避DDI引起的用药风险，提升临床合理用药水平提供了科学依据。 6 DDI临床研究结果的解读 以PK参数（如AUC0~INF和Cmax）为终点指标的RCT是为了确定底物暴露量变化是否有临床意义，并为临床DDI防控策略制定提供科学依据。一般以受变药DDI的无效应边界作为判定标准解释临床研究结果。无效应边界是指DDI所导致的药物系统暴露量变化的可接受范围，其临床意义不足以采取如禁用、慎用、用药剂量或方案调整及其他治疗监测等干预措施进行DDI的管理。无效应边界往往通过对PK、药效动力学或其他关于受变药的可用数据（如最大耐受剂量）分析得出的浓度-效应关系来确定；若DDI临床试验研究结果中的系统暴露量变化的90%CI完全落在上述无效应边界范围之内，则可认为不会出现具有显著临床意义的DDI。在上述方法无法确定无效应边界的情况下，或者当研究目的是使用指针底物来确定在研药物是否为促变药物时，也可采用80%~125%作为默认的无效应边界；若血液暴露比的90%CI完全落在80%~125%的等效性范围之内，则认为不会出现具有显著临床意义的DDI。 DDI真实世界研究可用于进行DDI的评价，但在新药研发初期无法开展此类大样本回顾性临床研究。当回顾性DDI真实世界研究结果为阳性，需要讨论是否应开展前瞻性RCT以确认潜在DDI；即使回顾性DDI真实世界研究结果为阴性，一般也不意味着得到了可用于说明书变更的有效信息。 在DDI临床研究中，许多在研药物是Ⅰ相代谢酶、Ⅱ相代谢酶或转运体的抑制剂或诱导剂。对于CYP酶抑制剂，根据其对指针底物的影响，可分为强效（AUC升高≥5倍）、中效（AUC升高≥2倍且<5倍）和弱效（AUC升高≥1.25倍且<2倍）；对于CYP诱导剂，根据其对指针底物的影响，可分为强效（AUC下降≥80%）、中效（AUC下降≥50%且<80%）和弱效（AUC下降≥20%且<50%）。这些分类有助于评估在研药物与其他药物合用时的DDI临床显著性。目前，Ⅱ相代谢酶和转运体的DDI效应评价尚缺乏标准化分类系统。 7 结语与展望 本文结合具体案例，系统回顾了DDI临床研究的现状。从独立或嵌套设计的DDI的RCT研究及其事后分析、基于健康医疗数据或自发呈报不良反应报告的DDI真实世界研究、DDI文献研究以及DDI临床研究的内容和类型等方面进行了全面总结。此外，本文还对DDI研究的最新进展进行了分析，探讨了定量药理研究方法在识别、评估和预测DDI中的应用与挑战，特别是随着数据分析技术和计算机模拟方法的发展，DDI的识别和管理正逐渐朝着更精确、个性化的方向迈进。由于篇幅限制，本文主要聚焦于小分子化学药物的DDI临床研究，以下几方面内容尚未展开探讨：（1）DDI相关RCT和RWS的方案设计；（2）其他类型药物的DDI，如治疗用生物制品、疫苗、中药和天然药物等；（3）DDI所致临床效应中的治疗效果，如奈玛特韦与CYP3A强抑制剂利托那韦联合使用，通过降低奈玛特韦体内代谢速率增加其抗病毒疗效；（4）DDI防控策略。 随着科学技术的不断进步，DDI临床研究将朝着更加精准和个性化的方向发展，结合细分种类或不同适应证领域药物的各自特点，出台更有针对性的DDI临床实践指南或共识有望为患者和医务工作人员提供合理用药参考。此外，未来DDI的体外实验数据、RCT数据、健康医疗数据和不良反应自发报告系统数据的链接和共享，以及DDI分析软件或人工智能大模型的深度开发，将更有助于基于计算机模型的DDI研究发展，以全面评估具体品种的DDI临床效应与患者获益风险，为指导临床合理用药、保障公众用药安全提供科学的依据。 参考文献 详见《药物评价研究》 2025年3月 第48卷第3期 文章信息源于公众号凡默谷，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。 学如逆水行舟，不进则退； 心似平原走马，易放难收。 行舟Drug 每日更新 欢迎订阅+ 医药大数据|行业动态|政策解读