Dexamethasone

More than half of patients maintained minimal residual disease (MRD) negativity (10-5) with DARZALEX FASPRO® for 24 months or longer in the Phase 3 PERSEUS study Data from Phase 3 CEPHEUS study show 60 percent overall MRD negativity (10−5) and improved PFS with DARZALEX FASPRO® in transplant-ineligible newly diagnosed patients CHICAGO, June 3, 2025 /PRNewswire/ -- Johnson & Johnson (NYSE: JNJ) today announced data from two studies highlighting that a DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)-based quadruplet regimen demonstrated deep and sustained minimal residual disease (MRD) negativity rates, and improved long-term progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM), regardless of transplant status.1,2,3 Findings were highlighted as oral presentations of an analysis of sustained MRD in transplant-eligible patients from the Phase 3 PERSEUS study (Abstract #7501) and a subgroup analysis of transplant-ineligible patients in the Phase 3 CEPHEUS study (Abstract #7516) at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. New analysis from the Phase 3 PERSEUS study shows the addition of DARZALEX FASPRO® to bortezomib, lenalidomide and dexamethasone (D-VRd), followed by an investigational maintenance regimen of DARZALEX FASPRO® with lenalidomide (D-R), led to improved and deepened rates of overall and sustained MRD negativity (10-5), defined as no cancer cells detected within 100,000 bone marrow cells) for at least 24 months, compared to VRd induction and consolidation with R maintenance. More than half of patients who received the DARZALEX FASPRO®-based regimen achieved sustained MRD negativity for 24 or more months and more than two-thirds of patients achieved sustained MRD-negativity at 12-months, showing 95.3 percent PFS at 48-months (95 percent confidence interval [CI], 0.3-2.3)—reinforcing the ability of DARZALEX FASPRO® to delay disease progression or death.1 "The data show that D-VRd followed by an investigational D-R maintenance regimen is a highly effective treatment option for transplant-eligible patients with newly diagnosed multiple myeloma," said Philippe Moreau*, M.D., head of the Hematology Department, University Hospital Hôtel-Dieu, Nantes, France and presenting author. "The depth and durability of MRD negativity observed—paired with unprecedented progression-free survival at four years—underscore the long-term benefit the DARZALEX FASPRO-based regimen can offer patients early in their treatment journey." At a median follow-up of 47.5 months, 24-month sustained MRD negativity rates at the 10⁻⁵ sensitivity threshold were more than double with D-VRd followed by investigational D-R maintenance (55.8 percent), compared to VRd followed by R maintenance (22.6 percent) (odds ratio [OR]=4.36; 95 percent CI, 3.15-6.05; P<0.0001). Similarly, MRD negativity at 12 months was higher with D-VRd and D-R maintenance at 64.8 percent compared to VRd and R maintenance (29.7 percent) (OR=4.42, 95 percent CI, 3.22-6.08, P<0.0001).1 Additional data from Phase 3 CEPHEUS study explore the benefits of DARZALEX FASPRO® in transplant-ineligible patients across cytogenetic risk status The post-hoc analysis of the Phase 3 CEPHEUS study focused exclusively on transplant-ineligible patients, reinforcing that adding DARZALEX FASPRO® to VRd significantly deepens response and prolongs PFS compared to VRd alone, even in patients who are older and considered frail by the Myeloma Geriatric Assessment score. At a median follow-up of 58.7 months, patients receiving D-VRd achieved markedly higher overall MRD negativity rates at the 10⁻⁵ sensitivity threshold with 60.4 percent versus 39.3 percent with VRd (OR 2.37; 95 percent CI, 1.47–3.80; P=0.0004). Furthermore, treatment with D-VRd resulted in high MRD-negativity rates at the 10⁻⁶ threshold (no cancer cells detected within 1,000,000 bone marrow cells) with 45.8 percent compared to 26.9 percent with VRd (OR 2.28; 95 percent CI, 1.40–3.73; P=0.0010). These deeper responses translated into improved long-term outcomes, with 69 percent of patients remaining progression free at 54-months when treated with D-VRd versus 48.0 percent with VRd (hazard ratio [HR] 0.51; 95 percent CI, 0.35–0.74). Overall survival (OS) numerically favored D-VRd (HR 0.66; 95 percent CI, 0.42–1.03), with an even greater benefit observed after censoring for COVID-19-related deaths (HR 0.55; 95 percent CI, 0.34–0.90).2 Additional data presented at ASCO included a subgroup analysis of the CEPHEUS trial for both transplant-ineligible and deferred NDMM patients who were considered high-risk for cytogenetic abnormalities (Abstract #7529). At a median follow-up of 58.7 months, overall MRD negativity rate was improved for patients with standard risk in D-VRd versus VRd. Rates by treatment arm in patients at high risk were comparable.3 "Across multiple studies, the growing body of data on DARZALEX-based regimens indicates impressive, deep responses and meaningful progression-free survival in patients with newly diagnosed multiple myeloma, including high risk," Jordan Schecter, MD, Vice President, Disease Area Leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine. "These consistent results across patient populations, regardless of transplant eligibility, reinforce the role of DARZALEX FASPRO as a cornerstone of frontline therapy." In the PERSEUS and CEPHEUS studies, the safety profiles were consistent with the known safety profile for DARZALEX FASPRO®. About the PERSEUS Study The PERSEUS study is being conducted in collaboration with the European Myeloma Network as the sponsor. PERSEUS is an ongoing, randomized, open-label, Phase 3 study comparing the efficacy and safety of D-VRd during induction and consolidation versus VRd during induction and consolidation in patients with NDMM eligible for ASCT. Following consolidation, patients received an investigational treatment regimen for maintenance that included DARZALEX FASPRO® in combination with lenalidomide or lenalidomide alone. The trial was not designed to isolate the effect of DARZALEX FASPRO® in the maintenance phase of treatment. The efficacy of DARZALEX FASPRO® in combination with lenalidomide for maintenance has not been established. The primary endpoint is PFS, and secondary endpoints include overall CR or better rate, and overall MRD-negativity (in patients with CR or better). The median age is 61.0 (range, 32-70) years for patients in the D-VRd arm and 59.0 (range, 31-70) years for patients in the VRd arm.2 The study is being conducted in 14 countries in Europe and Australia. About the CEPHEUS Study CEPHEUS (NCT03652064) is an ongoing, multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of D-VRd versus VRd in patients with newly diagnosed multiple myeloma who are transplant-ineligible or for whom transplant is not intended as initial therapy. Primary endpoint is overall MRD negativity rate at 10-5 sensitivity threshold. Secondary endpoints include CR or better rates, PFS, sustained MRD negativity rates for ≥12 months, MRD-negative rate at one year, overall response rates, time to and duration of response, PFS on next line of therapy, overall survival and safety. The trial has enrolled 396 patients in 13 countries. About Multiple Myeloma Multiple myeloma (MM) is a blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.4 In multiple myeloma, these malignant plasma cells proliferate and replace normal cells in the bone marrow.5 Multiple myeloma is the second most common blood cancer worldwide and remains an incurable disease.6 In 2024, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 will die from the disease.7 People with multiple myeloma have a 5-year survival rate of 59.8 percent. While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.8,9 About DARZALEX FASPRO ® and DARZALEX ® DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for nine indications in MM, four of which are for frontline treatment in newly diagnosed patients who are transplant-eligible or ineligible.3,6 It is the only subcutaneous CD38-directed antibody approved to treat patients with MM. DARZALEX FASPRO® is co-formulated with recombinant human hyaluronidase PH20, Halozyme's ENHANZE® drug delivery technology. DARZALEX® (daratumumab) received U.S. FDA approval in November 2015 and is approved in eight indications, three of which are in the frontline setting, including newly diagnosed patients who are transplant-eligible and ineligible.9 DARZALEX® is the first CD38-directed antibody approved to treat MM.9 DARZALEX®-based regimens have been used in the treatment of more than 618,000 patients worldwide. In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab.  For more information, visit .  DARZALEX FASPRO ® INDICATIONS AND IMPORTANT SAFETY INFORMATION    INDICATIONS  DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with MM:  In combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory MM who have received at least one prior therapy In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor (PI) In combination with carfilzomib and dexamethasone in patients with relapsed or refractory MM who have received one to three prior lines of therapy In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy As monotherapy in patients who have received at least three prior lines of therapy including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent IMPORTANT SAFETY INFORMATION   CONTRAINDICATIONS     DARZALEX FASPRO® is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.     WARNINGS AND PRECAUTIONS     Hypersensitivity and Other Administration Reactions     Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO®. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO®.    Systemic Reactions     In a pooled safety population of 1249 patients with MM (N=1056) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO® as monotherapy or in combination, 7 percent of patients experienced a systemic administration-related reaction (Grade 2: 3.2 percent, Grade 3: 0.7 percent, Grade 4: 0.1 percent). Systemic administration-related reactions occurred in 7 of patients with the first injection, 0.2 percent with the second injection, and cumulatively 1 percent with subsequent injections. The median time to onset was 2.9 hours (range: 5 minutes to 3.5 days). Of the 165 systemic administration-related reactions that occurred in 93 patients, 144 (87 percent) occurred on the day of DARZALEX FASPRO® administration. Delayed systemic administration-related reactions have occurred in 1 percent of the patients.  Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.     Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO®. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO® depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.     Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO® and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO®.     Local Reactions     In this pooled safety population, injection-site reactions occurred in 7 percent of patients, including Grade 2 reactions in 0.8 percent. The most frequent (>1 percent) injection-site reaction was injection-site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO®. Monitor for local reactions and consider symptomatic management.     Neutropenia     Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO® until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO®, higher rates of Grade 3-4 neutropenia were observed.     Thrombocytopenia     Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Consider withholding DARZALEX FASPRO® until recovery of platelets.     Embryo-Fetal Toxicity     Based on the mechanism of action, DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose.     The combination of DARZALEX FASPRO® with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide, or pomalidomide prescribing information on use during pregnancy.     Interference With Serological Testing     Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted.     Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO®. Type and screen patients prior to starting DARZALEX FASPRO®.     Interference With Determination of Complete Response     Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO®-treated patients with IgG kappa myeloma protein.     ADVERSE REACTIONS     In MM, the most common adverse reaction (≥20 percent) with DARZALEX FASPRO® monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20 percent for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, headache, pyrexia, cough, muscle spasms, back pain, vomiting, hypertension, upper respiratory tract infection, peripheral sensory neuropathy, constipation, pneumonia, and peripheral edema.     The most common hematology laboratory abnormalities (≥40 percent) with DARZALEX FASPRO® are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.     Please click here to see the full Prescribing Information for DARZALEX FASPRO ® .     DARZALEX ® INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS   DARZALEX ® (daratumumab) is indicated for the treatment of adult patients with MM:   In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory MM who have received at least one prior therapy In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor In combination with carfilzomib and dexamethasone in patients with relapsed or refractory MM who have received one to three prior lines of therapy In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent CONTRAINDICATIONS DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.   WARNINGS AND PRECAUTIONS   Infusion-Related Reactions   DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37 percent of patients with the Week 1 (16 mg/kg) infusion, 2 percent with the Week 2 infusion, and cumulatively 6 percent with subsequent infusions. Less than 1 percent of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. When DARZALEX® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11 percent for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1 percent) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42 percent, with 36 percent of patients experiencing infusion-related reactions on Day 1 of Week 1, 4 percent on Day 2 of Week 1, and 8 percent with subsequent infusions. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX® infusion. If ocular symptoms occur, interrupt DARZALEX® infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX®. Interference With Serological Testing   Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®. Neutropenia and Thrombocytopenia   DARZALEX® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets. Interference With Determination of Complete Response   Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein. Embryo-Fetal Toxicity   Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose. The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy. ADVERSE REACTIONS   The most frequently reported adverse reactions (incidence ≥20 percent) were: upper respiratory infection, neutropenia, infusion related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40 percent) with DARZALEX® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia. Please click here to see the full Prescribing Information. 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 or at . Follow us at @JNJInnovMed. Janssen Research & Development, LLC and Janssen Biotech, Inc., and Janssen Global Services, LLC 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 DARZALEX FASPRO®. 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 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 , , or on request from Johnson & Johnson. Johnson & Johnson does not undertake to update any forward-looking statement as a result of new information or future events or developments. Source: Johnson & Johnson * Philippe Moreau, M.D., head of the Hematology Department, University Hospital Hôtel-Dieu, Nantes, France, has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work. 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撰文｜Lei Chu2014年，O药和K药相继获批，拉开了肿瘤免疫治疗的大幕。中国PD-1第一梯队企业以精准的眼光和强悍的执行力，在2018-2019相继上市了4款PD-1单抗，将某些MNC甩在身后。后续更多PD-(L)1单抗在国内外相继上市，以广谱疗效改写了多种肿瘤的治疗指南，也深刻改变了创新药的研发格局。随着PD-(L)1单抗的临床应用日趋广泛，三个方面的问题逐渐凸显。第一是耐药性问题，对PD-(L)1有效的患者有60%以上会发生耐药，且耐药机制多样复杂。第二，疗效要求提升，不仅要PFS获益，更要OS的长期获益，PD-(L)1单药治疗的OS参差不齐，甚至不能达到OS获益。第三，生存期延长使肿瘤慢病化，对长期安全性和长期生活质量的需求提到更高位置。业界通常认为2021年之后，肿瘤免疫治疗进入“后PD1时代”。在这个阶段，针对癌症免疫循环(CIC)及肿瘤微环境的癌症免疫子循环的各个环节(图1)，可研发针对不同靶点、基于不同技术、呈现多种模式的肿瘤免疫治疗药物。实际上，不仅肿瘤免疫治疗进入了2.0时代，其他肿瘤治疗药物如ADC、激酶抑制剂等也进入了新阶段，对于各类药物的研发策略可概括为三新：新联合、新技术、新靶点。图1. 癌症免疫循环及肿瘤微环境的癌症免疫子循环来源：10.1016/j.immuni.2023.09.0112025 DIA药物信息大会暨展览会（以下简称“DIA”）专门设立了“肿瘤专场”，围绕“后PD-1时代”肿瘤治疗领域的技术进展、研发管线、临床研究、临床使用，企业界和医疗界的专家们分享了洞察和观点。图2. 2025DIA中国年会肿瘤专场现场  新联用：设想简单，现实复杂随着研究的逐渐深入，肿瘤越来越多的特征被揭示出来，从2000年的6个到2011年的11个，再到2022年的14个。对于肿瘤治疗，同时针对多个特征很可能会比针对单个特征，表现出更好的疗效。基于这个思路，多种药物联用成为研发更优肿瘤药物的策略之一。图3. 对肿瘤特征的理解逐渐深入如果仅讨论肿瘤免疫治疗的联用，主要有三种情形：PD-(L)1+化疗、PD-(L)1+靶向药物、PD-(L)1+免疫检查点抑制剂。2021年之后联合治疗的临床研究达到高峰，但也暴露出一些问题。对于PD-(L)1+靶向药物的联用模式，以Roche的阿替利珠单抗(T药)联合抗血管生成药物为例，联合贝伐单抗的IMbrave150研究显示PFS和OS都有获益，在获批一线治疗肝细胞癌后成为著名的“T+A”疗法。然而，T药联合卡博替尼的COSMIC-312研究则未能显示OS获益，这可能由药物、瘤种、研究设计和执行三方面原因导致。卡博替尼二线治疗晚期肝细胞癌，ORR仅有4%。COSMIC-312研究仅有28%的受试者为亚洲人群，其肝癌病因大多为病毒感染，而Nature发表的一项1600例患者的荟萃研究显示免疫治疗对非病毒感染所致肝癌疗效不明显。COSMIC-312研究中，联合治疗组后线治疗比例为37%，高于索拉非尼单药治疗组的20%，这对OS可能有不利影响。与T+A疗法相比，类似的“可乐组合”(可瑞达+乐卫玛)的LEAP系列研究则屡战屡败。PD-(L)1和其他药物联用的真实机制可能比预想的复杂，对于与抗血管生成药物联用有好有坏，好处是促进肿瘤血管正常化，减轻肿瘤微环境的缺氧，增加免疫细胞效应因子的渗透，改善PD-(L)1在肿瘤微环境中的效果；坏处是过度修剪肿瘤血管加重缺氧，增加免疫抑制细胞的渗透，并减少药物渗透。对于单药治疗疗效不足的药物，选择与适当的药物联用能够实现疗效的极大提升。GSK的贝兰他单抗(BCMA-ADC)在2020年基于开放、单臂II期试验DREAMM-2获得FDA加速批准，然而因确证性III期试验DREAMM-3失败而在2022年撤市。在总结经验教训后，后续的DREAMM-7/8研究在2024年显示贝兰他单抗联合硼替佐米+地塞米松治疗RRMM达到主要终点PFS和次要终点OS，GSK再次向FDA提交了联合治疗的上市申请。新技术：春色满园，双抗争艳双抗既可以视为新技术，也可以视为特殊形式的新联用，即靶点及其相关作用机制的联合，但是在有效性上必须优于两种靶点药物的联用，实现“1+1>2”的效果。“新联用”策略下广泛研究的PD-(L)1+抗血管生成，在“新技术”策略下则变化为目前炙手可热的PD-1/VEGF双抗，其中的突出代表是康方生物的依沃西单抗(AK112)。图4.临床III期试验HARMONi-2的设计来源：2024年世界肺癌大会(WCLC)在随机、双盲的临床III期研究HARMONi-2中，一线治疗PD-L1阳性(PD-L1 TPS≥1%)、不伴EGFR突变/ALK重排的晚期(IIIB-IV期)非小细胞肺癌患者，对于mPFS，依沃西单抗以11.1个月超越K药的5.8个月(HR=0.51, p<0.0001)。此外，依沃西单抗在客观缓解率(ORR)、疾病控制率(DCR)上均优于K药。依沃西单抗的成功很可能与独特结构有关，连接在Fc部分的VEGF scFv使整个分子对PD-1的结合亲和力显著增强超18倍，从而极大提升了对PD-1/PD-L1信号通路的阻断效果，同时PD-1 Fab也使整个分子对VEGF的结合亲和力增强超4倍，从而强化了对VEGFR信号通路的阻断能力。图5. 依沃西单抗协同结合PD-1和VEGF来源：康方生物官网依沃西单抗优异的临床数据推动了PD-(L)1/VEGF双抗的BD交易。在DIA会议召开前夕，三生制药宣布将SSGJ-707中国以外的全球权益转让给辉瑞，预付款高达12.5亿美元，创造中国创新药出海交易的预付款最高纪录。该药基于专有的双抗技术平台CLF2(共轻链线性Fabs IgG)，具有独特结构。临床II期试验显示一线治疗PD-1阳性、无EGFR/ALK改变NSCLC，单药ORR为70.8%；联合化疗的ORR分别为58.30%(非鳞NSCLC)和81.30%(鳞状细胞NSCLC)。基于以上良好的数据，三生制药即将开展针对K药的头对头试验。表1. 国产PD-(L)1/VEGF双抗创新药重磅出海交易来源：公开资料与上述抗原交联双抗不同，T细胞衔接器(TCE)属于细胞桥接双抗，其中一个靶点为T细胞表面抗原CD3，另一个靶点为肿瘤细胞表面的肿瘤相关抗原(TAA)，如BCMA、DLL3、CD20等。TCE通过在空间上将T细胞拉近肿瘤细胞，进而促进T细胞杀死肿瘤细胞。这类药物的作用机制与CAR-T相似，不同点是CAR-T为单靶点，与肿瘤细胞表面的TAA结合后直接发挥杀伤作用。TCE使用方便，不用像CAR-T那样等待较长的制备周期，血液学不良事件相对较少，且成本相对较低。科睿唯安预测BCMA/CD3双抗teclistamab在G7市场的2031年销售额达到18亿美元。TCE也可用于治疗实体瘤，如安进和百济神州合作研发的DLL3/CD3双抗tarlatamab(塔拉妥单抗)。在临床II期试验DeLLphi-301中，对于经治的小细胞肺癌(SCLC)患者，10mg组的mPFS为4.9个月，mOS为14.3个月。基于此研究数据，FDA加速批准该药治疗广泛期小细胞肺癌，使其成为首款治疗实体瘤的BiTE药物，期待后续的确证性试验能否将其转为完全批准。靶向蛋白降解剂(TPD)可以克服一些不可成药性和耐药性，因此这个赛道从2001年开始不断有新药研发，在类型上包括分子胶、异双功能降解剂(如PROTAC)、SERD(选择性雌激素降解剂)。目前，全球在研TPD的适应症不仅有肿瘤，如前列腺癌、B细胞淋巴瘤，还涉及自免疾病，如特应性皮炎、化脓性汗腺炎。Arvinas公司为该领域的先驱，具有首个临床阶段PROTAC药物ARV-471。在III期试验中，ARV-471对比氟维司群治疗CDK4/6i和内分泌疗法耐药的ER+/HER2-晚期乳腺癌患者，在ESR1突变的患者亚组(约40%)中达到主要终点(mPFS)，但在更大的意向受试者(ITT)人群中未达到统计学显著性。除了核心产品泽布替尼，百济神州针对BTK靶点还在研发嵌合式降解激活化合物(CDAC)BGB-16673，其结构特征属于PROTAC一类的靶向蛋白降解剂。新靶点：前仆后继，持续努力PD-1/PD-L1药物的巨大成功引发了围绕免疫检查点的研发热情，但是目前仅有LAG-3单抗relatlimab获批与O药联用治疗黑色素瘤，靶向CTLA-4的伊匹单抗(Y药)获批单药治疗或与O药联用治疗，而针对其他免疫检查点(如TIGIT、CD47、BTLA、4-1BB、OX40)的研究大多遭遇了波折。TIGIT靶点由基因泰克(Genentech)在2002年发现，主要表达在T细胞和NK细胞上，研究显示在联合用药方面存在潜力。2020ASCO，罗氏发布TIGIT单抗tiragolumab联合自家PD-L1单抗T药一线治疗PD-L1阳性晚期NSCLC患者的II期试验CITYSCAPE数据，联合组ORR优于T药单药组(31.3% vs 16.2%)，在PD-L1高表达(≥50%)患者中优势则更大(55.2% vs 17.2%)。先行者的良好数据叠加PD-(L)1内卷，鼓动全球知名药企争相引进TIGIT管线。事与愿违，TIGIT单抗的临床失败接踵而至。2022年3月，tiragolumab联合T药和化疗一线治疗广泛期SCLC的III期研究SKYSCRAPER-02未达到共同主要终点PFS和OS；5月，联合T药治疗PD-L1高表达晚期NSCLC的III期研究SKYSCRAPER-01未达到主要终点PFS。2025AACR，罗氏进一步披露了SKYSCRAPER-01完整的失败数据，共同终点PFS和OS均未达到。对TIGIT单抗寄予厚望的还有默沙东，但也未能幸免于败。2023年，vibostolimab与K药联用治疗NSCLC的II期研究KeyVibe-002显示疗效不如多西他赛；2024年，默沙东相继停止了TIGIT联合K药辅助治疗黑色素瘤、一线治疗SCLC的两项III期试验，最终在年末终止vibostolimab的临床开发项目。此外，BMS、诺华的TIGIT管线也相继遭遇临床失败，但阿斯利康、GSK、吉利德仍在坚持，TIGIT的命运或有转机。TIGIT的失败显示基础研究对机制的阐释可能并不透彻，理论上的联用潜力难以在复杂的临床研究中实现。TIGIT抑制剂与其他免疫检查点以及免疫细胞之间存在着错综复杂的相互作用(图5)，导致其在调节免疫系统时，可能会引发免疫相关不良反应。此外，联合用药的剂量、用药顺序、治疗周期等因素也需要仔细优化。图5. TIGIT靶点的作用机制针对非免疫检查点、相对较新的靶点，也有较多肿瘤治疗药物处于积极研发或已上市，如KRAS G12C小分子抑制剂、B7-H4 ADC、基于合成致死机制的SHP2小分子抑制剂、Claudin 6单抗/ADC/双抗/CAR-T、CDK2小分子抑制剂等。大约有三分之一的癌症携带KRAS(鼠类肉瘤病毒基因)突变，但是研发难点在于，KRAS蛋白缺乏明显的结合位点。KRAS G12C指第12位甘氨酸突变为半胱氨酸，药物分子可与半胱氨酸残基共价结合，从而发挥抑制效应。FDA分别在2021年5月和2022年12月，加速批准了全球首个和第二个KRAS G12C抑制剂，安进的sotorasib、Mirati(后被BMS收购)的adgrasib。中国药企快速跟进KRAS G12抑制剂的研发，信达生物的氟泽雷塞在2024年8月获批成为全球第三个KRAS G12C抑制剂。NMPA又在2024年11月、2025年5月相继批准益方生物/正大天晴的格索雷塞、艾力斯/加科思的戈来雷塞。这3个药物的首个适应症均为二线及以上治疗KRAS G12C突变的晚期NSCLC成人患者。值得注意的是，KRAS G12C抑制剂单药疗效可能会因为关联信号通路补偿性激活，安进和BMS的药物都是将KRAS锁定在off状态(与GDP结合状态)，而癌细胞可通过SHP2通路补偿KRAS通路信号。即使KRAS和SHP2均被抑制，癌细胞还可以通过PI3K通路来维持信号向下游传导。结语：新药研发，难而正确在“后PD-1时代”，肿瘤治疗药物的研发跳出了PD-(L)1研发内卷，呈现百花齐放、争奇斗妍的大好局面。科学界、企业界、资本界需要加强协作，推动更多源头创新的突破和转化。在新联合、新技术、新靶点的策略指引下，更多肿瘤疗法将不断问世，提供疗效更优、可负担性更好的治疗选择，加快向DIA会议提出的“全球人类健康共同体”迈进。一审| 黄佳二审| 李芳晨三审| 李静芝精彩推荐大事件 | IPO | 融资&交易 | 财报季 | 新产品 | 研发日 | 里程碑 | 行业观察 | 政策解读 | 深度案例 | 大咖履新 | 集采&国谈 | 出海 | 高端访谈 | 技术&赛道 | E企谈 | 新药生命周期 | 市值 | 新药上市 | 商业价值 | 医疗器械 | IND | 周年庆大药企 | 竞争力20强 | 恒瑞 | 石药 | 中生制药 | 齐鲁 | 复星 | 科伦 | 翰森 | 华润 | 国药 | 云南白药 | 天士力 | 华东 | 上药创新药企 | 创新100强 | 百济 | 信达 | 君实 | 复宏汉霖 | 康方 | 和黄 | 荣昌 | 亚盛｜康宁杰瑞｜贝达｜微芯｜再鼎｜亚虹跨国药企｜ＭＮＣ卓越｜辉瑞｜AZ｜诺华｜罗氏｜BMS｜默克｜赛诺菲｜GSK｜武田｜礼来｜诺和诺德｜拜耳供应链｜赛默飞｜药明｜凯莱英｜泰格｜思拓凡｜康龙化成｜博腾｜晶泰｜龙沙｜三星启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 中国医药手册