Лекарственно-индуцированное интерстициальное поражение легких у пациента с метастатической меланомой при использовании комбинации нурулимаб + пролголимаб

ObjectiveWe investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system.MethodsWe investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy.ResultsSixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days).ConclusionsThe incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients.

Drug-induced lung injury (DLI) results from the specific use of a drug, including prescription drugs, over-the-counter drugs, and supplements. A DLI is an adverse drug reaction that occurs in the pulmonary system including the lungs, bronchi, and pulmonary vessels. The following diagnostic criteria are generally used: (1) history of ingestion of a drug known to induce lung injury, (2) the clinical manifestation reported to be induced by a drug, (3) exclusion of other causes of the clinical manifestation, (4) improvement of the clinical manifestations after drug discontinuation, and (5) exacerbation of the clinical manifestations after resuming the drug. Pathogenetic mechanisms of DLI have not been precisely elucidated, but two possible mechanisms have been suggested. First, there are cytotoxic effects of drugs on alveolar type II and airway epithelial cells or vascular endothelial cells. The cytotoxic effects may be mediated by reactive oxygen species, proteases, and cytokines. Second, activation of immune cells may promote the development of DLI through acquisition of immunogenicity by binding of a drug or its metabolite to cytoplasmic proteins as a hapten. These two mechanisms may be involved in the pathogenesis of DLI independently or in combination, and they may be modified by a variety of host and environmental factors, such as genetic predisposition, age, underlying lung diseases, and interactions with concomitant drugs.

All cytotoxic antineoplastic drugs can potentially cause drug-induced lung injury (DLI), although the frequency and type of DLI vary and the time of DLI onset depends on the drug. Risk factors for DLI include longer treatment time, poor performance status, heavy smoking history, and underlying lung comorbidities. The risk of DLI caused by cytotoxic antineoplastic drugs increases when they are combined with other antineoplastic drugs and irradiation. Therefore, all patients treated with cytotoxic antineoplastic drugs are at risk of DLI. During treatment with cytotoxic antineoplastic drugs, patient oxygen saturation should be monitored by oximetry. When respiratory symptoms occur, it is important to suspect DLI and to perform computed tomography immediately to diagnose DLI.

The standard therapeutic strategy for patients with advanced cancer is treatment with antineoplastic drugs. With the progress in the development of antineoplastic drugs, the prognosis of these patients has improved, despite the difficulty of achieving a complete cure. Molecular target antineoplastic drugs have often provided a paradigm shift in cancer therapy and currently hold a prominent position in cancer therapeutic strategies. While these drugs have clinical benefits, the toxicity profile of these drugs is different from that of conventional cytotoxic chemotherapy. Molecular target antineoplastic drugs consisting of various types of molecules may demonstrate diverse characteristics, although drug-induced lung injury (DLI) is commonly observed in treatment with most of these antineoplastic drugs. In this chapter, reports of DLI associated with molecular target neoplastic drugs were reviewed in order to understand its characteristics and thereby lead to prevention of its occurrence and exacerbation. Diverse patterns of DLI have been commonly observed in patients treated with molecular target antineoplastic drugs, whereas similar DLI patterns have been obtained from various drug types. The incidence and frequency of fatality from DLI also display a wide range. These events were more frequently observed in Japanese patients than in other ethnic groups, suggesting the association of ethnicity with the development and severity of DLI. Clinicians should note the diversity of DLI and the role of ethnicity in DLI in treatment with molecular target antineoplastic drugs.

Recent studies have not only shown better prognosis of lymphoma with the advancement of therapeutic drug development, but also suggested more attention should be paid to drug-induced lung injury. Early diagnosis is critical for treatment of drug-induced lung injury. 18F-FDG-PET/CT, the standard imaging methodfor prognosis evaluation of Hodgkin's lymphoma and some non-Hodgkin's lymphoma, has also shown the potential for early detection of drug-induced lung injury in our study. A total of 579 lymphoma patients evaluated by 18F-FDG-PET/CT between June 2016 and March 2018 are studied retrospectively. Clinical and imaging characteristics are described in 32 patients (average age of 55), who were diagnosed with drug-induced lung injury. The incidence of drug-induced lung injury was 5.53% (32/579); most of the chemotherapy regimens include rituximab (90.63%, 29/32). Twelve patients demonstrated fever, cough, and dyspnea, and the other 20 had no significant symptoms. 18F-FDG-PET/CT showed multiple or diffused distribution of ground glass and patchy shadows, with increased FDG uptake in both lungs (SUVmax 2.28 ± 1.13, standardized uptake ratio-blood pool, SUR-BP = 0.59-4.07, median SUR-BP 1.32). SUVmax and SUR-BP in patients with symptoms (SUVmax 3.03 ± 1.33 and SUR-BP 2.12 ± 1.06) were significantly higher than in those without symptoms (SUVmax 1.84 ± 0.70 and SUR-BP 1.18 ± 0.48) (P = 0.002 for both SUVmax and SUR-BP). After temporary drug withdrawal, changing chemotherapy regimens, and corticosteroid usage, the pulmonary lesions in all patients were relieved, confirmed with chest CT. Drug-induced lung injury can be a co-finding during 18F-FDG-PET/CT assessment of lymphoma. With positive correlation between FDG uptake and symptoms, 18F-FDG-PET/CT provided value in early detection of lung injury in asymptomatic patients.

BACKGROUNDAll drugs have the potential to cause drug-induced lung injury both during and after drug administration. Acetaminophen has been reported to cause drug-induced lung injury, although this is extremely rare. Herein, we present an extremely rare case of acetaminophen-induced pneumonia.CASE SUMMARYA healthy 35-year-old Japanese woman visited a neighborhood clinic with complaints of fever and malaise following a tick bite. Her treatment included 1,500 mg acetaminophen (Caronal®) and subsequently minocycline (200 mg) and acetaminophen (2,000 mg; Caronal®) daily when her condition did not improve; the patient was eventually hospitalized. The patient’s chest computed tomography (CT) revealed consolidation and ground-glass opacities in the right middle and lower lobes. Minocycline was shifted to sulbactam/ampicillin. However, her fever did not improve during follow-up, and her chest CT revealed extensive ground-glass opacities in the right middle and lower lobes and thick infiltrative shadows in the bilateral basal areas. Drug-induced lung injury was suspected; hence, acetaminophen was discontinued. The fever resolved immediately, and inflammatory response and respiratory imaging findings improved. A drug-induced lymphocyte stimulation test was performed against acetaminophen (Caronal®), and significant proliferation of lymphocytes was noted only for acetaminophen (stimulation index, 2.1).CONCLUSIONEven common drugs such as over-the-counter drugs can cause drug-induced lung damage.

Since imaging finding of drug-induced lung injury (DLI) is varying and nonspecific, diagnosis of DLI must be performed by the integration of clinical, imaging, and pathologic findings, when available. The roles of imaging evaluation in the diagnosis and treatment of DLI include detection of preexisting chronic fibrosing interstitial pneumonia as risk of DLI, early detection of DLI, diagnosis of DAD-type DLI for the estimation of prognosis, aids to differential diagnosis, follow-up examination including evaluation of treatment effect, and so on.

Drug-induced lung injury (DLI) comprises a wide variety of pathologies, each with a unique imaging pattern, so there are no characteristic imaging findings to establish diagnosis. When DLI is suspected, evaluation must exclude progression of underlying disease, infection, and mimicking diseases. Correct diagnosis requires integration of clinical information and radiologic, laboratory, and pathological findings when available. We describe the radiologic findings of DLI, the roles of the findings in the management of patients with DLI, and the limitations of radiologic diagnosis.

Advanced and metastatic melanoma has historically been one of the most difficult cancers to treat, with few treatment options. For over 20 years, dacarbazine chemotherapy was the only treatment approved by the US Food and Drug Administration for melanoma. In recent years, breakthroughs have been made in the areas of monoclonal antibody immunotherapies and genetically targeted therapies, leading to FDA approval of several new drugs for metastatic melanoma that have demonstrated improved patient response and survival. In an effort to understand the changing landscape of therapies for advanced and metastatic melanoma, we have reviewed 38 publicly available randomized clinical trials from http://ClinicalTrials.gov in metastatic and unresectable melanoma since the year 2000, to assess developments in the design and conduct of clinical trials over time and to compare the clinical efficacy of old and new therapies. We first present a brief history of FDA approvals of therapies for melanoma, followed by an exploration of trends in the patient population and demographics, eligibility criteria, and statistical methods of clinical trials over time. Next, we compare the efficacy results of old and new study treatments, examining the endpoints of progression-free survival, overall survival, and response rate. Overall, we find that the clinical trial population largely reflected the general population of patients with melanoma in demographic factors, with the exception of patient age. Our findings suggest that the developments of immunotherapies and targeted therapies have improved patient trial results on the discussed endpoints.

The lungs are vulnerable to toxins because of their large surface area and act as a metabolic site for some substances. Drugs may induce specific respiratory reactions, or the lungs may be affected as part of a generalized response. Drug-induced lung injury (DLI) can involve the airways, lung parenchyma, mediastinum, pleura, pulmonary vasculature, and/or the neuromuscular system. The most common form of DLI is drug-induced interstitial lung disease. There are no disease types specific to DLI, and DLIs are diagnosed on the basis of clinical findings, chest CT images, and histopathologic findings. The first principle of management of DLI is early detection and cessation of treatment with the suspected drug. Response to corticosteroid therapy depends on the histopathologic pattern of drug-induced interstitial lung disease. Prognosis depends on the specific drug and underlying clinical, physiologic, and pathologic severity of lung disease. To minimize DLI morbidity and mortality, all health-care providers should be familiar with the possible adverse effects of medications they prescribe. Individual variability in drug response is an important concern in clinical practice and drug development. Such variability is multifactorial and includes extrinsic factors such as environmental features and genetic and intrinsic factors that affect the pharmacokinetics and pharmacodynamics of drugs.

Background. In an era of breakthroughs in cancer immunotherapy, CheckMate 067 studies declared the combination of PD-1 and CTLA-4 inhibitors a new standard of care for patients with metastatic melanoma (MM). A significant limitation of the widespread use of the combination of ipilimumab and nivolumab in routine clinical practice is the high risk of severe immune-mediated adverse events. Prolgolimab and nurulimab are a combination of fixed doses of original monoclonal antibodies (manufactured by JSC "BIOCAD," Russia) to the PD-1 receptor (prolgolimab) and the CTLA-4 receptor (nurulimab) (3:1 ratio). This paper presents the results of an international, multicenter, double-blind, placebo-controlled, comparative, randomized, phase II OBERTON clinical study to investigate the efficacy and safety of nurulimab + prolgolimab combination therapy with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable melanoma (uRM) or MM (NCT03913923). Materials and methods. The study included patients with uRM or MM who were not previously treated for metastatic disease. The patients were randomized into two groups (1:1). Patients in group 1 were treated with a nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) combination at a dose of 0.2 mL/kg (equivalent to 1 mg/kg of nurulimab and 3 mg/kg of prolgolimab) once every 3 weeks during the first 4 blinded infusions. Patients in group 2 received prolgolimab monotherapy at a dose of 3 mg/kg once every 3 weeks during the first 4 blinded infusions. Starting from infusion 5, patients in both groups received open prolgolimab 1 mg/kg once every 2 weeks. The primary endpoint of the study was progression-free survival (PFS). The study is registered on ClinicalTrials.gov under the number NCT05732805 and is currently ongoing, but recruitment of new patients has been completed. Results. One hundred seventeen patients were randomized and received at least one dose of the study therapy. At a median follow-up of 16.79 months, the median PFS was 12.2 (4.9; not achieved) months in the nurulimab + prolgolimab group and 2.8 (1.5; 4.7) months in the prolgolimab monotherapy group (95% confidence interval 0.36-0.90, hazard ratio 0.57). PFS at 24 months was 41% in the nurulimab + prolgolimab group and 25.4% in the prolgolimab monotherapy group. In both groups, the therapy was well tolerated. Grade 3-4 immune-mediated adverse events were reported in 15.5% of patients who received nurulimab + prolgolimab, compared with 1.7% of those who received prolgolimab alone. The most frequent grade 3-4 treatment-related adverse events in both treatment groups were increased alanine aminotransferase and aspartate aminotransferase and asthenia. Overall, the safety profile was favorable, as expected for the class of immune checkpoint inhibitors, anti-CTLA-4, and anti-PD-1 monoclonal antibodies. Discussion. The results demonstrate a favorable safety profile in both the nurulimab + prolgolimab combination and prolgolimab monotherapy groups as the first-line treatment for uRM or MM. The assessment of the primary endpoint, PFS, showed the benefit of combination immunotherapy followed by switching to prolgolimab compared to prolgolimab alone. Conclusion. Combination immunotherapy with the CTLA-4 inhibitor nurulimab and the PD-1 inhibitor prolgolimab, available as a combination of solutions of two drugs in a single vial, with a further switch to monotherapy with prolgolimab, can fill an important niche in the treatment of patients with uRM or MM. Confirmation of the obtained data on the efficacy and safety of the combined regimen of nurulimab + prolgolimab in comparison with PD-1 inhibitor monotherapy is expected from the ongoing phase III BCD-217-2 OCTAVA study (NCT05732805).

Background: BCD-217-2/OCTAVA (NCT05732805) is an international, multi-center, randomized, double-blind, placebo-controlled phase III study conducted to access the efficacy and safety of prolgolimab+nurulimab (BCD-217) combination therapy with continued prolgolimab therapy compared to prolgolimab monotherapy as 1st line treatment for patients (pts) with unresectable or metastatic melanoma (un/mM). BCD-217 is a fixed-dose combination of nurulimab (aCTLA-4, 5 mg/ml) and prolgolimab (aPD-1, 15 mg/ml) was recently approved as the 1st line treatment for un/mM in Russia. Here we present the primary analysis of the study. Methods: Pts with unresectable or metastatic cutaneous melanoma (IIIC-IVM1a-c) with treatment- naïve for unresectable/metastatic disease were randomized in 2 treatment arms: combination drug containing nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) at a dose of 0.2 ml/kg Q3W during the first four blinded infusions (nuru+prolgo arm) and prolgo arm received prolgolimab monotherapy at a dose of 3 mg/kg Q3W during the first four blinded infusions. Then both arms received prolgolimab maintenance up to two years. The primary endpoint of the study was progression-free survival (PFS). Results: 271 pts were randomized to nuru+prolgo (n=135) or prolgo monotherapy (n=136) arms. After the median of 15.8 mo follow-up the median PFS (mPFS) was 15.4 (10.3; ND) mo in the nuru+prolgo group and 10.8 (4.7; ND) mo in the prolgo monotherapy group (95% CI, HR 0.68 (0.482; 0.957), iRECIST). The mPFS benefit of nuru+prolgo arm compared to prolgo arm are maintained in RECIST 1.1 assessment: 9.9 mo vs 2.8 mo, respectively. ORR and DCR were also higher in NURU+PROLGO arm. mOS was not reached in both groups (95% CI, HR 0,88, (0.50; 1.55)). 12-mos OS was 84% in each arm. Grade 3-4 treatment-related AE were reported in 16.3% of pts in nuru+prolgo arm compared to 14.0% - prolgo arm. Immune-related AEs (irAE) of all grades were reported in 52.6% of cases in nuru+prolgo arm and 32.4% of cases - in prolgo arm (p 0.0007). Majority of them were mild. The proportion of gr.≥3 irAEs was 13.3% vs 5.9% in nuru+prolgo arm and prolgo arm, respectively (p 0.04). Treatment discontinuation due to AE was reported in 9.6% of cases for nuru+prolgo vs 4.4% of cases for prolgo arm. Conclusions: OCTAVA trial resuts demonstrated that the fixed-dose combination of nurulimab + prolgolimab is significantly more effective than aPD-1 monotherapy without a serious deterioration of the safety profile in patients with metastatic or unresectable cutaneous melanoma as 1st line therapy. Citation Format: Lev Demidov, Igor Samoylenko, Galina Kharkevich, Kristina Orlova, Vladimir Moiseenko, Igor Utyashev, Daniil Stroyakovskiy, Vadim Kozlov, Anastasia Mochalova, Svetlana Demidova, Marina Lyadova, Andrey Kutkovich, Pavel Skopin, Nadezhda Kovalenko, Sufia Safina, Vitaliy Volkov, Yulia Semiletova, Vera Vaschenko, Nikolaiy Kislov, Artem Poltoratsky, Irina Shumskaya, Sergey Kolomiets, Alexander Sobolev, Igor Belogortsev, Svetlana Odintsova, Sameer Rastogi, Timur Andabekov, Anastasia Zimina, Konstantin Penkov, Anna Semenova, Alexey Obukhov, Vasiliy Belyakovsky, Oleg Gladkov, Rakesh Neve, Natalia Falaleeva, Elena Poddubskaya, Amale Vaibhav, Dmitriy Kirtbaya, Yana Chapko, Maria Smagina, Irina Sorokina, Yulia Linkova, Arina Zinkina-Orikhan, Fedor Kriukov, Anton Lutsky, Evgenia Mikhailova. Proved clinical benefit of low-dose anti-CTLA4 + anti-PD-1 immunotherapy versus mono anti-PD-1 therapy in patients unresectable or metastatic melanoma: Phase III OCTAVA trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 653.

Immune checkpoint inhibitors control effector mechanisms and work to restore downregulated T-cells in patients with melanoma. Examples of such include programmed death-1 inhibitors and lymphocyte-activating gene 3 inhibitors. The combination of nivolumab, a programmed death-1 inhibitor, and relatlimab-rmbw, a lymphocyte-activating gene 3 inhibitor, has shown antitumor activity and improved progression-free survival in patients with unresectable or metastatic melanoma. The fixed-dose combination of nivolumab and relatlimab immunotherapy is approved for adults and pediatrics 12 years of age or older with metastatic or unresectable melanoma. Volume of distribution is 6.6 L for relatlimab and nivolumab, and half-life is 27 and 26 days, respectively. Clearance at steady state is 7.6 mL/h for nivolumab and 5.5 mL/h for relatlimab. Sex, age, race, and mild hepatic/renal impairment had no clinical effect on clearance. The exposure-response relationship and pharmacodynamic response for the safety and effectiveness of nivolumab/relatlimab-rmbw have not been fully characterized. Safety concerns include severe and fatal immune-mediated adverse reactions, infusion-related reactions, and complications of allogeneic hematopoietic stem cell transplantation, and fetal toxicity. Dosing is determined by patient's age and weight. Solution is infused over a 30-minute timeframe. In the RELATIVITY-047 trial, patients received nivolumab or nivolumab/relatlimab-rmbw. Results showed superiority of dual therapy over monotherapy with a progression-free survival of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) and hazard ratio of 0.75 (95% CI, 0.62-0.92); P = 0.006, respectively. No safety concerns were observed compared with monotherapy with treatment-related adverse events occurring in 18.9% of patients on combination therapy compared with 9.7% on nivolumab alone. The novel mechanism and improvement in progression-free survival compared with standard of care highlight the therapeutic advancement of nivolumab/relatlimab-rmbw in the treatment of unresectable and metastatic melanoma.

New-onset uveitis during CTLA-4 blockade therapy with ipilimumab in metastatic melanoma patient

In this editorial, we comment on the article by Zhao et al which highlighted how patients having nonalcoholic fatty liver disease (NAFLD) were more susceptible to drug-induced lung injury (DILI). This article looked at the downstream effects of metabolic profiles and biochemical processes after medication and substance use. Although previous studies looked at how NAFLD and DILI were related, there is a lack of information on the consequences of everyday medication and substance use. NAFLD is one of the most common chronic liver diseases worldwide and it has been found to be closely related to metabolic syndrome and cardiovascular disease. The aim of this editorial is to analyze the interaction between NAFLD and DILI, what clinical manifestations can occur and what the prognosis of these patients will be.