Nivolumab in the treatment of metastatic squamous cell carcinoma of the anal canal

What is cancer immunotherapy?

Immunotherapy is a set of treatments that are aimed at activating the immune system and causing it to destroy tumor cells. The rapid development of this area in recent years is due to the achievements of molecular genetics and genetic engineering. Many researchers and doctors have high hopes for immunotherapy. It often helps prolong the life of patients with advanced cancer who are not helped by classical chemotherapy drugs.

Currently, different types of immunotherapy are used in oncology: anticancer vaccines, reprogrammed T-lymphocytes, cytokines, oncolytic viruses.

A separate group consists of checkpoint inhibitors , which can simultaneously be classified as immunotherapy drugs and targeted drugs. Each of these drugs has a specific target - a molecule ( checkpoint ) that suppresses the immune system and prevents it from attacking the tumor.

In food, control points are needed so that the immune system can restrain itself and not attack healthy tissue. This prevents autoimmune diseases. Cancer cells can use checkpoints for protection.

Which control point does the opdivo block?

Cancer cells produce tumor antigens , substances that the immune system recognizes as foreign. In order for immune cells - T-lymphocytes - to begin attacking tumor tissue, they must “get acquainted” with its antigens. As a result of this “acquaintance,” the lymphocyte is activated, multiplies, and its numerous clones go in search of cancer cells.

However, on the surface of T-lymphocytes there are special receptor proteins - PD-1 . Tumor cells can display the protein ligand of this receptor, PD- L1, . PD-1 and PD-L1 fit together like a key to a lock. As a result, the T lymphocyte cannot be activated and does not attack the tumor.

Nivolumab blocks the PD-1 protein, so the T lymphocyte no longer receives a negative signal. It is again able to activate and destroy cancer cells.

For what types of cancer is Opdivo used?

Opdivo has now been shown to be beneficial in a number of cancers. It is used alone or in combination with other anticancer drugs.

Melanoma . Nivolumab is often used for advanced melanoma and is often given in combination with another checkpoint inhibitor, ervoy ( ipilimumab ). Indications for use of the drug:

• Melanoma that cannot be removed surgically or has metastasized.
• Melanoma, which was surgically removed but managed to metastasize.
• To prevent recurrence after melanoma and lymph nodes affected by cancer cells have been removed.

Non-small cell lung cancer . Opdivo is used if the tumor is accompanied by metastases, and if chemotherapy with platinum drugs does not help (during treatment the tumor grows, the patient's condition worsens). If certain mutations are identified in cancer cells, treatment is started with appropriate targeted drugs; if they do not help, nivolumab is prescribed.

Kidney cancer . Opdivo is prescribed for late-stage malignant kidney tumors when other drugs do not help.

Bladder cancer . The drug is used for urothelial carcinoma, local or with metastases, if the tumor grows during therapy with platinum-based chemotherapy.

Head and neck cancer . Nivolumab may be effective for squamous cell carcinoma that has recurred or metastasized when chemotherapy drugs have failed.

Liver cancer . The drug is used for hepatocellular carcinoma that has lost sensitivity to sorafenib .

Colorectal cancer . Opdivo can help adults and children over 12 years of age with colon and rectal cancer that has metastasized and does not respond to drugs such as fluoropyrimidine, oxaliplatin, or irinotecan.

Hodgkin's lymphoma . The drug may help if the tumor progresses or recurs after:

• autologous stem cell transplantation and treatment with brentuximab vedotin;
• using at least three types of treatment, including autologous stem cell transplantation.

Research into the effectiveness of Opdivo in various cancers is currently ongoing.

Nivolumab in second-line treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. A new promising direction in the treatment of patients with NSCLC is associated with the use of immune checkpoint inhibitors, in particular drugs that suppress the activity of the PD-1 pathway. These drugs demonstrate pronounced efficacy in various histological subtypes of disseminated NSCLC, progressing against the background of previous platinum-containing chemotherapy. The article discusses a clinical case of the successful use of nivolumab in the second line of therapy for metastatic lung adenocarcinoma.

Introduction

Lung cancer is the most commonly diagnosed malignancy in the world [1]. In the Russian Federation, lung cancer occupies a leading position in the structure of the incidence of malignant neoplasms among the male population and mortality in men and women - 17.6 and 17.4%, respectively. Non-small cell lung cancer (NSCLC) accounts for 80–85% of all forms of lung cancer, and almost 70% of cases have advanced disease at the time of diagnosis [2]. In this regard, the search for effective methods for treating locally advanced and metastatic forms of NSCLC remains one of the main problems in oncology.

Current standards of drug therapy for patients with NSCLC, with the exception of patients with driver mutations, are quite limited. Thus, in the first line, platinum-containing drugs are used both in monotherapy and in combination. These drugs have comparable efficacy with overall response rates ranging from 30 to 60%. The median survival in the group of platinum-containing regimens is 8–10 months, the time to progression is 4–6 months [3]. Treatment options for advanced or refractory NSCLC are extremely limited. The drugs currently recommended as second-line therapy for NSCLC include the cytotoxic drugs docetaxel and pemetrexed (the latter is indicated for patients with non-squamous cell carcinoma) [4, 5]. Since pemetrexed is one of the drugs of choice in the first-line treatment of patients with non-squamous NSCLC, docetaxel plays a leading role in subsequent drug treatment [6]. The clinical effectiveness of second-line drug therapy is insignificant: the objective response rate does not exceed 10%, the median progression-free survival (PFS) and overall survival is 3-4 and 7-9 months, respectively [5].

In recent years, there has been a steady positive trend in the treatment of patients with NSCLC due to the introduction of new methods. In particular, the prescription of highly effective targeted drugs taking into account the molecular subtype of the tumor has improved the prognosis of the disease, increased the effectiveness of treatment, and increased overall survival to 20 months or more in patients with driver mutations (EGFR, ALK, etc.). Meanwhile, the frequency of detection of mutations is 15–20% of all cases of NSCLC [7].

Today, a new direction is actively developing – immuno-oncology. Understanding the mechanisms of interaction between the tumor and the immune system has made it possible to develop new immunotherapeutic drugs—immune control point blockers.

In 2015, nivolumab and pembrolizumab were approved for clinical use in second-line treatment of patients with NSCLC in the United States. These drugs block the interaction between the programmed cell death receptor 1 (PD-1) and its ligands PD-L1 and PD-L2. Inhibition of PD-1 and its ligands PD-L1 and PD-L2 promotes the reactivation of tumor-specific T lymphocytes and prolongation of their antitumor effect [8].

Other immune checkpoint inhibitors are being actively studied in clinical trials.

The use of anti-PD-1 and anti-PD-L1 drugs has fundamentally changed the outlook for patients with advanced NSCLC that has progressed after prior platinum-containing chemotherapy. This is confirmed by the results of international randomized phase III studies, in particular CheckMate 017 involving patients with squamous cell lung cancer and CheckMate 057 involving patients with non-squamous NSCLC [8, 9].

The first interim analysis of CheckMate 017 showed a significant increase in median overall survival in the nivolumab group, 9.2 months compared with 6.0 months in the docetaxel group (p

In the CheckMate-057 study, the objective response rate reached 19 versus 12%, median overall survival was 12.2 versus 9.4 months, and one-year survival was 51 versus 39% in favor of nivolumab. The safety profile of nivolumab, in contrast to that of docetaxel, is more favorable [11].

According to these studies, PD-1 inhibitors, in particular nivolumab, are becoming a new option in the fight to increase survival, time to progression, and improve the quality of life of patients with disseminated NSCLC.

Clinical case

Patient T., born in 1965. In January 2013, when performing an X-ray of the lungs at the place of residence, an infiltrative shadow was revealed in the projection of the upper lobe of the right lung. I did not contact doctors about this. In January 2015, complaints of cough appeared. The patient came to the clinic.

Computed tomography (CT) of the chest on March 21, 2015: signs of post-inflammatory fibrosis of the subsegment of the upper lobe of the right lung, against which bronchoalveolar cancer cannot be excluded.

On March 26, surgical treatment was performed at the Irkutsk Regional Oncology Center - extended upper right lobectomy with bilateral mediastinal lymphadenectomy.

Histological conclusion: lung adenocarcinoma with areas of highly and moderately differentiated structure. No activating mutations in the EGFR gene or ALK translocation were detected.

Based on the histological report and examination, a diagnosis was made: cancer of the upper lobe of the right lung pT2N2M0, stage IIIa. As part of complex treatment, six courses of adjuvant polychemotherapy (PCT) were carried out according to the scheme “pemetrexed 500 mg/m2 intravenously + cisplatin 75 mg/m2 intravenously on the first day of a 21-day cycle” (last course – August 2015). She tolerated PCT courses with severe emetogenic toxicity. At the next follow-up examination in March 2021, according to CT data, asymptomatic progression of the disease was revealed due to the appearance of an additional space-occupying lesion in the left supraclavicular region and metastases in the costal pleura.

Additional ultrasound examination of the supraclavicular and subclavian lymph nodes showed damage to the supraclavicular lymph nodes on the left, with invasion into the soft tissue.

An ultrasound-guided biopsy was performed. Adenocarcinoma metastasis was morphologically confirmed.

On April 21, 2021, the first course of first-line chemotherapy was started according to the regimen “pemetrexed 500 mg/m2 + carboplatin AUC6” (cisplatin was not prescribed due to a history of severe emetogenic toxicity). Three courses were completed, and grade 2 hematological toxicity (leukopenia) was observed according to the CTC criteria. According to the control CT, the condition is without negative dynamics, the formation in the supraclavicular region has decreased.

PCT was increased to six courses at the same doses using granulocyte colony-stimulating factor. After six courses, the patient’s condition worsened: pain appeared in the left half of the chest, shortness of breath with moderate physical activity.

Control CT in August 2021: hydrothorax on the left, an increase in the number of formations in the pleura, growth of the supraclavicular lymph node on the left.

The results of medical genetic testing of the histological block showed positive expression of PD-L1.

By the decision of the medical commission, the patient was prescribed immunotherapy with nivolumab 3 mg/kg (200 mg per injection) intravenously once every two weeks, long-term, as a second line starting from September 2021, with evaluation of the effect after three months.

The patient tolerated the administration of the drug satisfactorily; no adverse events, including immune-mediated reactions, were recorded.

After four injections of the drug, the patient's condition improved.

Follow-up examination in December 2021 (after six injections): a decrease in the size and number of formations in the pleura on the left, a decrease in the amount of contents in the pleural cavity on the left, no signs of enlargement of the supraclavicular lymph node on the left. The dynamics were assessed as partial regression according to RECIST 1.1 criteria. Administration of the drug was continued as before until progression, with the effect assessed every three months.

In March 2021, the X-ray picture did not differ from that in December 2021: partial regression of the tumor remained. The administration of the drug was continued.

Clinically, the patient’s condition (as of August 2021) is without negative dynamics, ECOG is 0. The administration of drugs is tolerated satisfactorily, the quality of life does not suffer. The patient leads an active lifestyle. The next follow-up survey is scheduled for September 2021. Discussion

When choosing and conducting therapy for advanced non-squamous NSCLC, it should be taken into account that the disease at this stage is incurable. Therefore, the main goal of treatment is to balance the therapeutic effect (including survival) and the quality of life of patients [12, 13].

The reviewed clinical case shows a potential beneficial effect on long-term treatment outcomes when using nivolumab in the second line of treatment for advanced NSCLC. During treatment (the patient receives nivolumab for a year), partial remission is noted. In addition, the patient’s quality of life and social status are maintained throughout the entire period of use of the immuno-oncological drug.

Nivolumab significantly improves survival rates in patients with metastatic NSCLC, progressing after previous platinum-containing therapy, and preserves quality of life, as confirmed by the results of international studies.

Data from a phase 1 study of nivolumab monotherapy in pretreated patients with NSCLC, analyzing five-year overall survival, were presented at AACR 2017. In heavily pretreated patients with NSCLC who received three or more lines of therapy, the response rate with nivolumab reached 17.6%, with one-year overall survival of 42%, two-year survival of 23%, and five-year survival of 16% [11, 14]. Given the positive results from early phase studies, phase 3 studies were conducted comparing the efficacy of nivolumab with standard second-line therapy. Because in second-line therapy, the histological subtype of NSCLC matters in the choice of regimen, two separate studies were conducted for squamous and non-squamous NSCLC.

The international randomized CheckMate 017 trial included patients with squamous cell NSCLC progressing after platinum-containing chemotherapy. The researchers compared the efficacy and safety of nivolumab 3 mg/kg IV every two weeks and docetaxel 75 mg/m2 IV every three weeks. The primary endpoint was overall survival. In addition, PFS, objective response rate, and quality of life were assessed [11]. Median survival was 9.2 months (95% confidence interval (CI) 7.3–13.3) in the nivolumab group and 6.0 months (95% CI 5.1–7.3) in the docetaxel group. Nivolumab had a 41% lower risk of death than docetaxel (relative risk (RR) 0.59; 95% CI 0.44 to 0.79; p

The international randomized CheckMate 057 trial included patients with non-squamous NSCLC progressing after platinum-containing chemotherapy. The researchers compared the efficacy and safety of treatment with nivolumab 3 mg/kg intravenously every two weeks and docetaxel 75 mg/m2 intravenously every three weeks. The primary endpoint was overall survival. The study also assessed PFS, objective response rate, and quality of life [11]. Overall survival in the nivolumab group was superior to that in the docetaxel group. The median overall survival in the nivolumab group (292 patients) was 12.2 months (95% CI 9.7–15.0), in the docetaxel group (290 patients) 9.4 months (95% CI 8.1–10.7 ) (RR 0.73; 95% CI 0.59–0.89; p = 0.002). One-year overall survival was 51% (95% CI 45.0–56.0) in the nivolumab group and 39% (95% CI 33.0–45.0) in the docetaxel group. At extended follow-up, overall survival at 18 months reached 39% (95% CI 34.0–45.0) with nivolumab and 23% (95% CI 19.0–28.0) with docetaxel. The response rate was 19% in the nivolumab group and 12% in the docetaxel group (p = 0.02). Although the median PFS in patients treated with nivolumab was not significantly different from that in patients treated with docetaxel (2.3 and 4.2 months, respectively), the 1-year PFS rate in the nivolumab group was higher than in the docetaxel group (19 and 8% respectively). Nivolumab was associated with superior efficacy compared to docetaxel for all endpoints in subgroups based on target levels of PD-1 ligand expression on tumor cell membranes (≥ 1%, ≥ 5%, and ≥ 10%). Grade 3–4 adverse events occurred in 10% of patients in the nivolumab group and in 54% of patients in the docetaxel group, rates similar to those in the CheckMate 017 study [15, 16].

The results of these studies allow us to conclude that nivolumab is the drug of choice in the second line of treatment for NSCLC [6].

Conclusion

The reviewed clinical case confirms the high effectiveness of immuno-oncological drugs, such as the PD-1 blocker nivolumab, in metastatic non-squamous NSCLC. It is important that with the use of nivolumab not only an objective response is achieved, but also the achieved effect and quality of life are maintained for a long time.

Thus, PD-1 inhibitors are becoming the new standard of second-line therapy for patients with NSCLC.

How is nivolumab used?

The drug is produced in the form of a solution for intravenous infusion. A regular IV or port system is used if it was implanted in the patient according to indications. The procedure lasts on average one hour .

Some patients experience a reaction to the infusion, which manifests itself in the form of symptoms such as fever, chills, itching, redness and rash on the skin, difficulty breathing, severe weakness, and dizziness. Any discomfort should be reported to your doctor. The doctor may slow down the rate of infusion or stop it altogether.

The frequency of procedures varies:

• If nivolumab is used alone : ​​once every 2 weeks.
• If nivolumab is used in combination with ipilimumab : 1 time every 3 weeks - the first 4 doses; then once every 2 weeks.

Treatment is continued as long as it is beneficial and the patient does not experience serious side effects.

How is the patient's condition monitored during treatment?

In general, all targeted drugs, including nivolumab, are considered safer than chemotherapy drugs. However, Opdivo can sometimes cause serious and even life-threatening complications. Therefore, you need to properly prepare for the course of treatment, and regularly monitor the patient’s condition during it.

At the preparation stage, an examination is carried out. The doctor asks the patient some questions to find out important information:

• Have you ever had an allergic reaction to medications before?
• Are you currently taking any medications, vitamins, dietary supplements?
• Have you had an organ transplant?
• Have you ever been diagnosed with an autoimmune disease?

A woman should tell her doctor if she is pregnant or suspects she is pregnant if she is breastfeeding.

During the course of treatment, you will have to regularly undergo general and biochemical blood tests: this is necessary to monitor the number of red blood cells, leukocytes and platelets, kidney and liver function.

Nivolumab in the treatment of metastatic squamous cell carcinoma of the anal canal

The February 2021 issue of The Lancet published data on the effectiveness of nivolumab immunotherapy in treating HIV-infected patients with refractory metastatic anal squamous cell carcinoma.

“Squamous cell carcinoma of the anal canal is a rare disease, accounting for only 2% of all cases of malignant tumors of the gastrointestinal tract. Orphan disease. Nothing new in 20 years. Patients with local or regional recurrences usually receive surgical treatment. It can be cured in the early stages using a combination of radiation therapy and chemotherapy based on 5-fluorouracil and mitomycin" (Eng). “This regimen has not changed for 20 years, there are no randomized studies” (Kaskin) [3].

The study, conducted at 10 academic centers in the United States, enrolled patients who received at least one line of systemic therapy for surgically unresectable or metastatic anal cancer between May 14, 2015 and November 11, 2015. All had a life expectancy of at least 6 months with an ECOG physical status of 0-1. Patients with anal adenocarcinoma, active autoimmune disease or a history of autoimmune disease, or other comorbidities that required corticosteroid use were excluded from the study.

Nivolumab was administered intravenously every 2 weeks at a dose of 3 mg/kg. Patients achieved a median of 6 nivolumab treatments during the 10-month follow-up period. Toxicity was assessed at baseline before therapy and every 2 weeks before patients received their next dose of nivolumab. In addition, optional tumor samples were obtained from biopsies at baseline and after 2 doses of nivolumab. Radiological examinations consisted of CT or MRI at baseline and were repeated at 6-week intervals. The primary endpoint of the study, radiological response, was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

The study did not report any serious side effects. No patients with HIV infection experienced grade 4 adverse events, and no patients withdrew from the study due to treatment-related toxicity. One patient developed therapy-related autoimmune hypothyroidism, which resolved after a short course of corticosteroids. In another case, one patient was diagnosed with treatment-related grade 2 pneumonitis, which was successfully treated with corticosteroids and temporary cessation of nivolumab.

Blood test results from 30 patients who had blood drawn pre-treatment, before the 2nd, 4th and 6th dose of nivolumab, showed higher concentrations of PD-1 compared to patients who did not respond. Flow cytometry testing of pre-treatment biopsies revealed 40% higher PD-1 expression in patients who responded to nivolumab. This rate is significantly higher than the expression of PD-1 ligand observed in those patients who did not respond to nivolumab, the researchers reported [3].

At the interim database evaluation (May 16, 2021), 24 of 37 patients (24%) had disease progression; 16 patients died, although there were no treatment-related deaths. Dr. Eng and colleagues report that overall survival of HIV-associated patients with metastatic anal squamous cell carcinoma in the study was 11.5 months, which was significantly lower compared with 17 months in the Centers for Disease Control and Prevention. and Prevention) for the period from 2008 to 2012 [4].

“Immune checkpoint inhibitors may prolong overall survival compared with currently available treatment options, especially if used in the first lines of treatment.” More research is needed to confirm this. “Future studies would be wise to consider the use of nivolumab before distant metastases appear, and the combination of nivolumab with radiation therapy may also be promising,” says Kaskinu.

Immunotherapy with nivolumab promises to improve outcomes in patients with refractory metastatic anal cancer, including those with HIV infection, researchers say. The first results of the study were presented at ASCO, the final results were published on February 17 in the journal Lancet Oncology [1, 2]. Results from a phase II uncontrolled clinical trial showed that in 37 previously treated patients with metastatic anal squamous cell carcinoma who received at least one dose of nivolumab, 24% had radiologically demonstrated responses with limited toxicity. Median progression-free survival was 4.1 months and median overall survival was 11.5 months, for an overall survival of 48%. The study authors also noted that nearly 1 year after the start of the study, 6 of 9 participants were still receiving treatment after the end of the study. In an accompanying commentary, Stefano Caschinu, MD, PhD, of the Università di Modena e Reggio Emilia, Italy, acknowledges that these results offer hope. “For the first time in 20 years, there is something new in the treatment of metastatic squamous cell carcinoma of the anal canal” [3]. However, much remains to be learned about the use of immunotherapy for metastatic anal squamous cell carcinoma, says Dr. Kaskinu, noting that 75-80% of study participants did not benefit from nivolumab therapy.

This study may be the first completed study to treat metastatic anal cancer using immune checkpoint inhibitors, the researchers said. It may also be the first to include high-risk HIV-infected patients. Researchers note that up to 90% of cases of metastatic squamous cell carcinoma of the anal canal are associated with previous infection with human papillomavirus. “Provided that adequate CD4+ lymphocyte counts are maintained and close follow-up by an infectious disease specialist, we recommend that patients with HIV infection be considered for future clinical trials using immune checkpoint inhibitors so that these drugs can be further studied in a larger patient population,” they write.

Help ( NB! ) :

In Russia, nivolumab (PD-1 inhibitor) was registered on December 22, 2016 for only three indications:

• monotherapy for unresectable or metastatic melanoma in adults;
• monotherapy for unresectable or metastatic NSCLC after progression on chemotherapy;
• monotherapy for advanced renal cell carcinoma after previous systemic therapy.

Nivolumab is a human monoclonal antibody that blocks the interaction between the programmed death receptor (PD-1) and its ligands (PD-L1 and PD-L2). Nivolumab potentiates the immune response by blocking the binding of PD-1 to ligands PD-L1 and PD-L2.

Nivolumab is administered intravenously at a dose of 3 mg/kg over 60 minutes every 2 weeks until progression or intolerable toxicity. Patients should be under continuous monitoring (at least 5 months after the last dose of nivolumab), as adverse immune-mediated reactions can develop at any time during use or discontinuation of the drug.

When using nivolumab, immune-mediated adverse reactions are most often observed. Most of these adverse reactions, including severe ones, were managed with appropriate therapy or drug withdrawal. In the case of immunosuppressive therapy with glucocorticosteroids intended to eliminate adverse events, after improvement of the condition, the dose of glucocorticosteroids is reduced slowly over at least 1 month. Increasing or decreasing the dose of the drug is not recommended.

Sources:

1. Roxanne Nelson. Encouraging Results With Nivolumab in Metastatic Anal Cancer. https://www.medscape.com/viewarticle/864873
2. Van K Morris et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. The Lancet 2021. - Volume 18, No. 4, p446–453.
3. Stefano Cascinu et al. Anal cancer: from an orphan disease to a curable malignancy? https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30091-8/abstract
4. Laura J. Viens et al. Human Papillomavirus–Associated Cancers—United States, 2008–2012. https://www.cdc.gov/mmwr/volumes/65/wr/mm6526a1.htm
5. https://www.ascopost.com/https://clinicaltrials.gov/ct2/show/NCT02387996https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=7560c36a-e8e8-4092-8c46-e85f14a121e4&t
6. https://www.pharmvestnik.ru/

The material was prepared by the Department of NOIMTOiR: Doctor of Medical Sciences. T.Yu. Semiglazova, clinical resident E.A. Korobeynikova

What are the possible side effects?

The most common side effects with Opdivo include fatigue, muscle, bone and joint pain, diarrhea, decreased appetite, headaches, increased risk of respiratory tract infection, cough, nausea, itching and rash on the skin, fever, pain in the back and stomach, constipation.

In rarer cases, more serious complications are possible:

• Inflammation and scarring processes in the lungs (pneumonitis) . Manifests itself in the form of persistent cough, shortness of breath, and chest pain.
• Inflammation in the intestines (colitis) with the formation of ulcers . It manifests itself in the form of diarrhea, an increase in the amount of stool, blood impurities, and severe abdominal pain.
• Inflammation of the liver (hepatitis) . It manifests itself in the form of jaundice, severe nausea and vomiting, dark urine, pain under the right rib, and increased bleeding.
• Problems with the endocrine system (pituitary gland, thyroid, pancreas, adrenal glands) . The most common symptoms: increased fatigue, persistent headaches, weight gain or loss, dizziness, fainting, memory impairment, increased irritability, constipation, hair loss, increased amount of urine, constant thirst, decreased sexual desire.
• Renal disorders (nephritis, renal failure) . Possible symptoms: decreased amount of urine, blood in the urine, swelling in the ankles, decreased appetite.
• Skin disorders . Manifest in the form of rash, itching, blisters, ulcers on the mucous membranes.
• Inflammation of the brain (encephalitis) . Manifests itself in the form of fever, headaches, weakness, increased fatigue, confusion, tension in the neck muscles, hallucinations, and convulsions.
• Nervous system disorders . They manifest themselves as weakness, numbness and tingling in the arms and legs. Paralysis may occur.
• Eye disorders . They manifest themselves in the form of pain, redness of the eyes, blurred vision, and double vision.

Correct use of the drug, taking into account all indications and contraindications, and careful monitoring of the patient’s condition help prevent these conditions.

Opdivo 10 mg/ml 10 ml No. 1 bottle

Use of Opdivo

Monotherapy in adults - inoperable or metastatic melanoma; locally advanced or metastatic non-small cell lung cancer after previous chemotherapy; advanced renal cell carcinoma after previous systemic therapy.

Contraindications

Hypersensitivity; pregnancy and breastfeeding; age under 18 years (data on effectiveness and safety are not available).

Restrictions on use

Severe autoimmune diseases in the active stage, in which further activation of the immune system may pose a potential threat to life; moderate to severe liver dysfunction; severe renal dysfunction.

Selected
patient
groups The following patient groups did not participate in clinical studies:

• patients with baseline performance status >2, untreated brain metastases, autoimmune diseases, and patients receiving systemic immunosuppressants before the start of the study;
• Patients with symptomatic interstitial lung disease and ocular melanoma were excluded from clinical trials of non-small cell lung cancer and melanoma;
• patients with a history of grade 4 adverse reactions associated with previous anti-CTLA-4 therapy.

Due to the lack of data, nivolumab should be used with caution in these patient populations after individual risk-benefit assessment.

Use during pregnancy and breastfeeding

The drug is contraindicated for use during pregnancy and breastfeeding.

Side effects of Opdivo

• Infections and infestations: upper respiratory tract infection; bronchitis, pneumonia; rare encephalitis.
• Neoplasms benign, malignant and of unknown nature (including cysts and polyps): rare histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis).
• From the blood and lymphatic system: eosinophilia.
• From the immune system: infusion reactions, anaphylactic reactions, hypersensitivity.
• From the endocrine system: hyperglycemia, hypothyroidism, hyperthyroidism; adrenal insufficiency, hypopituitarism, hypophysitis, thyroiditis, diabetic ketoacidosis, diabetes mellitus.
• Metabolism and nutrition: decreased appetite; dehydration, metabolic acidosis.
• From the nervous system: peripheral neuropathy, headache, dizziness; polyneuropathy; rare Guillain-Barré syndrome, demyelination, myasthenic syndrome, autoimmune neuropathy (including paresis of the facial and abducens nerves).
• From the organ of vision: blurred vision, dry eyes; uveitis
• From the cardiovascular system: increased blood pressure, tachycardia, vasculitis; rare arrhythmia (including ventricular), atrial fibrillation.
• From the respiratory system: pneumonitis, shortness of breath, cough; pleurisy; rare pulmonary infiltration.
• From the gastrointestinal tract: diarrhea, nausea; colitis, stomatitis, vomiting, abdominal pain, constipation, dry mouth; pancreatitis; rare gastritis, duodenal ulcer.
• From the liver and biliary tract: hepatitis, hyperbilirubinemia; rare cholestasis.
• From the skin and subcutaneous tissue: rash, itching; vitiligo, dry skin, erythema, alopecia; erythema multiforme, psoriasis, rosacea, urticaria; rare toxic epidermal necrolysis3.
• From the musculoskeletal system: musculoskeletal pain, arthralgia; polymyalgia rheumatica.
• From the kidneys and urinary tract: tubulointerstitial nephritis, renal failure.
• General disorders and reactions to administration: increased fatigue; increased body temperature, edema (including peripheral); chest pain.
• From laboratory parameters: loss of body weight; increased activity of transaminases, lipase, amylase and alkaline phosphatase, increased creatinine levels, lymphopenia, leukopenia, thrombocytopenia, anemia, hyponatremia; increased concentration of total bilirubin, hypercalcemia, hypocalcemia, hyperkalemia. hypokalemia, hypomagnesemia, neutropenia, decrease in the absolute number of neutrophils, hypernatremia; rarely hypermagnesemia.
• Immunogenicity. Nivolumab, like other monoclonal antibodies, is immunogenic.

Overdose

No cases of overdose were identified.

Treatment: In case of overdose, treatment should consist of symptomatic drug therapy in accordance with the adverse reactions that occur with careful monitoring of the patient.

Routes of administration

Intravenously.

Nivolumab and pregnancy

Pregnancy during treatment with Opdivo and for 5 months after completion of the course is contraindicated. If the patient is of reproductive age and plans to be sexually active, you need to select effective methods of contraception together with your doctor.

Breastfeeding is also prohibited during treatment and for 3 months after it.

It is unknown whether treatment with nivolumab affects reproductive function. If the patient plans to have children in the future, you need to inform the doctor about this.

Opdivo®

Opdivo® can cause severe, including fatal, adverse reactions caused by effects on the immune system and due to its specific mechanism of action. Patients should be closely monitored (at least 5 months after the last dose) as adverse reactions due to Opdivo may occur at any time during use or after discontinuation of therapy. If an immune-mediated adverse reaction is suspected, adequate evaluation should be performed to confirm or rule out other etiologies. Based on the severity of the adverse reaction, use of Opdivo® should be discontinued with or without resumption of glucocorticosteroids.

In the case of immunosuppressive therapy with glucocorticosteroids intended to eliminate adverse reactions, after improvement of the condition, the dose of glucocorticosteroids is reduced slowly over at least 1 month. Rapid dose reduction may result in worsening severity or recurrence of adverse reactions. Immunosuppressive therapy with drugs other than glucocorticosteroids is prescribed if there is deterioration or lack of improvement with the use of glucocorticosteroids.

Opdivo should be discontinued while the patient is receiving an immunosuppressive dose of corticosteroids or undergoing immunosuppressive therapy.

Opdivo® should be discontinued for any recurrent moderate to severe immune-mediated adverse reactions and discontinued without resumption for severe immune-mediated pneumonitis and immune-mediated hepatitis, as well as life-threatening immune-mediated adverse reactions.

Use of Opdivo® in patients with rapidly progressing melanoma

Clinicians should discuss the delayed onset effect of Opdivo® before initiating treatment in patients with rapidly progressing disease.

Immune-mediated pneumonitis

Cases of severe pneumonitis or interstitial lung disease, including fatal cases, have been reported during therapy with Opdivo®. Patients should be monitored for signs and symptoms of pneumonitis, such as radiographic changes (eg, ground-glass opacity, inflammatory lesions), dyspnea, and hypoxia. Infections and disease-related symptoms must be excluded.

For grade 3 or 4 pneumonitis, use of Opdivo should be discontinued without resumption and glucocorticosteroids should be started at a dose equivalent to 2-4 mg/kg/day methyl prednisolone.

For grade 2 (symptomatic) pneumonitis, use of Opdivo® should be suspended and glucocorticosteroids should be started at a dose equivalent to 1-2 mg/kg/day methylprednisolone. If improvement occurs, the use of Opdivo® can be continued after a slow reduction in the dose of glucocorticosteroids. If deterioration or lack of improvement occurs that continues despite corticosteroids, the dose of corticosteroids should be increased to the equivalent of 2 to 4 mg/kg/day methylprednisolone and nivolumab should be discontinued without resumption.

Immune-mediated colitis

Cases of severe diarrhea or colitis have been reported during therapy with Opdivo®. Patients should be monitored for signs of diarrhea and additional symptoms of colitis, such as abdominal pain, mucus, or blood in the stool. Infections and disease-related symptoms must be excluded.

In case of grade 4 severity of diarrhea or colitis, the use of Opdivo® should be permanently discontinued and glucocorticosteroids should be started at a dose equivalent to 1-2 mg/kg/day methylprednisolone.

For grade 3 diarrhea or colitis, nivolumab should be suspended and glucocorticosteroids should be started at a dose equivalent to 1-2 mg/kg/day methylprednisolone. If improvement occurs, the use of Opdivo® can be continued after a slow reduction in the dose of glucocorticosteroids. If there is deterioration or lack of improvement that continues despite taking glucocorticosteroids, nivolumab should be discontinued without resumption.

In case of grade 2 severity of diarrhea or colitis, the use of Opdivo® should be suspended. Persistent diarrhea or colitis should be treated with corticosteroids at a dose equivalent to 0.5-1 mg/kg/day methylprednisolone. If improvement occurs, the use of nivolumab can be continued after a slow reduction in the dose of glucocorticosteroids. If deterioration or lack of improvement occurs that continues despite corticosteroids, the dose of corticosteroids should be increased to the equivalent of 1 to 2 mg/kg/day methylprednisolone and nivolumab should be discontinued without resumption.

Immune-mediated hepatitis

Cases of severe hepatitis have been reported during therapy with Opdivo®. Patients should be monitored for signs and symptoms of hepatitis, such as increased transaminases and total bilirubin. Infections and disease-related symptoms must be excluded.

For grade 3 or 4 increases in the level of transaminases and total bilirubin, the use of Opdivo should be discontinued without resumption and glucocorticosteroids should be started at a dose equivalent to 1 - 2 mg/kg/day methylprednisolone.

If the level of transaminases and total bilirubin increases in severity level 2, the use of Opdivo® should be suspended. Persistent elevation of these laboratory parameters should be corrected by administration of glucocorticosteroids at a dose equivalent to 1-2 mg/kg/day methylprednisolone. If improvement occurs, the use of nivolumab can be continued after a slow reduction in the dose of glucocorticosteroids. If deterioration or lack of improvement occurs that continues despite corticosteroids, the dose of corticosteroids should be increased to the equivalent of 1 to 2 mg/kg/day methylprednisolone and nivolumab should be discontinued without resumption.

Immune-mediated nephritis and renal dysfunction

Cases of severe nephritis or renal dysfunction have been reported with Opdivo® therapy and patients should be monitored for signs and symptoms. Most patients experienced an asymptomatic increase in serum creatinine. Disease-related etiology must be excluded.

With grade 4 increases in serum creatinine levels, the use of Opdivo® should be permanently discontinued and glucocorticosteroids should be started at a dose equivalent to 1 - 2 mg/kg/day methylprednisolone.

If there is a grade 2 or 3 increase in serum creatinine levels, the use of Opdivo® should be suspended and glucocorticosteroids should be started at a dose equivalent to 0.5 - 1 mg/kg/day methylprednisolone. If improvement occurs, the use of nivolumab can be continued after a slow reduction in the dose of glucocorticosteroids. If deterioration or lack of improvement occurs that continues despite corticosteroids, the dose of corticosteroids should be increased to the equivalent of 1-2 mg/kg/day methylprednisolone and nivolumab should be discontinued without resumption.

Immune-mediated endocrinopathy

Cases of severe endocrinopathy, including hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, diabetes mellitus and diabetic ketoacidosis, have been reported during treatment with Opdivo®.

Patients should be monitored for signs and symptoms of endocrinopathies and changes in thyroid function (at the start of treatment, periodically during treatment, and based on clinical assessment). Patients may experience fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension or nonspecific symptoms that may be similar to other conditions such as brain metastases or underlying medical conditions. Unless another etiology is identified, signs and symptoms of endocrinopathies should be considered immune-mediated.

In case of symptomatic hypothyroidism, the use of Opdivo® should be suspended and, if necessary, thyroid hormone replacement therapy should be administered. In case of symptomatic hyperthyroidism, the use of Opdivo® should be suspended and, if necessary, treated with antithyroid drugs. In case of acute thyroiditis, glucocorticosteroids should be prescribed at a dose equivalent to 1-2 mg/kg/day methylprednisolone. If improvement occurs, the use of Opdivo® can be continued after a slow reduction in the dose of glucocorticosteroids. It is necessary to continue monitoring thyroid function to monitor the adequacy of thyroid hormone replacement therapy.

In case of symptomatic grade 2 adrenal insufficiency, the use of nivolumab should be suspended and, if necessary, physiological replacement of glucocorticosteroids should be performed. In case of symptomatic grade 3-4 adrenal insufficiency, the use of nivolumab should be permanently discontinued and, if necessary, physiological replacement of glucocorticosteroids should be carried out. It is necessary to continue monitoring adrenal function and hormone levels to monitor the adequacy of glucocorticosteroid replacement therapy.

For symptomatic grade 2-3 hypophysitis, the use of Opdivo® should be suspended and, if necessary, hormone replacement therapy should be performed. In case of acute hypophysitis, glucocorticosteroids are prescribed at a dose equivalent to 1-2 mg/kg/day methylprednisolone. If improvement occurs, the use of Opdivo® can be continued after a slow reduction in the dose of glucocorticosteroids.

For symptomatic grade 4 hypophysitis, nivolumab therapy should be permanently discontinued. It is necessary to continue monitoring pituitary function and hormone levels to monitor the adequacy of hormone replacement therapy.

For symptomatic diabetes, nivolumab should be withheld and insulin replacement therapy administered if necessary. It is necessary to monitor blood sugar levels to ensure the adequacy of insulin replacement therapy.

Immune-mediated rash

Cases of severe rash (including rare cases of fatal toxic epidermal necrolysis), which may be immune-mediated, have been reported during treatment with Opdivo®. Nivolumab should be discontinued for grade 3 rash and discontinued without reinstatement for grade 4 rash. For severe rashes, treatment with glucocorticosteroids is prescribed at a dose equivalent to 1-2 mg/kg/day methylprednisolone.

Opdivo should be used with caution in patients who have previously experienced severe or life-threatening adverse skin reactions when treated with other immunostimulating anticancer drugs.

Other immune-mediated adverse reactions

The following immune-mediated adverse reactions were observed in less than 1% of patients treated with Opdivo® during clinical trials at any dosage and tumor type: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve palsy), Guillain's syndrome -Barre, hypopituitarism, myasthenic syndrome and encephalitis.

If immune-mediated adverse reactions are suspected, adequate evaluation should be carried out to confirm their etiology or exclude other causes of their occurrence. Based on the severity of the adverse reaction, use of Opdivo® should be discontinued and therapy with glucocorticosteroids should be initiated. If improvement occurs, nivolumab can be continued after slowly reducing the dose of glucocorticosteroids. Opdivo® should be discontinued without restarting if any recurrent severe immune-mediated adverse reactions or any life-threatening immune-mediated adverse reactions occur.

Infusion reactions

During clinical studies, cases of severe infusion reactions were observed. In the event of severe infusion reactions, the administration of Opdivo® should be discontinued and appropriate drug therapy should be prescribed. Patients with a mild or moderate infusion reaction may continue treatment with Opdivo® with continuous monitoring and premedication in accordance with current standards for the prevention of infusion reactions.

Patients on a controlled sodium diet

Each milliliter of Opdivo® contains 0.1 mmol (or 2.5 mg) sodium, which should be taken into account when treating patients on a controlled sodium diet.