Resectable NSCLC: Surgeon & Oncologist Perspectives on Neoadjuvant Therapy

Neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC) has several potential benefits, such as the reduction of tumor volume— this may increase the potential for complete surgical resection, which is essential for curative surgery; and timely treatment of small numbers of cancer cells that may have spread from the primary tumor to other parts of the body.¹ Ongoing clinical research in the neoadjuvant setting has brought forth the availability of immunotherapy in resectable NSCLC. While neoadjuvant immunotherapy introduces an additional step, it is intended to optimize the surgical outcome, shrink the tumors and make the patient more responsive to surgical removal.^1,2,3

One important advancement in the neoadjuvant therapy landscape has been the FDA approval of Opdivo^®(nivolumab) in combination with platinum-doublet chemotherapy, as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC, which is the first neoadjuvant immunotherapy combination in resectable NSCLC.⁴ Dr. David Tom Cooke, Professor and Founding Chief of the Division of General Thoracic Surgery, UC Davis Comprehensive Cancer Center, and Dr. Nisha A. Mohindra, Medical Oncologist and Associate Professor of Medicine in the Hematology Oncology Division at Northwestern University Feinberg School of Medicine, share their perspectives on Opdivo plus chemotherapy as a potential treatment for adult patients with resectable NSCLC.

Opdivo is associated with the following Warnings & Precautions: immune-mediated adverse reactions, which may be severe or fatal, and can occur in any organ system or tissue, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis and renal dysfunction; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. Please see Important Safety Information below.⁵

Over the past few years, research has changed the neoadjuvant therapy landscape in resectable NSCLC. Can you tell us about the role of immunotherapy in this setting— particularly Opdivo plus chemotherapy?

Dr. Mohindra: Immunotherapy can play an important role in neoadjuvant treatment for resectable NSCLC. An example of how this area of medicine continues to advance is the 2022 U.S. FDA approval of Opdivo plus chemotherapy as neoadjuvant treatment for certain patients with resectable NSCLC as the first immunotherapy-based treatment for use before surgery.⁴

The agency’s approval of this combination was based on data from the CheckMate -816 study. Opdivo was studied in this clinical trial of patients with early-stage NSCLC who were able to have surgery; 358 patients were included in the study— 179 patients received Opdivo plus chemotherapy before surgery and 179 received only chemotherapy. The primary endpoints of the trial were event-free survival and pathologic complete response.⁴

The primary analysis of CheckMate -816 showed that, for patients who were treated with Opdivo plus platinum-doublet chemotherapy before surgery, the risk of cancer spreading or returning was reduced by 37% compared to chemotherapy alone.⁴ Opdivo plus chemotherapy showed a median event-free survival of 31.6 months compared to 20.8 months for patients treated with chemotherapy alone.⁴ Additionally, 10 times more patients who were given Opdivo plus chemotherapy before surgery saw tumors disappear completely than those on chemotherapy alone after the surgery (24% versus 2.2% of patients, respectively, achieved a pathologic complete response).⁴

In CheckMate -816, adverse reactions occurred in 30% of patients (n=176) who were treated with Opdivo in combination with chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal reactions occurred in patients who received Opdivo in combination with chemotherapy. The most common (>20%) adverse reactions in the Opdivo plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). Adverse reactions leading to the discontinuation of Opdivo plus chemotherapy occurred in 10% of patients and 30% had at least one treatment withheld for an adverse reaction.⁴ After three years of follow-up, the safety profile of neoadjuvant Opdivo plus chemotherapy was consistent with the primary analysis, with no new safety signals observed.⁴

What are some misconceptions that surgeons may have about neoadjuvant treatment with immunotherapy?

Dr. Cooke: Some surgeons may initially express hesitancy toward neoadjuvant treatment due to concerns about potential delays in surgery and making the surgery more complicated or time-consuming. I would encourage those surgeons to look at the data. From my perspective as a surgeon, after reviewing the exploratory analysis of CheckMate -816, key results were that Opdivo did not lead to an increased incidence of adverse events or hinder the feasibility of subsequent surgery. In the trial, 83% (149/179) of patients in the Opdivo plus chemotherapy arm had definitive surgery compared to 75% (135/179) of patients in the chemotherapy arm.⁵ Adverse events of any grade led to delayed surgery in 3.4% (6/179) of the patients receiving Opdivo plus chemotherapy and in 5.1% (9/179) of those receiving chemotherapy alone, and led to cancellations in 1.1% (2/179) and 0.6% (1/179) of patients, respectively.⁴ Additionally, in the exploratory analysis of CheckMate -816, the median duration of surgery was numerically shorter in the Opdivo group (180 minutes versus 168 minutes).⁴ The use of minimally invasive approaches was more common in the Opdivo plus chemotherapy group.⁴ Pneumonectomies were less common in the Opdivo group compared to the chemotherapy-alone group; avoiding pneumonectomy and performing minimally invasive surgery can overall result in faster recovery and reduced postoperative complications— these differences were particularly notable in patients with stage IIIA disease.⁴

Is the practice landscape changing as it relates to neoadjuvant treatment of resectable NSCLC? If so, how?

Dr. Mohindra: We are seeing, based on the disease complexity, that there is a greater emphasis on working in a multidisciplinary team (MDT) setting. According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), lung cancer diagnosis and treatment should be informed by the consensus of specialists.⁶ In lung cancer, this typically includes radiation oncologists, medical oncologists, surgical oncologists, pathologists, palliative care experts, oncology nurses and social workers.^6,7

While the practice landscape is rapidly evolving, there remains a need for many hospitals and health systems to change to a collaborative MDT approach, particularly in the community setting. The NCCN Guidelines^®, which were updated in April 2023, now recommend, as an option, that all patients with resectable NSCLC be evaluated for preoperative therapy, be considered for nivolumab (Opdivo) plus chemotherapy for those patients with tumors ≥4 cm or node positive and no contraindications to immune checkpoint inhibitors.⁶ NCCN Guidelines also recommend, as an option, neoadjuvant nivolumab (Opdivo) plus chemotherapy be considered as a Category 2A therapy option for eligible patients with resectable (tumor ≥4 cm or node positive) NSCLC, regardless of PD-L1 expression.⁶

To learn more about Opdivo, visit www.opdivohcp.com.

INDICATION

OPDIVO^® (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies

OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy.

Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy.

Common Adverse Reactions

In Checkmate 816, the most common (>20%) adverse reactions in the OPDIVO plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%).

Please see US Full Prescribing Information for OPDIVO.

References

1. Aguado, Carlos, et al. Neoadjuvant Treatment in Non-small Cell Lung Cancer: New Perspectives with the Incorporation of Immunotherapy. World J Clin Oncol. 2022;13(5): 314–322.
2. ASCO. Types of Treatment for Non-Small Cell Lung Cancer. Available at www.cancer.net/cancer-types/lung-cancer-non-small-cell/types-treatment. Accessed September 2023.
3. National Cancer Institute. Non-Small Cell Lung Cancer Treatment (PDQ)–Health Professional Version. Available at www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Accessed September 2023.
4. Forde, Patrick M., et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022;386:1973-1985.
5. Opdivo Prescribing Information. Last Updated: 02/2023. Princeton, NJ: Bristol-Myers Squibb Company.
6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), for Non-Small Cell Lung Cancer V.3.2023. ©National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed September 18, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.
7. ASCO. The Oncology Team. Available at https://www.cancer.net/navigating-cancer-care/cancer-basics/cancer-care-team/oncology-team. Accessed September 2023.
   

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