Special guest Jason Porter, MD joins once again to discuss these various options as well as the importance of a multidisciplinary tumor team in the treatment of resectable non-small cell lung cancer. Dr. Porter is a medical oncologist and hematologist at the West Cancer Center and Research Institute where he is the Director of the Lung Cancer disease research group. Dr. Porter is a paid consultant of BMS. This podcast was sponsored by Bristol Myers Squibb
In the early stages of non-small cell lung cancer, is curative surgery or perioperative systemic therapy the right approach? Although every patient is different, there may be various ways to individually approach resectable non-small cell lung cancer. Special guest Jason Porter, MD, joins once again to discuss these various options as well as the importance of a multidisciplinary tumor team in the treatment of resectable non-small cell lung cancer. Dr. Porter is a medical oncologist and hematologist at the West Cancer Center and Research Institute where he is the Director of the Lung Cancer disease research group.
Learn more about a treatment option for patients with resectable (tumors ≥4 cm) and node positive NSCLC, regardless of PD-L1 expression.
https://www.opdivohcp.com/efficacy/nsclc/neoadjuvant
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 https://packageinserts.bms.com/pi/pi_opdivo.pdf
"(C) 2023 Bristol-Myers Squibb Company. OPDIVO® and the related logos are registered trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.
This podcast is intended for US Healthcare Professionals only."
1506-US-2300171 04/23
Joseph Ritchie:
Welcome back to the Bristol Myers Squibb Immuno-Oncology Podcast, a podcast dedicated to keeping listeners updated on current findings within the immuno-oncology treatment landscape. Today's program is intended for US healthcare professionals only. I'm Joseph Ritchie, an executive medical science liaison with BMS, and I'm again joined today by our wonderful guest, Dr. Jason Porter, a medical oncologist and hematologist at the West Cancer Center and Research Institute in Tennessee.
Please note that Dr. Porter is a consultant for BMS and was compensated for his role in this podcast. Thank you again for joining us today, Dr. Porter. Before we kick off the today's episode, can you please briefly go over some of the key highlights from last week's episode regarding CheckMate 9LA?
Dr. Jason Porter:
Thank you for having me again, Joe. To quickly recap, in last week's episode, we chatted about an approval regarding an OPDIVO or Nivolumab plus YERVOY, or ipilumumab-based combination treatment in first line non-small cell lung cancer. CheckMate 9LA was a cross-histology Phase III randomized open-label trial in patients who had metastatic or recurrent non-small cell lung cancer that evaluated OPDIVO plus YERVOY with two cycles of platinum-doublet chemotherapy in comparison with four cycles of platinum-doublet chemotherapy as a comparator arm.
In the extended follow-up analysis of CheckMate 9LA, the OPDIVO plus YERVOY combination treatment arm demonstrated continued durable survival as a first-line therapy for adult patients with recurrent or metastatic non-small cell lung cancer, with 27% of patients alive at three years in comparison with 19% of patients alive with chemotherapy only. Additionally, the study showed consistent overall survival benefit across PD-L1 positive and negative patients. For PD-L1-negative patients, 25% of patients in the OPDIVO plus YERVOY combination treatment arm were alive at three years in comparison to 15% of patients in the comparator arm.
Joseph Ritchie:
Thank you for that succinct summary, Dr. Porter. For our listeners today, we'll be discussing OPDIVO plus chemotherapy as the first and only neoadjuvant treatment option for patients with early-stage resectable non-small cell lung cancer. Based upon the results of the pivotal CheckMate 816 clinical trial.
Before we discuss data from this trial, I want to mention that OPDIVO and YERVOY are associated with the following warnings and precautions, severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, embryo fetal toxicity, and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analog and dexamethasone, which is not recommended outside of controlled clinical trials. Please stay tuned for the full indication and Important Safety Information about OPDIVO and YERVOY after this podcast episode.
Hello again, Dr. Porter, and welcome back. So today is all about CheckMate 816, and how it has paved the way for the use of OPDIVO in adult patients with resectable tumors greater than or equal to four centimeter or node positive in non-small cell lung cancer in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. Could you please speak to the significance of this treatment option within the non-small cell lung cancer landscape?
Dr. Jason Porter:
Currently, around 25% of patients who receive a diagnosis of non-small cell lung cancer have resectable disease. Unfortunately, we know that 30 to 55% of patients who get curative surgery will eventually die of disease recurrence, but we also know that neoadjuvant chemotherapy can be utilized to treat patients with resectable disease. However, the absolute difference in five-year recurrence-free survival and overall survival with neoadjuvant chemotherapy in comparison with surgery alone is approximately five to six percentage points.
Additionally, few patients achieve a complete pathologic response, which is an endpoint that usually serves as a potential early predictor of survival, so clearly, there is a need for more effective systemic treatments for non-metastatic disease across perioperative context. And based on the results of the CheckMate 816 study, there is a benefit in receiving neoadjuvant chemo immunotherapy for patients with stage 1B to stage 3A resectable non-small cell lung cancer.
Joseph Ritchie:
Thank you for providing the context in which OPDIVO plus chemotherapy fits into this treatment landscape. But before we chat about the clinical data, how would you describe the study design of CheckMate 816, and which patients are eligible for this treatment?
Dr. Jason Porter:
The CheckMate 816 study was an international, open-label Phase III trial that evaluated patients with resectable non-small cell lung cancer. A total of 358 patients before undergoing surgery were evenly randomized in a one-to-one ratio to be administered either OPDIVO 360 milligrams intravenously over 30 minutes plus platinum-doublet chemotherapy, or platinum-doublet chemotherapy alone every three weeks for up to three cycles. Definitive surgery was scheduled to occur within six weeks after the completion of neoadjuvant treatment, after which patients in both the treatment and comparator arms could receive up to four cycles of adjuvant chemotherapy, radiotherapy, or both.
Median follow-up time in all randomized patients was 29.5 months. CheckMate 816 accepted adult patients with resectable, histologically confirmed stage 1B, including patients with tumors greater than or equal to four centimeters to stage 3A non-small cell lung cancer, as per the staging criteria of the seventh edition of the American Joint Committee on Cancer or the AJCC 7, as well as an Eastern Cooperative Oncology Group performance status score of zero or one and no previous anti-cancer therapy.
Patients with unresectable or metastatic non-small cell lung cancer, known EGFR mutations or ALK translocations, grade two or greater peripheral neuropathy, active autoimmune disease or medical conditions requiring systemic immunosuppression were excluded from the study. The CheckMate 816 study stratified patients for randomization by their tumor PD-L1 expression level so greater than or equal to 1% versus less than 1%. Their disease stage, so stage 1B to 2 versus stage 3A, and six male versus female. 50% of the study participants had tumors with PD-L1 expression greater than or equal to 1%, 35% had stage 1B or 2 disease and 64% had stage 3A disease, 51% had tumors with squamous histology and 49% had tumors with non-squamous histology.
To assess efficacy, CheckMate 816 had two primary endpoints, the pathologic complete response, and event-free survival. Pathologic complete response was evaluated by a blinded, independent pathology review, and event-free survival was evaluated by blinded, independent central review. The study's key secondary endpoint is overall survival. Based on the results of this study, OPDIVO is indicated in the neoadjuvant setting for adult patients with resectable non-small cell lung cancer in which tumors are greater than or equal to four centimeters, or node positive, in combination with platinum-doublet chemotherapy.
Joseph Ritchie:
Let's talk a little bit more about those two co-primary endpoints. How are they defined in the CheckMate 816 study and what results led to the approval of OPDIVO plus chemotherapy as neoadjuvant treatment in early-stage resectable non-small cell lung cancer?
Dr. Jason Porter:
Pathological complete response was defined as having 0% residual viable tumor cells in the primary tumor and sampled lymph nodes according to blinded, independent pathological review. Event-free survival was defined as the time from randomization to any progression of disease, precluding surgery, progression or recurrence of disease after surgery, progression of disease in the absence of surgery or death from any cause. In the intention to treat population, 24% of all patients, regardless of resection, achieved pathological complete response in the OPDIVO plus chemotherapy arm in comparison with only 2.2% in the chemotherapy-only arm.
The estimated treatment difference for pathologic complete response was 21.6% with a P value of less than 0.0001. Furthermore, consistent pathologic complete response was observed in patients on OPDIVO plus chemotherapy regardless of stage. Patients at stage 1B to 2 reached pathologic complete response at 26% in the OPDIVO plus chemotherapy group, in comparison with 5% in the chemotherapy-only group. For patients at stage 3A, it was 23% in comparison with 1%, respectively.
Median event-free survival was 31.6 months with OPDIVO plus chemotherapy and 20.8 months with chemotherapy only, with a hazard ratio of 0.63, and a P value of 0.0052, this translates to a 37% reduced risk of disease progression, recurrence or death with the OPDIVO plus chemotherapy treatment arm. At two years, we continue to see consistent event-free survival benefit with 63.8% in the OPDIVO plus chemotherapy arm, and 45.3% with chemotherapy alone. As a note, however, CheckMate 816 was not powered to detect differences in the treatment effect within individual-stage subgroups or within PD-L1 subgroups, so these exploratory analyses should be interpreted with caution due to the limited amount of patients and potential imbalances, and baseline characteristics within those subgroups.
Joseph Ritchie:
Thank you for walking us through the efficacy data. As you mentioned earlier, overall survival was also a key secondary endpoint from the trial, and I believe this endpoint would be of great entrance to a lot of other practitioners. Based on your opinion, what is important to note about the data for overall survival?
Dr. Jason Porter:
Well, at the first pre-specified interim analysis, the overall survival data was immature and did not indicate statistical significance. With that being said, the hazard ratio was 0.57, and at two years, 83% of patients were alive with OPDIVO plus chemotherapy, and 71% of patients were alive with chemo. The data will continue to be monitored over time, and I'm excited to see the results.
Joseph Ritchie:
Earlier in our conversation you mentioned how neoadjuvant OPDIVO plus chemotherapy demonstrated superior pathologic complete response, as well as event-free survival regardless of PD-L1 status and disease stage. I think this nicely highlights the significance of starting therapy early for resectable patients, non-small cell lung cancer. When we think about bringing in systemic therapy, we want to balance the safety and ensure that we're not going to potentially prevent a patient from going into surgery.
Can you please elaborate on the reported safety profile for CheckMate 816, including the common serious adverse events experienced by the patients within the study?
Dr. Jason Porter:
First off, before I speak about the reported adverse reactions, I would like to address the mechanism of action for the immune checkpoint inhibitor in that it increases presentation of the tumor to the immune system. I fundamentally cannot understand taking the tumor out and then giving the immune system a boost. And so, it makes more sense to me that if I'm going to train, for instance, police officers, that I will send them first through an obstacle course that will be similar to what they're going to encounter in the field. And when I think about the tumor and giving the immune checkpoint inhibitor while the tumor's still in place with all of its antigens that could possibly stimulate the immune system, it makes more sense to provide neoadjuvant therapy.
And then, when we look at the safety profile of OPDIVO, I think it's really beneficial in addition to chemotherapy. In CheckMate 816, the most common adverse reactions in greater than 20% of patients receiving OPDIVO plus chemotherapy were nausea, constipation, fatigue, decreased appetite and rash. The most common grade three or four laboratory abnormalities in greater than 2% of patients receiving OPDIVO plus chemotherapy were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia. Serious adverse reactions occurred in 30% of patients who were treated with OPDIVO in combination with platinum-doublet chemotherapy, and in greater than 2% of patients this included pneumonia and vomiting.
No fatal adverse reactions occurred in patients who were in the OPDIVO plus chemotherapy arm. Treatment with OPDIVO plus chemotherapy was permanently discontinued due to adverse reactions in 10% of patients, and 30% had at least one treatment withheld as a result of an adverse reaction. The most common adverse reactions in greater than or equal to 1% of patients leading to permanent discontinuation of OPDIVO plus platinum-doublet chemotherapy were anaphylactic reaction, acute kidney injury, rash, and fatigue.
Another thing that's relevant to node is the kind of experience the surgeon is going to have when they take those patients to surgery after these resectable patients in early-stage non-small cell lung cancer undergo neoadjuvant treatment with OPDIVO plus chemotherapy. In terms of the surgical data, 83.2% in the OPDIVO plus chemotherapy arm and 75.4% in the platinum-doublet chemotherapy comparator arm underwent definitive surgery. Overall, the safety and the capability of my early-stage resectable patients with non-small cell lung cancer to undergo surgery after neoadjuvant OPDIVO plus chemotherapy has been very beneficial within my clinical practice.
Joseph Ritchie:
Besides the individual impact of neoadjuvant therapy in your clinical practice, one thing that comes to mind that can be very different in the metastatic and non-metastatic setting for your resectable patients with non-small cell lung cancer is the importance of the multidisciplinary team. Obviously, this involves identifying the patients before surgery, but in terms of having that discussion with your multidisciplinary team, what would you recommend as a best practice for other groups when they're coordinating decision-making for these early-stage patients within their multidisciplinary team?
Dr. Jason Porter:
I really, really think that every patient who's a surgical candidate should be presented at a multidisciplinary tumor board. I recommend that surgeons really need to look closely at the patient's profile and an endobronchial ultrasound or EBUS needs to be the standard of care for those patients because I need to stage and understand a medial spinal disease from the beginning. What you want to avoid is placing a patient under consideration as a surgical candidate and then having to backtrack and say that they are not a surgical candidate. Ultimately, this is going to happen inevitably, because in some patients, they may no longer be surgically resectable due to progression of disease or their performance status may deteriorate, so these things unfortunately do happen.
I know there are some settings where there is not a big tumor board in place and I know in small community settings that is often the case. In those instances, however, I think that every patient deserves a direct phone call to the physician that they're going to be referred to. As a medical oncologist, I'm going to refer to a surgeon who is not on the tumor board, I will call and have a discussion with that surgeon and tell them exactly what I'm thinking, get their impression as well, and then discuss again after the surgeon sees the patient. This ensures that we are on the same page about how we're going to approach our patient's care.
I also recommend early molecular testing, not PD-L1 status because fortunately that's not a deciding factor here as we discussed earlier, but testing for the presence of oncogenic drivers such as EGFR and ALK genomic tumor aberrations. So early testing for relevant biomarkers should be standard and we need to do that for each surgically-resectable patient, and they should all be presented to a surgeon upfront. The surgeon should not be making a unilateral decision on whether or not a patient is a surgical candidate or how to approach a patient's care before the medical oncologist addresses whether or not the patient can tolerate or receive immune checkpoint inhibitors. Radiation oncologists need to be involved in the conversation as well.
Joseph Ritchie:
Absolutely agree. Patients deserve that collaboration from their doctors. Let's say that you have your multidisciplinary discussion and you arrive at the decision to initiate neoadjuvant treatment with OPDIVO plus chemotherapy in an early-stage resectable patient with non-small cell lung cancer. What are some of the main factors that help you make your decision over the alternative, which would be to send the patient to a surgeon first?
Dr. Jason Porter:
First of all, the location of the disease is a priority concern. So for example, if a patient were to have subcarinal adenopathy at a single station and not contralateral medial spinal disease, I would administer neoadjuvant OPDIVO plus chemotherapy in this patient. If there is a patient with a smaller tumor that I'm a little bit less concerned about, I would possibly consider surgery upfront. However, if their tumor is at least four centimeters or node positive, then they are a candidate for neoadjuvant OPDIVO plus chemotherapy in that setting.
In CheckMate 816, we saw how 24% of patients achieved pathologic complete response with OPDIVO plus chemotherapy treatment, as opposed to only 2.2% with chemotherapy alone. If I think there is an obvious chance that I can give my patient a clear shot to achieve a pathologic complete response, I should give that therapy upfront. But even for smaller tumors, I think neoadjuvant OPDIVO plus chemotherapy regimen is relevant and can be used for treatment, as well as in nodal disease in which systemic therapy is needed early, however, I decide on a case-by-case basis.
Joseph Ritchie:
Thanks so much again for talking through all of the data regarding CheckMate 816, as well as sharing your experiences today. To summarize, what advice would you give to your peers if they wanted to go about incorporating OPDIVO plus platinum-doublet chemotherapy into their treatment algorithm for patients with early-stage resectable non-small cell lung cancer?
Dr. Jason Porter:
For patients with early-stage resectable non-small cell lung cancer, I think any patient that is going to have surgery and has at least a four-centimeter tumor or has nodal involvement is an appropriate candidate for neoadjuvant OPDIVO plus chemotherapy. Based on the pivotal results of CheckMate 816, patients treated with OPDIVO plus platinum-doublet chemotherapy achieve a superior pathologic complete response and event-free survival, in which 24% of patients in the OPDIVO plus chemotherapy arm achieved a pathologic complete response in comparison to 2.2% with chemotherapy alone.
Additionally, patients in the OPDIVO plus chemotherapy arm also had 37% reduced risk of progression, recurrence or death. I also highly recommend that all eligible patients be presented at a multidisciplinary tumor board to ensure physician alignment on treatment, especially since resectable non-small cell lung cancer patients have the option of neoadjuvant treatment prior to surgery.
Joseph Ritchie:
Thank you so much, Dr. Porter. Before we close today's episode sponsored by BMS, please listen to the full indications and important safety information for OPDIVO in YERVOY. Indications. OPDIVO and combination with platinum-doublet chemotherapy is indicated as neoadjuvant treatment of adult patients with resectable tumors greater than or equal to four centimeters or node-positive non-small cell lung cancer. OPDIVO in combination with YERVOY and two cycles of platinum-doublet chemotherapy is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations.
Important safety information. Severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reaction 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 or YERVOY.
Early identification and management are essential to ensure safe use of OPDIVO in YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries, including liver enzymes, creatinine, adrenocorticotropic hormone, and thyroid function at baseline, and periodically during treatment with OPDIVO and before each dose of YERVOY. 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 and YERVOY depending upon severity. Please see section two, Dosage and Administration, in the accompanying full prescribing information. In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy, one to two milligrams per kilogram per day, prednisone or equivalent, until improvement to grade one or less. Upon improvement to grade one or less, initiate corticosteroid taper and continue to taper over at least one 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, endocrinopathies and dermatologic reactions, are discussed below.
Immune-mediated pneumonitis. OPDIVO and YERVOY 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 incurred 3.1% of patients, including grade four, less than 0.1%, grade three 0.9%, and grade two 2.1%. Immune-mediated colitis. OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus 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% of patients including grade three, 1.7%, and grade two, 1%. Immune-mediated hepatitis and hepatotoxicity. OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% of patients, including grade four, 0.2%, grade three, 1.3%, and grade two, 0.4%.
Immune-mediated endocrinopathies. OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders and type one diabetes melitis, which can present with diabetic ketoacidosis, withhold OPDIVO in YERVOY depending on severity. Please see section two, Dosage and Administration, in the accompanying full prescribing information. For grade two or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effects 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% including grade three 0.4%, and grade two, 0.6%. In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% of patients, including grade three, 0.2%, and grade two, 0.3%.
In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% of patients, including grade two, 0.2%. In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% of patient, including grade three, less than 0.1%, and grade two, 1.2%. In patients receiving OPDIVO and monotherapy, hypothyroidism occurred in 8% of patients, including grade three, 0.2%, and grade two, 4.8%. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% of patients, including grade three, 0.4%, and grade two, 0.3% in two cases of diabetic ketoacidosis.
Immune-mediated nephritis with renal dysfunction. OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% of patients including grade four, less than 0.1%, grade three, 0.5%, and grade two, 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 and PD-L1-blocking antibodies.
Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliated rashes. YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous exfoliative rashes. Withhold or permanently discontinue OPDIVO and YERVOY depending on severity. Please see section two, Dosage and Administration, in the accompanying full prescribing information. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% of patients including grade three, 1.1%, and grade two, 2.2%.
Other immune-mediated adverse reactions. The following clinically-significant immune-mediated adverse reactions occurred at an incidence of less than 1%, unless otherwise noted. In patients who receive OPDIVO monotherapy or OPDIVO in combination with YERVOY, or 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-Barre 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.
In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcomes, occurred in less than 1% of patients, unless otherwise specified. Nervous system. Autoimmune neuropathy, 2%, myasthenic syndrome, myasthenia gravis, motor dysfunction. Cardiovascular. Angiopathy, temporal arteritis, ocular blepharitis, episcleritis, orbital myositis, scleritis, gastrointestinal pancreatitis, 1.3%.
Other, hematologic, immune. Conjunctivitis, cytopenias, 2.5%, eosinophilia, 2.1%, erythema multiforme, hypersensitivity, vasculitis, neurosensory hypoacusis, psoriasis. Some ocular IMR 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 reaction, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.
Infusion-related reactions. OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe grade three or life-threatening grade four infusion-related reactions. Interrupt or slow the rate of infusion and patients with mild grade one or moderate grade two infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% 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% and 2.7% of patients respectively.
Additionally, 0.5% and 1.4% of patients, respectively, experience 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 before and after being treated with OPDIVO or YERVOY.
Transplant-related complications include hyperacute graft-versus-host disease, acute graft-versus-host disease, chronic graft-versus-host disease, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome without an identified infectious cause. These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic hematopoietic stem cell transplantation. Follow patients closely for evidence of transplant-related complications and intervene properly. Consider the benefit versus risk of treatment with OPDIVO and YERVOY prior to or after allogeneic hematopoietic stem cell transplant.
Embryo-fetal toxicity. Based on its mechanisms of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY for at least five months after the last dose.
Increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analog and dexamethasone. In randomized clinical trials in patients with multiple myeloma. The addition of OPDIVO to a thalidomide analog 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 analog plus dexamethasone is not recommended outside of controlled clinical trials.
Lactation. There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on a breastfed child or the effects in milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for five months after the last dose. Serious adverse reactions. In CheckMate 816, serious adverse reactions occurred in 30% of patients who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in greater than 2% include pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy.
In CheckMate 9LA, serious adverse reactions occurred in 57% of patients, the most frequent, greater than 2%, serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in seven patients, and include hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.
Common adverse reactions. In CheckMate 816, the most common, greater than 20%, adverse reaction in the OPDIVO plus chemotherapy arm were nausea at 38%, constipation, 34%, fatigue, 26%, decreased appetite, 20% and rash, 20%. In CheckMate 9LA, The most common adverse reactions, greater than 20%, were fatigue, 49%, musculoskeletal pain, 39%, nausea, 32%, diarrhea, 31%, rash, 30%, decreased appetite, 28%, constipation, 21%, and pruritus, 21%.
Please see US full prescribing information for OPDIVO and YERVOY in the show notes. Before we end, I'd just like to thank you for providing your insights again today, Dr. Porter. I'd also like to thank our listeners for tuning in.
Dr. Jason Porter:
It was a pleasure. Thank you so much for having me back to discuss this important treatment.
Joseph Ritchie:
This concludes our discussion of the clinical efficacy and safety findings for OPDIVO in combination with platinum-doublet chemotherapy for neoadjuvant treatment in adult patients, early-stage non-small cell lung cancer. References for the information discussed on today's episode can be found in the show notes.
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