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Nivolumab plus Ipilumumab in NSCLC: A New Use for Tumor Mutational Burden?
Study Overview
Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).
Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).
Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.
Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).
Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.
Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).
With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).
Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.
Commentary
Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].
This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.
This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.
Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].
Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.
Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.
In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.
Application for Clinical Practice
This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.
— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC
1. Reck M, Rabe KF. Precision Diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med 2017;377:849–61.
2. Noone AM, Howlader N, Krapcho M, et al, editors. SEER Cancer Statistics Review, 1975-2015, National Cancer Institute. Bethesda, MD. Accessed at https://seer.cancer.gov/csr/1975_2015/.
3. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 Inhibition. N Engl J Med 2017;377:2500–1.
4. Gandhi L, Rodríguez-Abreu D,
5. Foundation One. Specimen instructions. Accessed at https://assets.ctfassets.net/vhribv12lmne/3uuae1yciACmI48kqEMCU4/607ecf55151f20fbaf7067e5fd7c9e22/F1_SpecimenInstructionsNC_01-07_HH.pdf.
6. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90.
Study Overview
Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).
Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).
Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.
Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).
Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.
Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).
With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).
Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.
Commentary
Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].
This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.
This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.
Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].
Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.
Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.
In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.
Application for Clinical Practice
This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.
— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC
Study Overview
Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).
Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).
Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.
Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).
Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.
Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).
With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).
Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.
Commentary
Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].
This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.
This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.
Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].
Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.
Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.
In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.
Application for Clinical Practice
This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.
— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC
1. Reck M, Rabe KF. Precision Diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med 2017;377:849–61.
2. Noone AM, Howlader N, Krapcho M, et al, editors. SEER Cancer Statistics Review, 1975-2015, National Cancer Institute. Bethesda, MD. Accessed at https://seer.cancer.gov/csr/1975_2015/.
3. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 Inhibition. N Engl J Med 2017;377:2500–1.
4. Gandhi L, Rodríguez-Abreu D,
5. Foundation One. Specimen instructions. Accessed at https://assets.ctfassets.net/vhribv12lmne/3uuae1yciACmI48kqEMCU4/607ecf55151f20fbaf7067e5fd7c9e22/F1_SpecimenInstructionsNC_01-07_HH.pdf.
6. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90.
1. Reck M, Rabe KF. Precision Diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med 2017;377:849–61.
2. Noone AM, Howlader N, Krapcho M, et al, editors. SEER Cancer Statistics Review, 1975-2015, National Cancer Institute. Bethesda, MD. Accessed at https://seer.cancer.gov/csr/1975_2015/.
3. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 Inhibition. N Engl J Med 2017;377:2500–1.
4. Gandhi L, Rodríguez-Abreu D,
5. Foundation One. Specimen instructions. Accessed at https://assets.ctfassets.net/vhribv12lmne/3uuae1yciACmI48kqEMCU4/607ecf55151f20fbaf7067e5fd7c9e22/F1_SpecimenInstructionsNC_01-07_HH.pdf.
6. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90.