THER-09. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES

Abstract BACKGROUND: Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS: We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS: In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION: KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

Download Full-text

CMET-18. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES

Neuro-Oncology ◽

10.1093/neuonc/noz175.219 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi55-vi55

Author(s):

Adam Lauko ◽

Assad Ali ◽

Soumya Sagar ◽

Addison Barnett ◽

Hong Li ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Brain Metastases ◽

Checkpoint Inhibitors ◽

Care Center ◽

Tertiary Care ◽

Wild Type ◽

Chi Square ◽

Kras Mutations ◽

Mutational Status

Abstract BACKGROUND Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

Download Full-text

CMET-23. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS

Neuro-Oncology ◽

10.1093/neuonc/noz175.224 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi56-vi56

Author(s):

Soumya Sagar ◽

Adam Lauko ◽

Addison Barnett ◽

Wei (Auston) Wei ◽

Samuel Chao ◽

...

Keyword(s):

Targeted Therapy ◽

Brain Metastasis ◽

Brain Metastases ◽

Systemic Therapy ◽

Checkpoint Inhibitors ◽

Care Center ◽

Performance Status ◽

Tertiary Care ◽

P Value ◽

Surgical Removal

Abstract BACKGROUND Melanoma is the third most common malignancy that results in brain metastasis and is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI). METHODS 351 patients, treated for MBM at our tertiary care center from 2000–2018, were grouped into: received chemotherapy, ICI, or targeted therapy. 34% of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model. RESULTS The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value < .001), lower KPS (HR = .97, p-value < .0001) and multiple brain lesions (HR = 1.117, p-value < .0001) were associated with significantly worse OS. CONCLUSIONS Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.

Download Full-text

THER-02. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.045 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i11-i11

Author(s):

Soumya Sagar ◽

Adam Lauko ◽

Addison Barnett ◽

Wei Wei ◽

Samuel Chao ◽

...

Keyword(s):

Targeted Therapy ◽

Brain Metastasis ◽

Brain Metastases ◽

Systemic Therapy ◽

Checkpoint Inhibitors ◽

Care Center ◽

Tertiary Care ◽

P Value ◽

Surgical Removal ◽

Melanoma Brain Metastasis

Abstract BACKGROUND: Melanoma brain metastasis is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI). METHODS: 351 patients, who underwent treatment for MBM at our tertiary care center from 2000 to 2018, were grouped into those that received chemotherapy, ICI, or targeted therapy. Thirty-four percent of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model. RESULTS: The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value < .001), lower KPS (HR = .97, p-value < .0001) and multiple brain lesions (HR = 1.117, p-value < .0001) were associated with significantly worse OS. CONCLUSIONS: Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.

Download Full-text

Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases

Scientific Reports ◽

10.1038/s41598-021-97566-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Adam Lauko ◽

Rupesh Kotecha ◽

Addison Barnett ◽

Hong Li ◽

Vineeth Tatineni ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Checkpoint Inhibitors ◽

Tertiary Care ◽

Local Treatment ◽

Cox Proportional Hazards Model ◽

Rank Test ◽

Mutational Status ◽

One Year ◽

The Impact

AbstractImmune checkpoint inhibitors (ICIs) have resulted in improved outcomes in non-small cell lung cancer (NSCLC) patients. However, data demonstrating the efficacy of ICIs in NSCLC brain metastases (NSCLCBM) is limited. We analyzed overall survival (OS) in patients with NSCLCBM treated with ICIs within 90 days of NSCLCBM diagnosis (ICI-90) and compared them to patients who never received ICIs (no-ICI). We reviewed 800 patients with LCBM who were diagnosed between 2010 and 2019 at a major tertiary care institution, 97% of whom received stereotactic radiosurgery (SRS) for local treatment of BM. OS from BM was compared between the ICI-90 and no-ICI groups using the Log-Rank test and Cox proportional-hazards model. Additionally, the impact of KRAS mutational status on the efficacy of ICI was investigated. After accounting for known prognostic factors, ICI-90 in addition to SRS led to significantly improved OS compared to no-ICI (12.5 months vs 9.1, p < 0.001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (p = 0.04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (p = 0.84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (p = 0.004). Patients with NSCLCBM who received ICI-90 had improved OS compared to no-ICI patients. Additionally, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit, which should be taken into account in the development of future trials.

Download Full-text

THER-10. IMPACT OF BRAF MUTATIONAL STATUS ON THE EFFICACY OF IMMUNOTHERAPY FOR MELANOMA BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.053 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i12-i13

Author(s):

Adam Lauko ◽

Soumya Sagar ◽

Addison Barnett ◽

Wei Wei ◽

Samuel Chao ◽

...

Keyword(s):

Brain Metastases ◽

Tertiary Care ◽

Rank Test ◽

P Value ◽

Wild Type ◽

Braf Mutations ◽

Mutational Status ◽

Melanoma Brain Metastases ◽

Melanoma Patients ◽

Braf Mutant

Abstract BACKGROUND: BRAF mutations occur in 50% of melanoma patients. Targeted agents – BRAF and MEK inhibitors and immunotherapy improve survival of melanoma patients with BRAF mutations. These agents have intracranial efficacy as shown in clinical trials. However, the efficacy of immunotherapies (immune checkpoint blockade) in melanoma brain metastases and the correlation with BRAF status is not as well characterized. METHODS: We reviewed 351 patients with melanoma brain metastases treated at our tertiary care center between 2000 and 2018, 75 of which received immunotherapy with known BRAF mutational status. Two-year, 5-year, and median overall survival (OS) was calculated from the start of immunotherapy to compare the efficacy of immunotherapy in BRAF mutant and BRAF wild type patients using the log-rank test. RESULTS: At the time of diagnosis of brain metastasis, the median age was 61 (23–87) years, median KPS was 80 (50–100), number of intracranial lesions was 2 (1–15), and 79% had extra-cranial metastases. Sixty-three patients were treated with stereotactic radiosurgery (SRS), 27 underwent whole brain radiation (WBRT) and 21 underwent surgery. When treated with immunotherapy, BRAF mutant and BRAF wild type median survival was 15.7 months (95% CI=9.4 – 42.4) and 6.9 (95% CI=4.1– 26.7) months (p-value=0.205), respectively. Two-year BRAF mutant and BRAF wild type survival was 35% (95% CI=21 – 58) and 28% (95% CI=16 – 51), and 5-year survival was 22% (95% CI=10 – 46) and 23% (95% CI=11 – 47), respectively. CONCLUSIONS: Twenty percent of patients with BRAF mutant and BRAF wild-type patients treated with immunotherapy derive a long-term benefit from immunotherapy and multimodality treatment and are alive 5 years from diagnosis of brain metastases. This was rarely seen in the pre-immunotherapy era in melanoma brain metastases. There was no difference in outcome based on the BRAF mutational status with use of immunotherapy in melanoma brain metastases.

Download Full-text

THER-16. EFFICACY OF UPFRONT IMMUNE CHECKPOINT INHIBITORS IN LUNG CANCER BRAIN METASTASIS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.059 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i14-i14

Author(s):

Addison Barnett ◽

Adam Lauko ◽

Assad Ali ◽

Hong Li ◽

Soumya Sagar ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Proportional Hazards Model ◽

Checkpoint Inhibitors ◽

Tertiary Care ◽

Primary Lung Cancer ◽

Cox Proportional Hazards Model ◽

Rank Test

Abstract INTRODUCTION: Immune checkpoint inhibitors (ICI) have resulted in improved outcomes in a subset of patients with lung cancer. However, data describing the efficacy of ICI in lung cancer brain metastasis (LCBM) is limited. We analyzed overall survival (OS) in patients with LCBM treated with upfront ICI, defined as having received ICI within 90 days of LCBM diagnosis, compared to non-ICI therapies. METHODS: We reviewed 665 patients with LCBM who were diagnosed between 2000 and 2018 at a major tertiary care institution. Of those patients, 240 received ICI, 164 of which received ICI after 90 days and 76 received ICI within 90 days. Propensity score (PS) was calculated using a logistic regression model including age, KPS, number of baseline brain lesions, and presence of extra-cranial metastasis (ECM) at the time of BM diagnosis. OS from BM diagnosis between PS matched cohorts were compared using Kaplan-Meier, the Log-Rank test, and Cox proportional hazards model. RESULTS: Prior to PS matching, median survival between ICI and non-ICI cohorts was not significantly different (10.9 months for both, p=0.81), although more ICI patients had ECM (57.1% vs 40.9%, p=0.006). Following PS matching, the ICI (n=76) and non-ICI (n=76) cohorts had a median age (62.4 vs 62.3 years), KPS (80 for both), lesion number (2 for both), and ECM (56.6% for both). Of matched patients, 94% received SRS, 52% received WBRT, and 29% underwent surgical resection. Compared to non-ICI, the ICI cohort has a 2-year OS hazard ratio, HR=0.87 (95% CI=0.58–1.31, p=0.51). Median and 1-year survival were not significantly different between ICI and non-ICI cohorts (median: 10.9 vs 9.1 months; 1-yr: 43.0% vs 42.4%). CONCLUSION: Patients with BM from primary lung cancer who received ICI within 90 days of their BM diagnosis did not have improvement in OS compared to patients who received non-ICI therapies.

Download Full-text

CMET-12. EFFICACY OF UPFRONT IMMUNE CHECKPOINT INHIBITORS IN LUNG CANCER BRAIN METASTASIS

Neuro-Oncology ◽

10.1093/neuonc/noz175.213 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi53-vi53

Author(s):

Addison Barnett ◽

Adam Lauko ◽

Hong Li ◽

Assad Ali ◽

Soumya Sagar ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Tertiary Care ◽

Cox Proportional Hazards ◽

Rank Test ◽

Cox Proportional Hazards Models

Abstract INTRO/OBJECTIVE Immune checkpoint inhibitors (ICI) have improved outcomes in a subset of patients with lung cancer. However, data describing the efficacy of ICI in lung cancer brain metastasis (LCBM) is limited. We analyzed overall survival (OS) in patients with LCBM treated with upfront ICI, defined as having received ICI within 90-days of LCBM diagnosis, compared to non-ICI therapies. METHODS We reviewed 665 patients with LCBM diagnosed between 2000 and 2018 at a major tertiary care institution. Of those patients, 240 received ICI, 164 of which received ICI after 90-days and 76 received ICI within 90-days. Propensity score (PS) was calculated by logistic regression model including age, KPS, number of baseline brain lesions, and presence of extra-cranial metastasis (ECM) at time of LCBM diagnosis. OS from LCBM diagnosis between PS matched cohorts were compared using Kaplan-Meier, the Log-Rank test, and Cox proportional hazards models. RESULTS Prior to PS matching, median survival between ICI and non-ICI cohorts was not significantly different (10.9 months for both, p=0.81), although more ICI patients had ECM (57.1% vs 40.9%, p=0.006). Following PS matching, the ICI (n=76) and non-ICI (n=76) cohorts had median age (62.4 vs 62.3 years), KPS (80 for both), lesion number (2 for both), and ECM (56.6% for both). Of matched patients, 94% received SRS, 52% received WBRT, and 29% underwent surgical resection. Compared to non-ICI, the ICI cohort had a 2-year OS hazard ratio=0.87 (95% CI=0.58–1.31, p=0.51). Median and 1-year survival were not significantly different between ICI and non-ICI cohorts (median: 10.9 vs 9.1 months; 1-yr: 43.0% vs 42.4%). CONCLUSION Patients with LCBM who received ICI within 90-days of their diagnosis did not have improvement in OS compared to patients who received non-ICI therapies. Evaluation of clinical factors that may affect the efficacy and durability of immunotherapy is ongoing and will be presented.

Download Full-text

Clinicopathological Profile of Patients with Lung Carcinoma in a Tertiary Care Center

Journal of Health and Allied Sciences NU ◽

10.1055/s-0040-1718977 ◽

2020 ◽

Author(s):

M.T. Chandramouli ◽

Giridhar Belur Hosmane

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Lung Carcinoma ◽

Care Center ◽

Tertiary Care ◽

Smoking History ◽

Tertiary Care Center ◽

Cell Type ◽

Lung Cancer Patients ◽

Incidence And Mortality

Abstract Introduction Among malignant diseases, lung carcinoma is the most common cancer in men worldwide in terms of both incidence and mortality. Its increasing incidence in developing countries like India is an important public health problem. This work aimed to study the demographic, clinical, radiological, and histological features of patients with confirmed lung cancer. Materials and Methods A total of 50 patients with histologically confirmed lung cancer at a tertiary care center in India from August 2016 to September 2018 were studied and analyzed. Results Out of 50 diagnosed lung cancer patients, 86% were men and 14% women; 31 (62%) patients were aged more than 60 years. Majority were smokers (84%) and all were men. Cough (94%) was the most common presenting symptom followed by dyspnea (68%), chest pain (48%), and hemoptysis (38%). Of the 50 patients, 29 (58%) had soft tissue density mass lesion on radiograph. Squamous cell carcinoma (SCC) was the diagnosed histological cell type in 24 (48%) patients and adenocarcinoma in 21 (42%) patients. Distant metastasis was observed in 20 (40%) patients. Conclusion In this study, the most common histopathological cell type is SCC. Patients aged more than 50 years and smokers are at high risk of lung cancer. Patients with a smoking history and persistent respiratory symptoms should be promptly evaluated for lung malignancy.

Download Full-text

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

International Journal of Molecular Sciences ◽

10.3390/ijms22147717 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7717

Author(s):

Guido Giordano ◽

Pietro Parcesepe ◽

Giuseppina Bruno ◽

Annamaria Piscazzi ◽

Vincenzo Lizzi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Line Treatment ◽

Second Line ◽

Wild Type ◽

First Line ◽

Braf Mutations ◽

Mutational Status ◽

First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

Download Full-text