ABSTRACT
Background The phase III CheckMate 816 study demonstrated statistically significant and clinically meaningful improvements in event-free survival (EFS) and pathologic complete response (pCR) with neoadjuvant N + C vs C in patients (pts) with resectable NSCLC. Here, we report 3-y efficacy, safety, and exploratory biomarker analyses from CheckMate 816. Methods Adults with stage IB (tumors >=4 cm)-IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS <= 1, and no known EGFR/ALK alterations were randomized to N 360 mg + C Q3W or C alone Q3W for 3 cycles followed by surgery. Primary endpoints were EFS and pCR, both per blinded independent review. Exploratory analyses included EFS by surgical approach and extent/completeness of resection, and EFS and pCR by a 4-gene (CD8A, CD274, STAT-1, LAG-3) inflammatory signature score derived from RNA sequencing of baseline (BL) tumor samples. Results At a median follow-up of 41.4 mo (database lock, Oct 14, 2022), continued EFS benefit was observed with N + C vs C (HR, 0.68;95% CI, 0.49-0.93);3-y EFS rates were 57% and 43%, respectively. N + C improved EFS vs C in pts who had surgery, regardless of surgical approach or extent of resection, and in pts with R0 resection (table). Recurrence occurred in 28% and 42% of pts who had surgery in the N + C (n = 149) and C arms (n = 135), respectively. In the N + C arm, BL 4-gene inflammatory signature scores were numerically higher in pts with pCR vs pts without, and EFS was improved in pts with high vs low scores (data to be presented). Grade 3-4 treatment-related and surgery-related adverse events occurred in 36% and 11% of pts in the N + C arm, respectively, vs 38% and 15% in the C arm. Conclusions Neoadjuvant N + C continues to provide long-term clinical benefit vs C in pts with resectable NSCLC, regardless of surgical approach or extent of resection. Exploratory analyses in pts treated with N + C suggested that high BL tumor inflammation may be associated with improved EFS and pCR. Clinical trial identification NCT02998528. Editorial acknowledgement Medical writing and editorial support for the development of this , under the direction of the authors, was provided by Adel Chowdhury, PharmD, Samantha Dwyer, PhD, and Michele Salernitano of Ashfield MedComms, an Inizio company, and funded by Bristol Myers Squibb. Legal entity responsible for the study Bristol Myers Squibb. Funding Bristol Myers Squibb. Disclosure P.M. Forde: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, F-Star, G1 Therapeutics, Genentech, Iteos, Janssen, Merck, Novartis, Sanofi, Surface;Financial Interests, Institutional, Research Grant: AstraZeneca, BioNTech, Bristol Myers Squibb, Corvus, Kyowa, Novartis, Regeneron;Financial Interests, Personal, Other, Trial steering committee member: AstraZeneca, BioNTech, Bristol Myers Squibb, Corvus;Non-Financial Interests, Personal, Member of the Board of Directors: Mesothelioma Applied Research Foundation;Non-Financial Interests, Personal, Advisory Role, Scientific advisory board member: LUNGevity Foundation. J. Spicer: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, CLS Therapeutics, Merck, Protalix Biotherapeutics, Roche;Financial Interests, Personal, Other, Consulting fees: Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Novartis, Protalix Biotherapeutics, Regeneron, Roche, Xenetic Biosciences;Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Bristol Myers Squibb, PeerView;Non-Financial Interests, Personal, Other, Data safety monitoring board member: Deutsche Forschungsgemeinschaft;Non-Financial Interests, Personal, Leadership Role, Industry chair: Canadian Association of Thoracic Surgeons. [Formula presented] N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi;Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer Ingelheim, Novartis, Sanofi, AbbVie, Amgen, Eli Lilly, Grunenthal, Tak da, Owkin;Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen;Financial Interests, Institutional, Funding: BMS;Non-Financial Interests, Personal, Officer, International Thymic malignancy interest group, president: ITMIG;Other, Personal, Other, Family member is an employee: AstraZeneca. M. Provencio: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Janssen, Pfizer, Roche, Takeda;Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche, Takeda. S. Lu: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, GenomiCare, Hutchison MediPharma, Roche, Simcere, ZaiLab;Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Hanosh, Roche. M. Awad: Financial Interests, Personal, Other, Consulting fees: ArcherDX, Ariad, AstraZeneca, Blueprint Medicine, Bristol Myers Squibb, EMD Serono, Genentech, Maverick, Merck, Mirati, Nektar, NextCure, Novartis, Syndax;Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Genentech, Eli Lilly. T. Mitsudomi: Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, BridgeBio Pharma;Financial Interests, Personal, Other, Consulting fees: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, MSD, Novartis, Ono, Pfizer;Financial Interests, Personal, Speaker's Bureau: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant, Invitae, Merck, MSD, Novartis, Ono, Pfizer, Taiho;Financial Interests, Personal, Advisory Board: AstraZeneca;Non-Financial Interests, Personal, Leadership Role, Former president: IASLC. E. Felip: Financial Interests, Institutional, Research Grant: Fundacion Merck Salud, Merck KGAa;Financial Interests, Personal, Other, Consulting fees: Amgen, AstraZeneca, Bayer, BerGenBio, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GlaxoSmithKline, Janssen, Merck, MSD, Novartis, Peptomyc, Pfizer, Sanofi, Takeda;Financial Interests, Personal, Speaker's Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck, MSD, PeerVoice, Pfizer, Sanofi, Takeda, touchONCOLOGY;Non-Financial Interests, Personal, Member of the Board of Directors: Grifols. S.J. Swanson: Financial Interests, Personal, Speaker's Bureau: Ethicon. F. Tanaka: Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Chugai, Eli Lilly, Ono, Taiho;Financial Interests, Personal, Other, Consulting fees: AstraZeneca, Chugai, Ono;Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Covidien, Eli Lilly, Intuitive, Johnson & Johnson, Kyowa Kirin, MSD, Olympus, Ono, Pfizer, Stryker, Taiho, Takeda. P. Tran: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb;Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. N. Hu: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. J. Cai: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb;Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb;Financial Interests, Personal, Other, Travel support for attending meetings and travel: Bristol Myers Squibb. J. Bushong: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb;Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J. Neely: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb;Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. D. Balli: Financial Interests, Personal, Other, patents planned, issued, or pending: Bristol Myers Squibb;Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S.R. Broderick: Financial Interests, Personal, Advisory Board: AstraZeneca. All other authors have declared no conflicts of interest.Copyright © 2023 International Association for the Study of Lung Cancer. Published by E sevier Inc.
ABSTRACT
Introduction: Cancer healthcare has been affected by Coronavirus disease 2019 (COVID-19) pandemic, interfering the normal function of oncology units and increasing diagnostic delay. Nevertheless, the rising incidence of respiratory infections led to an increase in medical consultations and chest imaging explorations. The aim of the study was to assess whether the increase in medical evaluations in the context of the pandemic led to an increase in the detection of early-stage thoracic tumours. Methods: We performed a retrospective single-institution study, collecting data from patients diagnosed with thoracic tumours between March, 1, 2020 and December, 31, 2021. We analysed their demographic and clinical data, symptoms at diagnosis and those who were diagnosed due to SARS-CoV-2 infection. Results: A total of 378 patients were analysed. Main results are shown in Table-1. Only 5.3% of newly diagnosed thoracic tumours were related to a suspected or confirmed SARS-CoV-2 infection. However, these patients were not diagnosed at earlier stages (p = 0.414). When we evaluated symptoms at diagnosis, we found that asymptomatic patients presented in earlier stages (p <0.000, Figure-1), being the majority incidental findings during the follow-up of oncological and non-oncological pathologies. Regarding symptomatic patients, most presented as locally advanced or metastatic diseases and no changes have been observed in the pattern of presentation compared to studies prior to the pandemic. [Formula presented] Conclusions: COVID-19 pandemic did not seem to increase thoracic tumours diagnosis in our study. Lung cancer diagnosed in patients due to SARS-CoV-2 infection was not detected in earlier stages. Clinical presentation was similar to previous reported outside COVID-19 pandemic. Nevertheless, we find that asymptomatic patients diagnosed incidentally presented more frequently in localized stages in comparison with symptomatic patients. [Formula presented] Keywords: COVID19, Lung Cancer, Diagnosis
ABSTRACT
Background: Previous reports indicate that lung cancer patients are at an increased risk of severe COVID-19 disease and higher mortality rate compared to general population. However, prognostic factors are not yet clearly identified. The LunG canceR pAtients coVid19 Disease (GRAVID) study aimed to describe clinical characteristics, outcomes and predictors of poor prognosis in patients with lung cancer and COVID-19. Methods: In this large nationwide prospective study, medical records of lung cancer patients with COVID-19 diagnosis from 65 spanish hospitals were included. Clinical features, treatments and disease outcomes were collected. The primary endpoint was to determine any-cause mortality;secondary endpoints were hospitalization and admission at intensive care units (ICU). Risk factors of poor prognosis were identified by univariable and multivariable logistic regression models. Results: Overal, 447 patients were analysed. Mean age was 67.1 ± 9.8 years, and the majority were men (332, 74.3%) and current/former smokers (383 (85.7%). NSCLC was the most frequent cancer type (377, 84.5%), being adenocarcinoma (228, 51.0%) the predominant histology. 354 patients (79.2%) had unresectable stage III or metastatic disease, and 266 (59.5%) where receiving anticancer treatment, mostly first-line chemotherapy. 350 (78.3%) patients were hospitalized for a mean of 13.4 ± 11.4 days, 9 (2.0%) patients were admitted to ICU, and 146 (32.7%) patients died. Advanced disease and corticosteroid treatment at hospitalization were predictors of mortality. Non-terminal stage hospitalized patients with lymphocytopenia and high LDH showed an increased risk of death. Severity of COVID-19 correlated to mortality, admission at ICU and mechanical ventilation. Conclusion: With underlying comorbidities and immunocompromised status, patients with lung cancer and COVID-19 present high hospitalization and mortality rates. These outcomes, alongside the identification of prognostic factors, may inform physicians on risks and benefits for this population to provide individualized oncological care.
ABSTRACT
Introduction: There are currently no predictive biomarkers for long-term survival after neoadjuvant chemoimmunotherapy. However, the identification of non-small lung cancer (NSCLC) patients who obtain long-term benefit from chemoimmunotherapy is essential to optimize therapies. Methods: Using samples from NADIM clinical trial (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with nivolumab, we have evaluated the capacity of ctDNA levels before treatment initiation to predict overall survival (OS) and progression-free survival (PFS) by calculating Harrell’s C-statistic and we compare its predictive value with classical survival surrogates as the pathological response and clinical response assessed according to RECIST criteria v.1.1. The ctDNA was analyzed by NGS, using the Oncomine Pan-Cancer Cell-Free Assay™ (Thermo Fisher Scientific®). To explore the prognostic value of the amount of ctDNA at baseline, for each positive plasma sample, we calculated the sum of the mutant allele frequency (MAF) for all detected mutations. Patients who died from COVID19 were excluded from this analysis. Results: In our study, clinical responses based on RECIST criteria were not predictive for OS or PFS. On the contrary, in the multivariate analysis, patients with low ctDNA levels (<1% MAF), in the baseline sample, had significantly improved PFS and OS than patients in whom the opposite situation occurred (adjusted HR: 0.22;95%CI: 0.06-0.75;P=0.016 and adjusted HR: 0.04;95%CI: 0.00-0.45;P=0.008 for PFS and OS, respectively). The adjusted C-statistic (c) to predict PFS for ctDNA was 0.68 (95%CI: 0.51-0.84), which was superior to that of RECIST criteria (c=0.61;95%CI: 0.45-0.78) and similar to that of pathological response (c=0.68;95%CI: 0.52-0.84). Similarly, baseline ctDNA levels predicted OS (c=0.85;95%CI: 0.72-0.99) better than RECIST criteria (c=0.68;95%CI: 0.44-0.93). Conclusion: Pre-treatment ctDNA levels predicted more accurately long-term survival than radiological assessments in NADIM study and might be useful for the design of new clinical trials.
ABSTRACT
Introduction: Neoadjuvant chemoimmunotherapy been shown to be highly effective in resectable stage IIIA NSCLC. Now we provide long term survival data Methods: This was an open-label, multicentre, single-arm phase 2 trial in which patients with histologically or cytologically documented stage IIIA NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 and who were deemed locally to be surgically resectable by a multidisciplinary clinical team were treated with neoadjuvant intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6;6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). Here we report progression-free survival (PFS) and Overall survival (OS) at 36 and 42 months, assessed in the modified intention-to-treat population (ITT), which included all patients who received neoadjuvant treatment, and in the per-protocol population (PP), which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Results: Median follow-up time was 37.9 months (95%CI: 36.7-40.7), with a 94% maturity at 36 months. Among the ITT population (N=46), 37 patients, constituting the PP population, received subsequent adjuvant therapy. Of them, 27 (58.7%) patients completed the adjuvant treatment (16 cycles), 10 (21.7%) patients received between 3 and 15 cycles of adjuvant therapy, and 9 (19.6%) patients did not receive adjuvant therapy. At the time of data cutoff (March 2021), progression disease was diagnosed in 14 patients and 9 deaths were recorded in the ITT population. Of these, three deaths corresponded to patients who did not undergo surgery and had disease progression, four deaths corresponded to patients who underwent surgery and had disease progression, and the two remaining deaths corresponded to patients who were diagnosed as being disease free but died from COVID19 infection. Notably, among patients who could not undergo surgery (N=5), one of them is still alive and with no evidence of disease. PFS at 36 and 42 months in the ITT population were 69.6% (95%CI: 54.1-80.7), in both cases. Similarly, PFS at 36 and 42 in the PP population were 81.1% (95%CI: 64.4-90.5) in both cases. The percentage of patients who were alive at 36 and 42 months in the modified ITT population were 81.86% (95% CI: 66.8-90.6) and 78.94% (95%CI: 63.1-88.6), respectively. Likewise, OS at 36 and 42 months in the PP population was 91.0% (95%CI: 74.2-97.0) and 87.3% (95%CI: 69.3-95.1), respectively. Conclusion: The efficacy of nivolumab in combination with platinum-based chemotherapy in patients with resectable stage IIIA NSCLC is clearly supported by long term survival data. Keywords: NADIM trial, neoadjuvant chemo-therapy, long term survival
ABSTRACT
Background: Coronavirus disease 2019 (COVID19) is diagnosed by detecting the virus by reverse transcription polymerase chain reaction (RT-PCR). The majority of p go on to develop antibodies (Ab) against viral proteins. However, it is not known how long these antibodies last nor whether cancer treatments could affect the duration of immune response. The prognosis and greater or lesser vulnerability of the oncological population are also unknown. Methods: This prospective, longitudinal, multicenter serological study in the setting of SARS-CoV-2 was carried out in 50 Spanish hospitals. Eligibility criteria was a diagnosis of any thoracic cancer. The first determinations were performed between April 21, 2020 and June 3, 2020, either for p in follow up or in active treatment. Between September 10, 2020, and November 20, 2020, the second antibody (Ab) determination was performed in all previously seropositive p. Clinical and treatment data were collected, as was their clinical situation at study end. Study objectives were to prospectively determine seroprevalence in unselected lung cancer p during the first wave of the pandemic;the natural history of these p;the persistence of immunity more than 4 months after first determination;protection or lack thereof against reinfection after this period, and the nature of such protection;and the influence of treatments on maintenance or loss of immunity. Results: Of 1,500 p studied, 128 were seropositive, representing an overall prevalence of 8.5% seropositivity [95% confidence interval [CI], 7.2%, 10.1%]. Seventy-five percent were in active cancer treatment. COVID-19 infection was suspected in 47.7% [95% CI, 38.8%, 56.6%]. A second determination was performed on average 4.5 months later [IQR: 4;5] and obtained for 104 of the initially seropositive p (81%). A second determination could not be obtained in 24 p, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% (32/104) of p. The severity of the infection, the need for hospitalization (p: 0.032) and the presence of symptoms at diagnosis (p: 0.02), including fever (p: 0.005) and nasal congestion (p: 0.005), were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Ab loss. At time of last follow-up among those p for whom a second determination was performed, 89% (93 p) had completely recovered from the virus, with no lasting after effects. Only 1 of the 128 (0.78%) seropositive p had died from COVID-19. Conclusions: The prevalence of infection in lung cancer p is similar to that of the general population. Immunity against SARS-CoV-2 does not appear to be compromised by treatment, persisting beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population.
ABSTRACT
Background: Patients with cancer may be more susceptible to infection and at increased risk of more severe COVID-19 disease;however, prognostic factors are not yet clearly identified. The LunG canceR pAtients coVid19 Disease (GRAVID) study aimed to describe clinical characteristics, outcomes, and predictors of poor outcome in patients with lung cancer and COVID-19. Methods: In this large nationwide study, we reviewed medical records of patients with lung cancer and confirmed COVID-19 diagnosis from 65 Spanish hospitals. Clinical features, treatments and disease outcomes were collected. The primary endpoint was to determine all-cause mortality;secondary endpoints were hospitalization and admission to intensive care units (ICU). Risk factors for poor prognosis were identified by univariate and multivariate logistic regression models. Results: Overall, 447 patients were included for analysis. Mean age was 67 1 ± 9 8 years;332 (74 3%) were men, and 383 (85 7%) current/former smokers. NSCLC was the most frequent type of cancer (377, 84 5%), consisting mainly of adenocarcinoma (228, 51 0%), and stage III metastatic or unresectable disease (354, 79 2%). Two-hundred and sixty-six (59 5%) patients were receiving anticancer treatment, mostly first-line chemotherapy. In total, 350 (78 3%) patients were hospitalized for a mean of 13 4 ± 11 4 days, nine (2 0%) patients were admitted to the ICU, and 146 (32 7%) died. Advanced disease and the use of corticosteroids to treat COVID-19 during hospitalization were predictors of mortality. Hospitalized, non-endof-life stage patients with lymphocytopenia and high LDH had an increased risk of death. Severity of COVID-19 correlated to higher mortality, ICU admission, and mechanical ventilation rates. Conclusions: Due to their underlying comorbidities and immunocompromised status, patients with lung cancer and COVID-19 show high hospitalization and mortality rates. These outcomes, alongside the identification of prognostic factors, may inform physicians on the risks and benefits in this population, in order to provide individualized oncological care.
ABSTRACT
Background: The COVID-19 pandemic has produced devastating effects on the health care system, also affectingcancer patient care. When the pandemic reached Spain by the end of February 2020, the scarce data aboutCOVID-19 infection in cancer patients pointed out a higher risk of complications due to cancer diagnosis and also tocancer therapies. These conjectures led to concerns about hospital follow-up and cancer therapies of cancerpatients. More recent studies have included a higher number of patients, but heterogeneous according to cancertype and tumor stage, with few melanoma patients recorded. Given that different tumor types are associated withspecific comorbidities that have a known impact on COVID-19 evolution, analysis of COVID-19 by cancer types ismandatory. Similarly, analysis by tumor stage is relevant, as advanced cases could have different responses to viralinfection due to tumor-related immunosuppression and general condition deterioration. Methods: In Spain we have completed a national registry of melanoma patients infected by SARS-Cov-2 since April1st, 2020 to June 8th, 2020. Patients with a previous diagnosis of melanoma, presenting with Sars-Cov-2 infectionto our network of hospitals, were eligible for enrollment. A prospective observational study with a case registryfollowed by a retrospective analysis of patient data has been performed. Results: 64 patients have been included. Median age is 68 years (range 6 to 95 years), 22 (34%) patients arefemales, and 35 (55%) patients have stage IV melanoma. Twenty-one (33%) patients were on active anticancertreatment with anti PD-1 antibodies, 19 (30%) patients with BRAF plus MEK inhibitors, and 24 (37%) patients werenot on active treatment. Asymptomatic/paucisymptomatic evolution was recorded in 19 (30%) patients and mildseverity in 13 (20%) patients, not requiring hospital admission by COVID-19. Serious and life-threateningcomplications were recorded in 18 (28%) and 14 (22%) patients, respectively, including 28 (44%) patients whorequired oxygen therapy and 3 (5%) patients who had ICU admission. COVID-19 episode is resolved in 55 cases, including 34 (53%) patients cured, eight (12%) patients who have died due to melanoma progression, and 13 (20%)patients due to COVID-19. The median age of patients who died from COVID-19 was 74 years (range 49 to 91), while for those cured it was 64 years (range 6 to 95);85% of patients who died were males, while this ratedecreased to 62% for those cured. The mortality rate from COVID-19 was 20% for both stage IV and localizedmelanoma, while according to melanoma treatment it was 21%, 16%, and 21% for immunotherapy, BRAF plus MEKinhibitors, and for those who were not undergoing active cancer treatment, respectively. Conclusion: Our results show that the risk of death in melanoma patients is higher in males and older patients, andit is similar according to tumor stage and melanoma therapy. The impact of cancer diagnosis and treatments onCOVID-19 evolution is lower than previously expected.