Higher Number Of Metastatic Sites Research Articles

Overall Survival and Prognostic Factors in Metastatic Triple-Negative Breast Cancer: A National Cancer Database Analysis.

Metastatic triple-negative breast cancer (TNBC) is aggressive with poor median overall survival (OS) ranging from 8 to 13 months. There exists considerable heterogeneity in survival at the individual patient level. To better understand the survival heterogeneity and improve risk stratification, our study aims to identify the factors influencing survival, utilizing a large patient sample from the National Cancer Database (NCDB). Women diagnosed with metastatic TNBC from 2010 to 2020 in the NCDB were included. Demographic, clinicopathological, and treatment data and overall survival (OS) outcomes were collected. Kaplan-Meier curves were used to estimate OS. The log-rank test was used to identify OS differences between groups for each variable in the univariate analysis. For the multivariate analysis, the Cox proportional hazard model with backward elimination was used to identify factors affecting OS. Adjusted hazard ratios and 95% confidence intervals are presented. In this sample, 2273 women had a median overall survival of 13.6 months. Factors associated with statistically significantly worse OS included older age, higher comorbidity scores, specific histologies, higher number of metastatic sites, presence of liver or other site metastases in those with only one metastatic site (excluding brain metastases), presence of cranial and extra-cranial metastases, lack of chemotherapy, lack of immunotherapy, lack of surgery to distant sites, lack of radiation to distant sites, and receipt of palliative treatment to alleviate symptoms. In the multivariate analysis, comorbidity score, histology, number of metastatic sites, immunotherapy, and chemotherapy had a statistically significant effect on OS. Through NCDB analysis, we have identified prognostic factors for metastatic TNBC. These findings will help individualize prognostication at diagnosis, optimize treatment strategies, and facilitate patient stratification in future clinical trials.

A Real World Observational Study Characterizing Patients With Advanced Prostate Cancer Treated With or Without Androgen Receptor-Pathway-Inhibitor Therapies in Alberta, Canada

BackgroundData are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. MethodsThis retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or nonmetastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. ResultsThis study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI = 32.84-NA) vs. 34.19 (95% CI = 33.33-38.83; P = .03)), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. ConclusionsOutcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

The outcome in patients with BRAF-mutated metastatic melanoma treated with anti-programmed death receptor-1 monotherapy or targeted therapy in the real-world setting.

Immunotherapy and targeted therapy are currently two alternative backbones in the therapy of BRAF-mutated malignant melanoma. However, predictive biomarkers that would help with treatment selection are lacking. This retrospective study investigated outcomes of anti-programmed death receptor-1 monotherapy and targeted therapy in the first-line setting in patients with metastatic BRAF-mutated melanoma, focusing on clinical and laboratory parameters associated with treatment outcome. Data from 174 patients were analysed. The median progression-free survival (PFS) was 17.0 months (95% CI; 8-39) and 12.5 months (95% CI; 9-14.2) for immunotherapy and targeted therapy, respectively. The 3-year PFS rate was 39% for immunotherapy and 25% for targeted therapy. The objective response rate was 72% and 51% for targeted therapy and immunotherapy. The median overall (OS) survival for immunotherapy has not been reached and was 23.6 months (95% CI; 16.1-38.2) for targeted therapy, with a 3-year survival rate of 63% and 40%, respectively. In a univariate analysis, age < 70 years, a higher number of metastatic sites, elevated serum LDH and a neutrophil-lymphocyte ratio above the cut-off value were associated with inferior PFS regardless of the therapy received, but only serum LDH level and the presence of lung metastases remained significant predictors of PFS in a multivariate analysis. Present real-world data document the high effectiveness of immunotherapy and targeted therapy. Although targeted therapy had higher response rates, immunotherapy improved PFS and OS. While the prognostic value of LDH was confirmed, the potential use of blood cell count-derived parameters to predict outcomes needs further investigation.

Real-world clinical and survival outcomes of patients with early relapsed triple-negative breast cancer from the ESME national cohort

BackgroundEarly metastatic relapse of triple-negative breast cancer (mTNBC) after anthracyclins and/or taxanes based (A/T) primary treatment represents a highly aggressive cancer situation requiring urgent characterisation and handling. Epidemio-Strategy-Medico-Economical-Metastatic Breast Cancer (ESME-MBC) database, a multicenter, national, observational cohort (NCT03275311) provides recent data on this entity. MethodsAll ESME patients diagnosed between 2008 and 2020 with mTNBC occurring as a relapse after a systemic neoadjuvant/adjuvant taxane and/or anthracycline-based chemotherapy were included. Early relapses were defined by a metastatic diagnosis up to 12 months of the end of neo/adjuvant A/T chemotherapy. We assessed overall survival (OS) and progression-free-survival under first-line treatment (PFS1) by early versus late relapse (≥12 months). ResultsPatients with early relapse (N = 881, 46%) were younger and had a larger tumour burden at primary diagnosis than those with late relapses (N = 1045). Early relapse rates appeared stable over time. Median OS was 10.1 months (95% CI 9.3–10.9) in patients with early relapse versus 17.1 months (95% CI 15.7–18.2) in those with late relapse (adjusted hazard-ratio (aHR): 1.92 (95% CI 1.73–2.13); p < 0.001). The median PFS1 was respectively 3.1 months (95% CI 2.9–3.4) and 5.3 months (95% CI 5.1–5.8); (aHR: 1.66; [95% CI 1.50–1.83]; p < 0.001). Among early relapsed patients, a higher number of metastatic sites, visceral disease but not treatment types, were independently associated with a poorer OS. ConclusionThese real-world data provide strong evidence on the dismal prognosis, higher treatment resistance and major unmet medical need associated with early relapsed mTNBC.Database registration: clinicaltrials.gov Identifier NCT032753

Efficacy outcomes and prognostic factors from real-world patients with advanced non-small-cell lung cancer treated with first-line chemoimmunotherapy: The Spinnaker retrospective study

BackgroundEfficacy outcomes and prognostic factors of real-world patients with advanced non-small cell lung cancer (aNSCLC) treated with first-line chemoimmunotherapy are still limited. Patients and MethodsIn the retrospective Spinnaker study, data was collected from patients in six United Kingdom and one Swiss oncology centres with first-line pembrolizumab plus platinum-based chemotherapy. Efficacy outcomes and potential prognostic factors were estimated aiming at developing a prognostic model. ResultsThree-hundred-eight patients were included, 32% ≥ 70 years, with ≥ 3 metastatic sites in 33%, brain or liver metastases in 10% and 12%, respectively. With a median follow-up of 18.0 months (mo.) (range, 15.9–20.1), median overall survival (OS) and progression-free survival (PFS) were 12.7 mo. (range, 10.2–15.2), and 8.0 mo. (range, 7.1–8.8), respectively. The neutrophils-to-lymphocytes ratio (NLR) and systemic immune-inflammatory index (SII) (i.e., NLR × platelet count) were both significantly higher in ECOG PS 1 (p = 0.0147 and p = 0.0018, respectively), underweight or normal body mass index (p = 0.0456 and p = 0.0062, respectively), ≥3 metastatic sites (p = 0.0069 and p = 0.112), pretreatment steroids (p = 0.0019 and p = 0.0017). By MVA, the number of metastatic sites ≥ 3 (p < 0.001 and p = 0.002), squamous histology (p = 0.033 and p = 0.013) and SII ≥ 1444 (p = 0.031 and p = 0.009, respectively) were associated with both worse OS and PFS and led to a highly discriminating three-class risk prognostic model. ConclusionReal-world PFS with chemoimmunotherapy in aNSCLC patients is similar to that reported in clinical trials. A high number of metastatic sites, squamous histology and high SII are adverse prognostic factors that might contribute to a clinically useful prognostic model.

Is the BRAF mutation still an unfavorable risk factor in patients with metastatic melanoma in the era of modern therapies?

e21544 Background: BRAF-mutated (MUT) melanoma is characterized by specific clinical features including more aggressive biological behavior than BRAF wild-type (WT) melanoma. BRAF mutations are historically known as negative prognostic factor for to shorter overall survival (OS) in patients with stage IV disease with melanoma. Methods: Consecutive patients with unresectable or metastatic melanoma started treatment with BRAF inhibitors (BRAFi), BRAFi and MEK inhibitors (MEKi) or IT (anti-PD-1 antibody) between 1/Jan/2013 and 31/Dec/2020. Clinical factors including age, gender, primary location of melanoma, ECOG performance status, baseline LDH level, and location of metastases, response to treatment were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2021. Results: In total 1456 patients were enrolled. BRAF mutation was found in 723 (49.7%) patients and 733 (50.3%) patients were BRAF WT. All BRAF WT patients received first-line IT, while BRAF MUT patient received first-line treatment with BRAFi (n = 134/723, 18%), BRAFi and MEKi (n = 426, 58%) or anty-PD-1 (n = 173, 24%). BRAF MUT patients were significantly younger (median 60 vs 69; p &lt; 0.0001), had worse ECOG (p = 0.0008), elevated LDH (p &lt; 0.0001), had higher number of metastatic sites (p &lt; 0.0001) and brain metastases (p &lt; 0.0001). The estimated median OS (mOS) in BRAF WT group was 17.3 month while in BRAF MUT - 14.8 months (p = 0.33; HR = 0.94, Cl 95% 0.8-1.1). mOS in BRAF MUT group treated with BRAFi was - 10.0, while with BRAFi and MEKi combination - 14.9. BRAF WT and BRAF MUT groups treated with IT did not differ significantly in baseline characteristics. BRAF MUT group treated with IT achieved mOS of 26.2 months, while in BRAF WT 17.3 months. Conclusions: The analysis showed no differences in the median OS between BRAF MUT and BRAF WT patients with unresectable or metastatic melanoma treated with novel therapies (BRAFi-MEKi combination or IT), despite unfavorable prognostic factors in the BRAF MUT group. Moreover mOS was significantly prolonged in the BRAF MUT patients treated with IT.

Differential prognostic effect of systemic inflammation in patients with NSCLC treated with immunotherapy or chemotherapy: A post hoc analysis of the phase III OAK trial.

9056 Background: A pro-inflammatory diathesis as measured by the neutrophil-to-lymphocyte ratio (NLR) heralds an adverse disease course in non-small cell lung cancer (NSCLC). Whether the NLR identifies patients who derive a differential degree of benefit from immunotherapy versus chemotherapy is not known. Methods: This post hoc analysis used data from the phase III OAK trial, which randomized previously treated patients with NSCLC to receive atezolizumab or docetaxel. The main objective was to assess the differential impact of pre-treatment NLR on overall survival (OS) depending on the treatment modality. In addition, we assessed patients genomic characteristics according to inflammatory status using circulating free (cf)DNA NGS analysis. Results: A total of 600 and 575 patients with an available NLR were included in the atezolizumab and docetaxel cohort, with a median NLR of 4 (IQR: 2.6-6.7) for the pooled population. NLR ≥ 4 was associated with positive smoking status (88.6% vs 78.1%, p &lt; 0.01), male sex (66.4% vs 57.6%, p = 0.01), worse performance status (71.3% vs 55.2%, p &lt; 0.01), higher number of metastatic sites (63.2% vs 51.6%, p = 0.01), squamous histology (32.1% vs 21.4%, p &lt; 0.01), and tissue KRAS mutation (30% vs 18.7%, p = 0.02), but not with PD-L1 expression, nor with tissue EGFR/ALK status. Pre-treatment NLR of ≥ 4 was more strongly associated with mortality following atezolizumab with an adjusted hazard ratio (HR) of 1.64 (95%CI:1.35-2.01) compared to docetaxel (HR 1.32, 95%CI: 1.08-1.60, multivariable (MVA) interaction p = 0.08. Exclusion of EGFR/ALK positive patients further increased the prognostic ability of baseline NLR in favor of atezolizumab (HR 1.67, 95%CI: 1.35-2.06), as compared with the docetaxel arm (HR 1.24, 95%CI: 1.02-1.52, MVA interaction p = 0.02). The HR for the risk of death for patients with NLR≥ 4/PD-L1 negative tumours (compared to NLR &lt; 4/PD-L1 positive) was significantly higher in the atezolizumab cohort (HR 2.28, 95%CI: 1.72-3.03) than in the docetaxel cohort (HR 1.42, 95%CI: 1.08-1.86, MVA interaction p = 0.01). NGS pretreatment cfDNA data showed that patients with a high blood tumor mutational burden (cut-off 16 Mut/Mb) had a higher median NLR (4.6 vs 3.7, p = 0.01). After adjusting for multiple comparisons, none among the selected variants of interest (EGFR, KRAS, TP53, KEAP1, STK11, SMARCA4, ARID1A and targeted DDR genes), were significantly associated with the NLR. Conclusions: In this post-hoc analysis, a baseline low NLR identifies patients with NSCLC who derive a greater survival benefit from atezolizumab as compared to those identified in the docetaxel cohort, irrespective of genomic features. Patients with a low NLR and PD-L1 positive tumors derive the greatest benefit with immunotherapy and the NLR could complement PD-L1 expression in tailoring treatment in this setting. Clinical trial information: NCT02008227.

Institutional review of African American (AA) patients with metastatic triple-negative breast cancer.

e13059 Background: Atezolizumab+ Abraxane (Ate+Abx) was approved as 1st line treatment in metastatic TNBC based on IMPASSION (IM) 130 trial and was subsequently withdrawn per IM131 trial. Treatment of mTNBC remains challenging. Pembrolizumab with chemotherapy received accelerated approval based on Keynote-355. Poor outcomes among AA patients (pts) are linked to biological differences, BRCA1/2 mutations, obesity, and socioeconomic barriers. In TNBC clinical trials, AA pts continue to be underrepresented, e.g., 5.8% (26) in IM130 and 4.9% (21) in IM131. Our cancer center sees over 300 new BC pts a year, and at least 50% identify as AA. Here we examine our institutional experience. Methods: IRB-approved retrospective database search was conducted between 01/01/2019- 04/16/2021 to identify 11 pts treated with Ate+Abx for mTNBC at Medstar Washington Hospital Center, DC. Demographic variables manually extracted were age, BMI, insurance type and outcomes. Results: 10/11 (91%) pts were AA with lines of therapy ranging 1-6. 20% (2/10) showed partial response (PR) on 3-month (M) interval imaging per the RECIST 1.1 scoring. PD occurred in 6/10 (60%) of pts, although PD-L1 was positive in 90% (9/10) pts. Time to progression (TTP) was 1-7 M (median 3M) compared to TTP of 5.59 to 7.46M (median 7.16M) for all races in the IM130 study. Autoimmune colitis, peripheral neuropathy, and fatigue were notable adverse effects (AEs). 2/10 (20%) pts discontinued treatment due to AEs. Colitis and neuropathy in IM130 were &lt;1%. Mean age at drug initiation was 52.2 vs. 55 years in IM130, indicating earlier onset of mTNBC in the AA population. Conclusions: Trends of higher PD and earlier TTP were noted in our AA pts. Young age at metastasis, high number of previous lines of therapy, high number of metastatic sites, and obesity were noted amongst our AA mTNBC pts. Positive PD-L1, BRCA mutations, metastatic sites, BMI, or insurance type did not correlate with outcomes. Pts with PR vs. PD were not different in terms of insurance, metastasis sites, and BMI. Differences in AEs are noted; however, the small pt population size and lack of a control group are limitations. While the FDA has withdrawn Ate from trials for mTNBC, this study suggests a need for more AA pts to be included in clinical trials for TNBC. Lack of health care access, insufficient education, inadequate recruitment, and distrust of the medical system are contributing factors that require continued efforts.[Table: see text]

REchallenge of NIVOlumab (RENIVO) or Nivolumab-Ipilimumab in Metastatic Renal Cell Carcinoma: An Ambispective Multicenter Study.

Introduction Immune checkpoint inhibitors (ICI) have been approved for front-line therapy in metastatic renal cell carcinoma (mRCC). However, progressive disease often occurs and subsequent therapies are needed. ICI rechallenge may be an option, but there is a lack of data regarding efficacy and prognostic factors. We assessed efficacy of ICI rechallenge and factors associated with better outcomes. Patients and Methods. This ambispective multicenter study included 45 mRCC patients rechallenged with nivolumab ± ipilimumab between 2014 and 2020. Primary endpoint was investigator-assessed best objective response rate (ORR) for ICI rechallenge (ICI-2). Factors associated with ICI-2 progression-free survival (PFS) were evaluated with multivariate Cox models. Results ORR was 51% (n = 23) at first ICI therapy (ICI-1) and 16% (n = 7) for ICI-2. Median PFS was 11.4 months (95% CI, 9.8–23.5) and 3.5 months (95% CI, 2.8–9.7), and median overall survival was not reached (NR) (95% CI, 37.8–NR) and 24 months (95% CI, 9.9–NR) for ICI-1 and ICI-2, respectively. Factors associated with poorer ICI-2 PFS were a high number of metastatic sites, presence of liver metastases, use of an intervening treatment between ICI regimens, Eastern Cooperative Oncology Group performance status ≥2, and poor International Metastatic RCC Database Consortium score at ICI-2 start. Conversely, ICI-1 PFS >6 months was associated with better ICI-2 PFS. In multivariate analysis, there were only statistical trends toward better ICI-2 PFS in patients with ICI-1 PFS >6 months (p=0.07) and toward poorer ICI-2 PFS in patients who received a treatment between ICI regimens (p=0.07). Conclusion Rechallenge with nivolumab-based ICI has some efficacy in mRCC. We identified various prognostic factors in univariate analysis but only statistical trends in multivariate analysis. Our findings bring new evidence on ICI rechallenge and preliminary but unique data that may help clinicians to select patients who will benefit from this strategy.

Is sarcopenia a missed factor in the management of patients with metastatic breast cancer?

BackgroundSarcopenia has emerged as an important parameter to predict outcomes and treatment toxicity. However, limited data are available to assess sarcopenia prevalence in metastatic breast cancer and to evaluate its management. MethodsThe SCAN study was a cross-sectional multicenter French study that aimed to estimate sarcopenia prevalence in a real-life sample of metastatic cancer patients. Sarcopenia was identified by low muscle mass (estimated from the skeletal muscle index at the third lumbar, via computed tomography) and low muscle strength (defined by handgrip strength). Three populations were distinguished based on EWGSOP criteria: a sarcopenic group with low muscle mass AND strength, a pre-sarcopenic group with low muscle mass OR strength and a normal group with high muscle mass AND strength. ResultsAmong 766 included patients, 139 patients with breast cancer and median age of 61.2 years (29.9–97.8 years) were evaluable; 29.5% were sarcopenic and 41.0% were pre-sarcopenic. Sarcopenic patients were older (P < 0.01), had a worse PS-score (P < 0.05), and a higher number of metastatic sites (P < 0.01), the majority being hepatic and bone. A moderate agreement between the oncologist's diagnosis and sarcopenia evaluation by muscle mass and strength was recognized (Cohen's kappa = 0.45). No associations were found between sarcopenia and adverse event occurrence in the 12 patients for whom these were reported. Sarcopenic patients were underdiagnosed and nutritional care and physical activity were less proposed. ConclusionIt is necessary to evaluate sarcopenia due to its impact on patient prognosis, and its utility in guiding patient management in metastatic breast cancer.

Prognostic Impact of Cytoreductive Nephrectomy in Patients with Metastatic Renal Cell Carcinoma: Data from a Large Population-Based Database.

Cytoreductive nephrectomy (CN) was considered a well-established treatment modality for patients with metastatic renal cell carcinoma (RCC) in the interferon era. However, its role after the introduction of multiple targeted therapies is less well established. Herein, We evaluated the effect of CN on overall survival (OS) on patients with RCC who were identified through the Surveillance, Epidemiology, and End Results database (SEER). A total of 5,483 patients with metastatic RCC were identified from 2010 to 2016 using the SEER database. Factors pertaining to the following variables were collected: presence or absence of CN; age; gender; grade; status of metastasis to bone, liver, lung and brain; tumor stage; nodal status; histological subtypes; and chemotherapy status. Subjects who had CN were matched with those who did not in all previously mentioned covariates using inverse probability weighting. These weights were then used in adjusted Cox regression models to report doubly robust estimates. CN was associated with 67% reduction in the hazards of death. Advanced T-stage, N1 disease, advanced tumor grade, non-clear histology and metastasis to bone, liver, lung or brain are independent risk factors for death. Patients with T4 disease benefited less of CN compared to those with T1 disease, while higher number of metastatic sites didn't predict worse outcome among those who had CN. CN could provide a survival advantage in favorable risk patients with RCC in the era of targeted therapy.

A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab

Simple SummaryPembrolizumab, a monoclonal antibody targeting programmed cell death 1, improves the survival of patients with advanced melanoma. This study aimed to investigate the association of baseline clinical characteristics, laboratory and imaging variables, and gene expression profiling scores on tumor tissue analysis of advanced melanoma patients who were treated with pembrolizumab, with survival using univariate and multivariate analysis. Baseline organ function (reflected by the presence of active brain metastases, number of metastatically affected organs, albumin) and systemic inflammatory/immunologic status (reflected by albumin, C-reactive protein, absolute lymphocyte count, neutrophil-to-lymphocyte ratio) are the most important clinical and/or laboratory parameters predictive of survival. Novel biomarkers include the baseline presence of BRAFV600 or NRASQ61/G12/G13 mutant circulating tumor DNA and baseline total metabolic tumor volume assessed by whole-body 18F-FDG-PET/CT. Gene expression profiling scores by the NanoString PanCancer IO360 panel were not conclusive in our patient population.Background: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. Methods: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival. Results: 183 patients were included (stage IV 85.2%, WHO performance status ≥1 31.1%; pembrolizumab first-line 25.7%), of whom 112 underwent baseline 18F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) ≥ 2ULN (upper limit of normal), CRP ≥ 10ULN, or ALC < 750/mm3 delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV ≥ 80 mL encompassed 17/21 patients with LDH ≥ 2ULN, CRP ≥ 10ULN, or ALC < 750/mm3. No significant associations were observed between baseline GEP scores and survival. Conclusion: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab.

Immune checkpoint inhibitors versus second line chemotherapy for patients with lung cancer refractory to first line chemotherapy

PurposeAnti Programmed Death-ligand (PD1/PD-L1) directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC) who progress after first line chemotherapy. The best strategy after early progression under first line has not been specifically studied. Patients and methodsWe conducted a multicenter, retrospective study including all consecutive NSCLC patients progressing within the first 3 months following introduction of first-line chemotherapy and being treated with second line ICI monotherapy or chemotherapy between March 2010 and November 2017. We analysed the clinicopathological data and outcome under second line chemotherapy vs. second line ICI: objective response rate (ORR), progression-free survival (PFS), overall survival (OS. ResultsWe identified 176 patients with refractory disease, 99 who received subsequent immunotherapy and 77 undergoing chemotherapy. The 2 populations were comparable regarding the main prognostic criteria, median age was 60, main histology was adenocarcimoma (68.2%). PFS was not significantly different between both treatments 1.9 [1.8–2.1] versus 1.6 month [1.4–2.0] (P=0.125). Compared to chemotherapy, ICI treated patients had a superior OS (P=0.03) (Median [95% CI] OS 4.6 [2.8–6.7] versus 4.2 months [3.4–5.9] and a non-significant improvement in ORR (17.2% versus 7.9%, respectively, P=0.072). Poor performance status (ECOG PS≥2) and a higher number of metastatic sites (≥3) were associated with poorer prognosis. KRAS-mutated patients did not seem to benefit more from ICI than chemotherapy. ConclusionsICI appears to be the preferred second-line treatment for patients who are refractory to first line chemotherapy.

Nivolumab for Previously Treated Patients with Non-Small-Cell Lung Cancer—Daily Practice versus Clinical Trials

Based on the results of the CheckMate 017 and CheckMate 057 studies, nivolumab therapy has become a new standard treatment for both squamous and non-squamous non-small-cell lung cancer (NSCLC). However, due to the specific inclusion criteria of these clinical trials, the efficacy and safety of nivolumab in real-world practice were not certain. In general, the real-world results of nivolumab treatment have been consistent with those obtained in clinical trials. Additional analyses of the real-world data have made the identification of prognostic factors possible. Good performance status is the most significant predictor of clinical benefit. Brain metastases, liver metastases, EGFR mutation, malignant pleural effusion, and a high number of metastatic sites were identified as negative prognostic factors. By contrast, a longer time to disease progression (>6 months) from the beginning of prior chemotherapy and an objective response to chemotherapy seem to have positive prognostic value in the case of nivolumab treatment. In terms of patient age, the data are inconclusive. Some blood biomarkers can also be considered significant prognostic factors.

Hyperprogressive disease during treatment with immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC).

e21664 Background: Hyperprogressive disease (HPD) is a new pattern of progressión during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study prognostic factors of HPD. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included in the analysis. The variables were compared by chi-square and Fisher test, then we performed a multivariate logistic regression model to analyse the effects of the covariates, and finally we performed a Kaplan Meier survival analysis. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. Nine of 104 patients (8.7%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 9 patients, and was associated with worse overall survival in the multivariate analysis by Cox regression (12.6 vs 2.6 months; HR 13.94, p &lt; 0.001). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 8.59, p = 0.026). Conclusions: The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC.

Molecular profiling of metastatic breast cancer (MBC) and target-based therapeutic matching in an Asian tertiary phase I oncology unit.

3561 Background: Somatic profiling of MBC has highlighted actionable mutations and driven trials of matched targeted therapy (tx). Previous phase I studies have reported improved outcomes following matched therapies with tumour molecular profiles. Here, we review next generation sequencing (NGS) and treatment outcomes of Asian MBC patients (pts) in the phase I unit of a tertiary centre. Methods: Pts with MBC referred to a phase I unit underwent NGS (n = 152). Tumour tissue was sequenced via the amplicon based Ion Ampliseq Cancer (IAC) v2 (50 genes) platform from 2014-2017 prior to institutional change to Foundation Medicine 1 (FM1) (324 genes) 2017-2019. Patients were counselled on findings and enrolled onto matched therapeutic trials where available. Results: NGS was successfully performed in 107 pts (IAC 46%, FM1 54%) of which tumour subtypes include hormone receptor positive 63%, triple negative breast cancer (TNBC) 28% and Her2 positive 19%. Median lines of prior tx for MBC was 4 (range 0-12). 89% had prior chemotherapy (CT), 57% prior endocrine therapy (ET). 72/107 (67%) sequenced patients had further treatment and 18 (25%) were matched to tx based on NGS findings (15 clinical trial, 3 off trial). Matching rates on both NGS platforms were similar (IAC 22% vs FM1 28%). Mutated pathways with potential matched tx included PIK3CA/AKT/PTEN (52%), DNA damage response (DRR) (15%), and FGFR (11%) pathways. PIK3 mutations were seen in 43% and associated with higher number of metastatic sites (p = 0.03); most prevalent aberrations were PIK3CA H1047R (41%) and PIK3CA E542K (13%). Matched cases were more heavily pretreated (mean lines of prior tx 5.3 matched vs 3.7, unmatched p = 0.05), and showed a median progression free survival (mPFS) of 24 weeks [w] and clinical benefit rate (complete/partial response or stable disease ≥ 12 weeks) of 53% on matched tx. Comparison by NGS platform showed improved mPFS for matched vs unmatched pts sequenced on FM1 vs IAC (FM1: 26 vs 19w, HR = 0.76 [95% CI: 0.3-1.9]; IAC: 8 vs 12w; HR = 1.21 [95% CI: 0.5-2.8]). Interestingly, 1 pt with SMARCB mutation, reportedly associated with the FGFR pathway, had a PFS of 70w on tx with a pan-FGFR inhibitor after progressing on 3 prior lines of tx (ET and CT). Conclusions: Molecular profiling of MBC in a phase I unit led to matched tx in 25% of cases. Matched pts showed encouraging mPFS with a suggestion of benefit in those matched after sequencing on a broader gene panel (FM1).

Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors

Abstract Background Hyperprogressive disease (HPD) is a new pattern of progression during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study possible prognostic factors related to HPD. Methods We collected data of 66 patients diagnosed with advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and May 2019. Several variables as clinical, tumour-related and therapeutical were included and univariate and multivariate Cox regression analysis were performed. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported. Results Cohort of 50 men and 16 women, median age of 67 years and 80% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 66% were active or ex-smokers and 34% had never smoked. 62% of patients had adenocarcinoma histology, 32% scamous and 3% had not otherwise specified (NOS) carcinoma histology. 30 of the 66 patients (45%) had 2 or more metastatic sites. 53% of patients had unknown PDL1 status; 9% had no PDL1 expression, 9% low expression and 27% high expression. 82% of patients had progressed to prior line of treatment, while 18% were treatment-naive. Seven of 66 patients (10.6%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 7 patients, and was associated with worse overall survival in the multivariate regression Cox analysis (43.6 vs 11.3 months; HR 4.35, p = 0.0037). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 6.74, p = 0.009). Conclusion The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Lessons learned from routine, targeted assessment of liquid biopsies for EGFR T790M resistance mutation in patients with EGFR mutant lung cancers

Background: Plasma cfDNA evaluation at acquired resistance to targeted therapies in lung cancer is routine, however, reports of extended clinical application and pitfalls in laboratory practice are still limited. In this study we describe our experience with cfDNA testing using EGFR T790M as a prototype.Methods: Patients with metastatic EGFR-mutant NSCLC patients who underwent plasma EGFR T790M testing at acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) from January 2016 through August 2017 were identified. Molecular laboratory records were reviewed to assess performance of testing by digital PCR, concordance between plasma and tissue testing, turnaround time (TAT), plasma T790M variant allele frequency (VAF), and its correlations with metastatic sites and clinical outcomes.Results: 177 patients underwent T790M cfDNA testing during this period. Plasma T790M was positive in 32% of patients. The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs. 15 days, p < .0001), and led to osimertinib use in 84% of positive patients. In 52 patients with plasma and tissue T790M evaluation, the concordance was 77%. Plasma T790M VAF did not correlate with time to osimertinib discontinuation (p = .4). Plasma T790M status correlated with a higher number of metastatic sites (4 vs. 3, p < .001) and bone metastases (p = .0002).Conclusion: Plasma EGFR T790M testing had shorter TAT compared to tissue testing, however, it was longer than anticipated. Test sensitivity is higher in patients with osseous metastases and with higher metastatic burden suggesting a more limited role for early detection. T790M VAF was not associated with clinical outcomes.

Clinical and molecular factors predicting resistance to first-line (1L) FOLFOX in patients (pts) with advanced esophagogastric cancer (EGA) and patterns of subsequent therapy.

4047 Background: In the US, FOLFOX is the most widely used 1L treatment for advanced EGA. We evaluated if FOLFOX resistance (FR) impacted subsequent therapy and characterized the clinical and molecular factors that predict resistance to 1L FOLFOX. Methods: We reviewed pts with advanced Her2-negative EGA treated with 1L FOLFOX from Jan 2013 to Aug 2017. Response or stable disease (SD) at time of first restaging scan defined pts as FOLFOX sensitive (FS); progression defined FR. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank-Sum tests. Outcomes were correlated with clinical variables and MSK-IMPACT data. Microsatellite instable (MSI) pts were excluded from gene and pathway analysis. Overall survival (OS) was calculated from start of FOLFOX using Kaplan-Meier methods. Landmark analysis (2 months [mo] after starting FOLFOX) was used to compare OS between groups. Results: We identified 311 pts, median age 62, 73% male, 82% ECOG 0/1. 246 pts (79%) were FS and 65 (21%) were FR. FR pts had a higher number of metastatic sites, p = 0.001. Median OS was 13.4 mo in FS pts vs 4.3 mo in FR pts (p &lt; 0.001). At time of analysis, 213 pts (172 FS pts and 41 FR pts) and 110 pts (90 FS pts and 20 FR pts) had received 2nd-line (2L) and 3rd-line (3L) chemo respectively. In pts who received 2L chemo (ctx), there was no difference in ctx duration between FS and FR pts (2.1 vs 1.4 mo, p = 0.67). However, in pts who received 3L ctx, the duration was longer in FS vs FR pts (1.6 vs 0.5 months, p = 0.002). In IMPACT tested pts (n = 130), univariate analysis identified EGFR (33.3% vs 10.7%, p = 0.032) and WNT pathway (26.7% vs 4.9%, p = 0.015) alterations more frequently in FR pts vs FS pts. 12 pts were MSI, all were FS (3 SD, 8 PR, 1 CR). Of 63 pts who had IMPACT germline testing, 7 (11%) had germline mutations identified, including CDH1 (n = 2) and ATM (n = 1), all were FS. No pts were enrolled on genotype-matched trials as a result of IMPACT testing. Conclusions: From time of first restaging scan, FR pts have inferior OS to FS pts. The duration of 3L ctx was longer in FS vs FR pts. Higher number of metastatic sites and EGFR and WNT pathway alterations were associated with FR; MSI was not. IMPACT did not facilitate enrolment on genotype-matched studies.

Prognostic Value of Baseline ALBI Score Among Patients With Colorectal Liver Metastases: A Pooled Analysis of Two Randomized Trials

BackgroundBaseline albumin-bilirubin (ALBI) score has been shown to be a reliable prognostic predictor among patients with hepatocellular carcinoma. The current study aims at evaluating its prognostic impact among patients with colorectal liver metastases treated with first-line systemic therapy. Materials and MethodsThrough the Project Data Sphere portal, de-identified clinical trial datasets of 2 clinical trials (NCT00115765; PACCE [Panitumumab Advanced Colorectal Cancer Evaluation Study] trial) and (NCT00364013; PRIME [Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy] trial) were downloaded. Baseline ALBI score was calculated for each included patient in this study. Kaplan-Meier curve/log-rank testing was used to evaluate overall and progression-free survival according to ALBI grades. Additional Cox regression models were run in order to evaluate factors affecting overall and progression-free survival. Factors with P-value < .05 in univariate analysis were included in multivariate analysis. ResultsA total of 1434 patients with colorectal liver metastases were included in this study. Kaplan-Meier survival analysis was conducted to assess the impact of ALBI grade on overall and progression-free survival in the study cohort. For both endpoints, higher ALBI grade was associated with worse overall and progression-free survival (P < .001 for both endpoints). The following factors were significant for overall survival in univariate Cox regression analysis (P < .05): age, Eastern Cooperative Oncology Group (ECOG) score, lactate dehydrogenase (LDH), number of metastatic sites, body mass index, and ALBI score. When these factors were evaluated in multivariate Cox regression analysis, the following factors were predictive of worse overall survival: higher ALBI score (P < .001), higher number of metastatic sites (P < .001), higher LDH (P < .001), higher ECOG score (P < .001), and older age (P < .001). Similarly, the following factors were significant for progression-free survival in univariate Cox regression analysis (P < .05): age, race, ECOG score, LDH, number of metastatic sites, body mass index, type of chemotherapy, and ALBI score. When these factors were evaluated in multivariate Cox regression analysis, the following factors were predictive of worse progression-free survival: higher ECOG score (P < .001), higher LDH level (P < .001), higher number of metastatic sites (P < .001), and higher ALBI score (P < .001). ConclusionsHigher baseline ALBI score is associated with worse overall and progression-free survival among patients with colorectal liver metastases treated with first-line systemic therapy.