Ninety-day mortality and clinical outcomes of patients with solid tumours and COVID-19 infection during the first pandemic outbreak in Catalonia, Spain: A multicentre retrospective study.

To describe the clinical outcomes and risk factors for 90-day mortality in patients with solid tumours (ST) and coronavirus disease 2019 (COVID-19) during the first outbreak in Catalonia. This is a multicentre retrospective study including adults with ST and COVID-19 confirmed by real time reverse transcription polymerase chain reaction between 13 March and 30 April 2020. Clinical and survival data were collected. Follow-up ended on 30 July 2020. Multivariate and survival analysis were performed. A hundred and fifteen patients were included. In all, 42.6% had advanced disease and were receiving anticancer treatment; 7% were admitted to the ICU and 22.6% died during hospitalisation. Thirty-day mortality was 27.8%, which increased to 33.9% at 90 days. Ninety-day mortality was associated with current smoker status (hazard ratio [HR]: 2.91, 95% CI [confidence interval]: 1.03-8.33, P = .044), baseline ECOG-PS 2 to 3 (HR: 3.88, 95% CI: 1.77-8.46, P < .001]), dyspnoea (HR: 3.02, 95% CI: 1.31-6.96, P = .009), a respiratory rate ≥ 24 (HR: 2.24, 95% CI: 1.02-4.92, P = .046) and sepsis (HR: 3.97, 95% CI: 1.78-8.88, P < .001). Of the 76 survivors, 73.6% had a follow-up visit. Of those, 33.9% had their cancer controlled and 23.2% had progressed. Thirty-five survivors were receiving anticancer treatment before COVID-19 diagnosis though 14 had to discontinue the treatment. Eight survivors without previous anticancer therapy started therapy. The median time to start anticancer therapy after COVID-19 was 45 days (interquartile range: 28-61). In conclusion, 90-day mortality in patients with ST and COVID-19 was 33.9%; current smoker status, poor ECOG-PS, dyspnoea, respiratory rate ≥24 and sepsis were independent risk factors for mortality; and survivors did not restart their anticancer treatment until 1.5 months after COVID-19 diagnosis.

Circulating leukocyte-platelet complexes as a predictive biomarker for the development of immune-related adverse events in advanced non-small cell lung cancer patients receiving anti-PD-(L)1 blocking agents.

BACKGROUND: Anti-PD-(L)1 blocking agents can induce immune-related adverse events (irAEs), which can compromise treatment continuation. Since circulating leukocyte-platelet (PLT) complexes contribute to inflammatory and autoimmune diseases, we aimed to analyze the role of these complexes as predictors of irAEs in non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1. MATERIALS AND METHODS: Twenty-six healthy donors (HD) and 87 consecutive advanced NSCLC patients treated with anti-PD-(L)1 were prospectively included. Percentages of circulating leukocyte-PLT complexes were analyzed by flow cytometry and compared between HD and NSCLC patients. The association of leukocyte-PLT complexes with the presence and severity of irAEs was analyzed. RESULTS: NSCLC patients had higher percentages of circulating leukocyte-PLT complexes. Higher percentages of monocytes with bound PLT (CD14 + PLT +) were observed in patients who received prior therapies while CD4 + T lymphocytes with bound PLT (CD4 + PLT +) correlated with platelets counts. The CD4 + PLT + high percentage group presented a higher rate of dermatological irAEs while the CD4 + PLT + low percentage group showed a higher rate of non-dermatological irAEs (p < 0.001). A lower frequency of grade ≥ 2 irAEs was observed in the CD4 + PLT + high percentage group (p < 0.05). Patients with CD4 + PLT + low and CD14 + PLT + high percentages presented a higher rate of grade ≥ 3 irAEs and predominantly developed non-dermatological irAEs (p < 0.01). CONCLUSIONS: Our results suggest that circulating leukocyte-PLT complexes and the combination of CD4 + PLT + and CD14 + PLT + percentages can be used as a predictive biomarker of the development and severity of irAEs in advanced NSCLC patients receiving anti-PD-(L)1 agents.

Kinetics of IFNγ-Induced Cytokines and Development of Immune-Related Adverse Events in Patients Receiving PD-(L)1 Inhibitors.

Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFß) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFß levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.

Association Between Lung Immune Prognostic Index and Durvalumab Consolidation Outcomes in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. MATERIAL AND METHODS: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). RESULTS: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. CONCLUSION: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC.

An update on lorlatinib: a novel first line treatment for ALK-positive advanced lung cancer.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of ALK-rearranged non-small cell lung cancer (NSCLC), but these patients will eventually develop resistance and progression of disease after 10 months of first-generation and more than 30 months after second-generation TKIs. Lorlatinib is a third-generation highly selective ALK-TKI capable of inducing significant and durable CNS responses and overcoming known ALK resistance mutations. AREAS COVERED: This review summarizes the mechanism of action, efficacy, and safety of lorlatinib in ALK-positive NSCLC. The authors provide their expert opinions on the use of this drug, including its future prospects. EXPERT OPINION: Lorlatinib has shown good efficacy and safety in ALK-positive NSCLC patients progressing to first- and second-generation ALK-TKIs. The phase III trial CROWN evaluating lorlatinib as first-line therapy has provided promising results; however, the comparing arm was crizotinib, supplanted now by second-generation agents. Whether lorlatinib can replace them as upfront strategy is a relevant question that still remains open. In our opinion, longer follow-up and face-to-face studies are required to determine which is the best treatment sequence strategy. The advent of liquid biopsy will contribute to treatment tailoring according to the genomic profile at progression.

Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era: The European EXOTIC Registry.

Introduction: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. Methods: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Results: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%-95%) and mean tumor mutational burden was 7.06 (range: 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03). Conclusions: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.

Targeting BRAF-mutant non-small cell lung cancer: Current status and future directions.

Lung cancer harbouring BRAF mutations accounts for 4% of all non-small cell lung cancer (NSCLC) cases, identifying a relevant subset of patients that need to be promptly managed. Three subtypes of BRAF mutations have been described: class I (V600E), and class II and III (non-V600), with different prognostic and predictive outcomes. Pivotal phase II trials have demonstrated the efficacy of the double BRAF/MEK inhibition with dabrafenib plus trametinib in patients harbouring V600E mutations, making BRAF a mandatory requirement in the genetic portrait of advanced non-squamous lung cancer patients. However, non-V600 mutations represent around 50% of BRAF-mutant NSCLC patients, for which no specific targeted approaches are approved. A paradigm shift from the double BRAF/MEK inhibition to combinations with agents with distinct mechanisms of action, such as immune-checkpoint inhibitors, pan-RAF and selective ERK 1/2 inhibitors, is under investigation and may change the therapeutic landscape of BRAF-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with BRAF mutations.

Radon and Lung Cancer: Current Trends and Future Perspectives.

Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. In Europe, there are several radon-prone areas, and although the 2013/59 EURATOM directive is aimed to regulate indoor radon exposition, regulating measures can vary between countries. Radon emits alpha-ionizing radiation that has been linked to a wide variety of cytotoxic and genotoxic effects; however, the link between lung cancer and radon from the genomic point of view remains poorly described. Driver molecular alterations have been recently identified in non-small lung cancer (NSCLC), such as somatic mutations (EGFR, BRAF, HER2, MET) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), mainly in the non-smoking population, where no risk factor has been identified yet. An association between radon exposure and oncogenic NSCLC in non-smokers has been hypothesised. This paper provides a practical, concise and updated review on the implications of indoor radon in lung cancer carcinogenesis, and especially of its potential relation with NSCLC with driver genomic alterations.

Targeting molecular alterations in non-small-cell lung cancer: what's next?

In recent years, major advances have been achieved in our understanding of non-small-cell lung cancer (NSCLC) with oncogenic driver alterations and in the specific treatment of these with tyrosine kinase inhibitors. Currently, state-of-the-art management of patients with NSCLC (particularly adenocarcinoma or non-adenocarcinoma but with mild tobacco exposure) consists of the determination of EGFR, ALK, ROS1 and BRAF status, as they have US FDA and EMA approved targeted therapies. The increase in molecular knowledge of NSCLC and the development of drugs against other targets has settled new therapeutic indications. In this review we have incorporated the development around MET, KRAS and NTRK in the diagnosis of NSCLC given the therapeutic potential that they represent, as well as the drugs approved for these indications.

Unexpected Cardiotoxicity in Patients With HER2-Mutant NSCLC Treated With Trastuzumab Deruxtecan: A Case Report.

Antibody-drug conjugates targeting receptor tyrosine-protein kinase erbB-2 (ERBB2, HER2) have emerged as promising targeted options for HER2-mutant NSCLC. Among antibody-drug conjugates targeting HER2, trastuzumab deruxtecan was found to have the most impressive efficacy and is a potential new standard of care. Drug-related interstitial lung disease remains a serious unpredictable identified risk for patients treated with trastuzumab deruxtecan, requiring careful monitoring and multidisciplinary management. We report the first two cases of drug-related cardiotoxicity with acute myocarditis that developed after the first trastuzumab deruxtecan cycle. Routine cardiovascular risk screening is advisable, with close collaboration between cardiology specialists and oncologists.

Gefitinib plus tremelimumab combination in refractory non-small cell lung cancer patients harbouring EGFR mutations: The GEFTREM phase I trial.

INTRODUCTION: A phase I open-label multicentre study was initiated to evaluate the association of tremelimumab with gefitinib in EGFR-mutant NSCLC patients who progressed after first-generation EGFR-TKI. Here we provide the efficacy data from the entire cohort. MATERIAL AND METHODS: Patients with advanced EGFR-mutant NSCLC with progression after response to EGFR-TKI were enrolled. Study treatment was gefitinib 250 mg daily and tremelimumab at 3 dose levels: 3, 6 and 10 mg/kg IV Q4W for 6 cycles followed by Q12W until progression or unacceptable toxicity. The primary objective was safety and tolerability, and to establish a RP2D. RESULTS: Between January 2014 and July 2015, 27 patients (21 in the escalating dose cohort and 6 in expansion cohort) received at least one dose of tremelimumab. DLTs occurred in 4 patients: 1 at 3 mg/kg (one grade 3 diarrhoea), 1 at 6 mg/kg (one grade 3 diarrhoea) and 2 at 10 mg/kg (one grade 3 diarrhoea and one grade 3 AST/ALT increase) of tremelimumab. Grade 3 TRAE occurred in 22 patients (81%), most frequently diarrhoea (30%) and ALT/AST increase (15%). Stable disease was the best overall response in 72% patients, with median PFS of 2.2 months (95% CI, 1.8-4.2). All patients discontinued treatment, most frequently due to disease progression (63% of patients). CONCLUSION: The recommended dose of tremelimumab in combination with gefitinib in EGFR-mutant NSCLC patients was 3 mg/kg. The gastrointestinal toxicity and the limited efficacy data prevented further evaluation of this combination. (GEFTREM; clinical trial number NCT02040064).

Complete Remission After Immunotherapy-Induced Abdominal Tuberculosis in a Patient With Advanced NSCLC Treated With Pembrolizumab: A Case Report.

The use of immune checkpoint inhibitors (ICIs) has drastically transformed the therapeutic landscape in lung cancer. Special focus has been put on immune-related toxicity; however, infections can also seem during ICI treatment. Although rare, tuberculosis (TB) has been increasingly identified after ICIs, and it seems that the programmed cell death protein 1 and programmed death-ligand 1 pathway is directly involved in its pathophysiology. Here, we describe the case of a patient with advanced NSCLC who developed abdominal TB after 32 months of pembrolizumab and who remains in tumor remission 10 months after discontinuation of this drug. Routine screening for latent TB before ICI treatment is advised, with closer collaboration between infectious disease specialists and oncologists.

Clinical Utility and Outcomes Impact of Crystal Digital PCR of Sensitizing and Resistance EGFR Mutations in Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: EGFRm represent 15% of advanced NSCLC in European patients. LB for molecular profiling offers a non-invasive alternative to tissue. cdPCR is a high-sensitive and low-cost LB to detect molecular alterations. We aimed to describe cdPCR clinical utility for EGFRm detection in advanced NSCLC. METHODS: Prospective blood sample collection in patients with advanced NSCLC harbouring EGFRm either at diagnosis, under response or at PD between January 16 and September 20 at Gustave Roussy. LB was performed by cdPCR (Stilla): sensitizing (exon19; exon21 [p.L858R]) and exon 20 p.T790M resistance EGFRm. We defined high tumour burden (high-TB) as >2 metastatic sites. We analysed EGFRm detection by cdPCR and its correlation with progression-free and overall survival (PFS, OS). RESULTS: A total of 252 blood samples were collected in 140 patients. At baseline (n=25), sensitizing EGFRm were detected in 64% of samples, 88% in patients with high-TB (n=8) and 40% among those with intracranial/intrathoracic isolated lesions (n=5). At PD to tyrosine-kinase inhibitors (TKI) (n=117), detection rate (sensitizing EGFRm) was 56%; 30% in patients with intracranial/thoracic isolated lesions (n=37) vs. 67% in those with high-TB (n=63). At PD to first/second generation TKI (n=81), the p.T790M mutation was found in 22% (18/81); detection rate was 9% for intracranial/thoracic (n=23) vs. 32% for high-TB (n=41) cases. The clearance of EGFRm allelic frequency was correlated with radiological response. The absence of EGFRm detection at TKI-failure was associated with longer OS (39.1 vs. 18.4 months; P=.02). CONCLUSIONS: cdPCR is a sensitive LB for sensitizing and resistance EGFRm detection. cdPCR positivity was more likely observed in systemic PD cases with high-TB. It is a low-cost EGFRm detecting approach to guide treatment in NSCLC, however metastatic profile should be taken into account.

Durvalumab consolidation in patients with unresectable stage III non-small cell lung cancer with driver genomic alterations.

INTRODUCTION: Durvalumab is the standard-of-care as consolidation therapy after chemo-radiotherapy in stage III unresectable non-small cell lung cancer (NSCLC); however, its activity across patients with NSCLC harbouring driver genomic alterations (dGA) is poorly characterised. MATERIAL AND METHODS: Multicentre retrospective study including patients with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and October 2020 at 26 centres in Europe and America. Clinical and biological data were collected; dGA included: EGFR/BRAF/KRAS mutations (m) and ALK/ROS1 rearrangements (r). We evaluated progression-free survival (PFS) and overall survival (OS) based on dGA. RESULTS: Out of 323 patients included, 43 patients had one dGA: KRASm (n = 26; 8 G12C), EGFRm (n = 8; 6 del19/ex21), BRAFm (n = 5; 4 V600E) and ALKr (n = 4). The median age was 66 years [39-84], gender ratio 1:1, with 98% performance status (PS) 0-1 and 19% non-smokers; 88% had adenocarcinoma. PD-L1 was positive in 85% (n = 4 missing). In the whole cohort, the median PFS was 17.5 months (mo.) (95% CI, 13.2-24.9) and median OS 47 mo (95%CI, 47-not reached [NR]). No statistically significant differences in terms of the median PFS were observed between patients with dGA vs. non-dGA: 14.9 mo (95% CI, 8.1-NR) vs. 18 mo. (95% CI, 13.4-28.3) (P = 1.0); however, when analysed separately: the median PFS was NR (11.3-NR) in the KRASm G12C vs. 8.1 mo (5.8-NR) in the EGFRm del19/ex21 vs. 7.8 mo (7.7-NR) in the BRAFm V600E/ALKr (P = 0.02). CONCLUSIONS: We observed limited activity of durvalumab consolidation in patients with stage III unresectable NSCLC with EGFR/BRAFm and ALKr but not for those harbouring KRASm. Larger prospective studies are needed to confirm these findings.

Pleural effusion is a negative prognostic factor for immunotherapy in patients with non-small cell lung cancer (NSCLC): The pluie study.

BACKGROUND: Pleural effusion (PE) is a common metastatic site of NSCLC, associated with poor outcomes. As very few data are available about immune checkpoint inhibitors (ICI) and PE, we aimed to assess the clinical outcome of PE in NSCLC treated with ICI. METHOD: Multicenter international retrospective study of patients with metastatic NSCLC treated with ICI, between 2012 and 2019. Stratification according to the presence of PE at ICI baseline or appearance under ICI treatment (PE group) versus no history of PE (non-PE group). Primary endpoints were overall survival (OS) and early death rate (EDR, OS ≤ 3 months). RESULTS: A total of 538 patients were included: 196 in the PE group and 342 in the non-PE group. In the PE group, median age was 64, 31.6 % were female, 77.6 % had non-squamous histology, PD-L1 was ≥50 % in 38.6 % of cases (95 missing). PE was more likely associated with >2 metastatic sites (70.4 % vs. 50 %) and worse performance status (PS ≥ 2, 30.8 % vs 23.1 %). Globally, the overall median OS was 9.7 months [95 %CI: 8.1-11.8]; 6.3 [95 % CI: 4.0-8.6] in PE vs. 11.4 [95 %CI: 9.7-13.8] in the non-PE respectively, P = 0.002. Overall the EDR was 31.4 %; higher in the PE group (38.3 % vs. 27.5 %; OR 1.63, 95 %CI: 1.13-2.37, P = 0.01). In the PE PD-L1≥50 % group, EDR was 33.3 %. In multivariate analysis, after adjustment on PS, liver/intracranial/bone metastasis, ICI line and dNLR, PE remained an independent prognostic factor for OS [HR: 1.38, 95 %CI: 1.09-1.74, P = 0.007]. In the PE group, PE appeared under ICI for 31 patients (16.4 %). We observed lower EDR in this group compared to patients whom PE was already present (29.0 % vs 40.5 %, P = 0.2). CONCLUSION: PE is associated with worse immunotherapy outcomes in NSCLC treated with ICI, including in patients with ≥50 % PD-L1 tumors. Thus, in these patients, combination strategies should be explored.

Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma.

BACKGROUND: Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations. METHODS: We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan-Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS: Median age was 58.9 years (range 42.8-81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2-3 previous treatment lines. Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1-38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9-7.3] and the median OS 10.1 months (95% CI 5.9-14.3). The objective response rate (ORR) was 44.4% (23.7-66.8%) and the disease control rate (DCR) 72.2% (49.4-88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1-10.5) versus (vs.) 4.8 (95% CI 3.5-6.1) and a median OS of 12.3 months (95% CI 8.6-16.0) vs. 6.7 months (95% CI 3.9-9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0-6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported. CONCLUSIONS: Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC.

Immunotherapy-induced isolated ACTH deficiency in cancer therapy.

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4447 cancer patients treated with ICI antibodies, 37 (0.8%) (23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 years)) were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n = 20, 54.1%), followed by melanoma (n = 8, 21.6%). The most common ICI antibody inhibitors reported were nivolumab (n = 18, 48.6%), pembrolizumab (n = 16, 43.2%), and ipilimumab (n = 8, 21.6%). About half of the patients (n = 19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n = 10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit, all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting the treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected.

Immune-Related Adverse Events and Corticosteroid Use for Cancer-Related Symptoms Are Associated With Efficacy in Patients With Non-small Cell Lung Cancer Receiving Anti-PD-(L)1 Blockade Agents.

Background: Immune-related adverse events (irAEs) have been associated with improved efficacy in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1 blockade agents, while the concurrent use of corticosteroids seems to worsen it. We evaluated outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents in relation to the presence of irAEs and the reasons for using corticosteroids: whether for palliative cancer-related reasons or for the management of irAEs. Methods: Clinical outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents were calculated with regard to the presence of irAEs and the use of corticosteroids. A landmark analysis was performed to avoid immortal time bias due to the time-dependent nature of irAEs. Results: Out of a total of 267 patients, the 56.9% of patients who experienced irAEs had significantly improved outcomes. In the landmark analysis, median progression-free survival (PFS) was 12.4 months for patients with irAEs vs. 4.1 months for patients without irAEs (p < 0.001), while median overall survival (OS) was 28.2 vs. 12.5 months, respectively (p < 0.001). Likewise, objective response and disease control rates were significantly higher in patients experiencing irAEs: 48.6 vs. 22.8% and 77.1 vs. 39.6% (p < 0.001), respectively. Median OS was significantly shorter for patients receiving ≥10 mg of prednisone equivalent daily for cancer-related symptoms than for the rest of patients (<10 mg prednisone equivalent daily or for management of irAEs): 6 vs. 15.9 months (p < 0.001). Conclusions: IrAEs were associated with improved efficacy in advanced NSCLC patients when a landmark analysis was applied. Patients receiving corticosteroids had significantly poorer outcomes when they were used for cancer-related symptoms.

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI).

BACKGROUND: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. METHODS: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. RESULTS: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1-12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9-1.5] and mOS [1.9 mo.; 95%CI, 1.5-2.4; p < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2-5.6] and OS [HR 4.53; 95% CI, 1.8-11.1], both p < 0.0001. CONCLUSION: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.