Quality of life impact in patients with cutaneous toxicities caused by EGFR inhibitors and immunotherapy.

BACKGROUND: novel oncologic therapies, including epidermal growth factor receptor inhibitors (EGFR-Is) and immune checkpoint inhibitors (ICIs), are associated with a new spectrum of adverse reactions, with prominent cutaneous toxicities. The impact of cutaneous adverse events (cAEs) on patients' quality of life (QoL) represents an unmet clinical need. OBJECTIVES: 1) to assess whether cutaneous toxicities directed therapies are effective in reducing the QoL burden via the submission of two patient reported outcome measures (PROMs); 2) to investigate whether class of oncologic therapy, type of cAE and toxicity severity differently impact on patients' QoL. METHODS: a prospective observational study was conducted at the Dermatology department of the Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, from October 2018 to October 2019. Patients aged ≥ 18 years, under therapy with EGFR-Is or ICIs and experiencing a treatment-related cAE were eligible for the study. Dermatology Life Quality Index (DLQI) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30 version 3.0 (EORTC QLQ-C30) were administered to patients at first clinical visit (T0), at 1-month (T1), and at 3-month (T2) dermatological follow-up. RESULTS: Sixty cAEs of 51 patients have been recorded. A significant difference in the mean score for both DLQI and EORTC QLQ-C30 was found along the 3-months dermatological follow-up (p <0.0001). A similar QoL improvement was reported for PROMs stratified by class of therapy and toxicity severity (p <0.0001). No difference was reported for patients with pyogenic granuloma-like lesions and psoriasiform eruption as per DLQI. Class of therapy and toxicity severity did not differently impact on patients' QoL at selected timepoints; we reported a higher EORTC QLQ-C30 score at T2 for patients developing psoriasiform eruption compared to other types of cAEs. CONCLUSIONS: Early patients' referral to dermatologists and tailored management could result in better QoL.

Response to first-line pembrolizumab in metastatic KRAS-mutated non-small-cell lung cancer.

Aims: This retrospective study aims to identify a possible predictive role of KRAS mutations in non-small-cell lung cancer in response to first-line pembrolizumab, either as monotherapy or combined with chemotherapy. Methods: Patients received pembrolizumab alone (n = 213) or associated with chemotherapy (n = 81). Results: A mutation in the KRAS gene was detected in 27% of patients. In patients on pembrolizumab alone, median progression-free survival in KRAS-mutated cases was longer than in wild-type cases (11.3 vs 4.4 months; p = 0.019), whereas median overall survival did not reach statistical significance (22.1 vs 12.5 months; p = 0.119). Patients receiving chemo-immunotherapy with KRAS-positive tumors had a similar progression-free survival (9.7 vs 7.3 months; p = 0.435); overall survival data were immature. Conclusion: This study suggests a correlation between KRAS status and response to pembrolizumab.

The Role of Human Papilloma Virus (HPV) in Primary Lung Cancer Development: State of the Art and Future Perspectives.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Notably, the incidence of lung cancer among never-smokers, predominantly women, has been rising in recent years. Among the various implicated risk factors, human papilloma virus (HPV) may play a role in the development of NSCLC in a certain subset of patients. The prevalence of high-risk HPV-DNA within human neoplastic lung cells varies across the world; however, the carcinogenetic role of HPV in NSCLC has not been completely understood. Bloodstream could be one of the routes of transmission from infected sites to the lungs, along with oral (through unprotected oral sex) and airborne transmission. Previous studies reported an elevated risk of NSCLC in patients with prior HPV-related tumors, such as cervical, laryngeal, or oropharyngeal cancer, with better prognosis for HPV-positive lung cancers compared to negative forms. On the other hand, 16% of NSCLC patients present circulating HPV-DNA in peripheral blood along with miRNAs expression. Typically, these patients have a poorly differentiated NSCLC, often diagnosed at an advanced stage. However, HPV-positive lung cancers seem to have a better response to target therapies (EGFR) and immune checkpoint inhibitors and show an increased sensitivity to platinum-based treatments. This review summarizes the current evidence regarding the role of HPV in NSCLC development, especially among patients with a history of HPV-related cancers. It also examines the diagnostic and prognostic significance of HPV, investigating new future perspectives to enhance cancer screening, diagnostic protocols, and the development of more targeted therapies tailored to specific cohorts of NSCLC patients with confirmed HPV infection.

Facial Papulopustular Eruption during the COVID-19 Pandemic in Patients Treated with EGFR Inhibitors.

Papulopustular rash (PPR) is the most frequent cutaneous adverse event during treatment with epidermal growth factor receptor inhibitors (EGFRis). Although often mild in severity, it can impair patients' quality of life and may also be a reason for discontinuing or changing the dose of the antineoplastic treatment. During COVID-19 pandemics, the use of surgical masks drastically increased and it had an impact on the face skin microenvironment, favoring the worsening of dermatological pathologies. We reported the relapse of PPR in patients treated with EGFR inhibitors who consistently wore face masks (>6 hours/day). All the patients developed the PPR within 6 months of starting mask use. Compared to the PPR occurred previously, after mask use, the skin eruption was more severe and affected mainly those regions of the face which came into contact with the mask. Patients received topical or systemic treatment, obtaining complete response in 65.7% of the cases. The establishment of an early treatment for the PPR allows continuing the oncologic treatment, without any suspension which could result in a decreased oncologic outcome. In conclusion, when using these devices, it is recommended to use special precautions, particularly in oncologic patients, by using a daily prophylactic skincare and replacing masks regularly with regular and frequent breaks.

Clinical Stage III NSCLC Patients Treated with Neoadjuvant Therapy and Surgery: The Prognostic Role of Nodal Characteristics.

BACKGROUND: The aim of this study is to analyze the prognostic factors in patients that underwent induction therapy and surgery for clinical stage III NSCLC. METHODS: Clinical and pathological characteristics of stage III NSCLC patients for N2 involvement that underwent neoadjuvant treatment (NAD) and surgery from 1/01/1998 to 31/12/2017 were collected and retrospectively analyzed. Tumor characteristics, yClinical, yPathological stage and lymph node characteristics were correlated to Overall Survival (OS). RESULTS: The analysis was conducted on 180 patients. Five-year OS (5YOS) was 50.9%. Univariable analysis results revealed old age (p = 0.003), clinical N2 post-NAD (p = 0.01), pneumonectomy (0.005), persistent pathological N2 (p = 0.039, HR 1.9, 95% CI 1.09−2.68) and adjuvant therapy absence (p = 0.049) as significant negative prognostic factors. Multivariable analysis confirmed pN0N1 (p = 0.02, HR 0.29, 95% CI 0.13−0.62) as a favorable independent prognostic factor and adjuvant therapy absence (p = 0.012, HR 2.61, 95% CI 1.23−5.50) as a negative prognostic factor. Patients with persistent N2 presented a 5YOS of 35.3% vs. 55.8% in pN0N1 patients. Regarding lymph node parameters, the lymph node ratio (NR) significantly correlated with OS: 5YOS of 67.6% in patients with NR < 50% vs. 29.5% in NR > 50% (p = 0.029). CONCLUSION: Clinical response aided the stratification of prognosis in patients that underwent multimodal treatment for stage III NSCLC. Adjuvant therapy seemed to be an important option in these patients, while node ratio was a strong prognosticator in patients with persistent nodal involvement.

Unweaving the mitotic spindle: A focus on Aurora kinase inhibitors in lung cancer.

Lung cancer is one of the most aggressive malignancies, classified into two major histological subtypes: non-small cell lung cancer (NSCLC), that accounts for about 85% of new diagnosis, and small cell lung cancer (SCLC), the other 15%. In the case of NSCLC, comprehensive genome sequencing has allowed the identification of an increasing number of actionable targets, which have become the cornerstone of treatment in the advanced setting. On the other hand, the concept of oncogene-addiction is lacking in SCLC, and the only innovation of the last 30 years has been the introduction of immune checkpoint inhibitors in extensive stage disease. Dysregulation of cell cycle is a fundamental step in carcinogenesis, and Aurora kinases (AURKs) are a family of serine/threonine kinases that play a crucial role in the correct advance through the steps of the cycle. Hyperexpression of Aurora kinases is a common protumorigenic pathway in many cancer types, including NSCLC and SCLC; in addition, different mechanisms of resistance to anticancer drugs rely on AURK expression. Hence, small molecule inhibitors of AURKs have been developed in recent years and tested in several malignancies, with different results. The aim of this review is to analyze the current evidences of AURK inhibition in lung cancer, starting from preclinical rationale to finish with clinical trials available up to now.

Uncommon single and compound EGFR mutations: clinical outcomes of a heterogeneous subgroup of NSCLC.

Molecular characterization of non-small-cell lung cancer (NSCLC) is essential to define the correct therapeutic algorithm in metastatic disease. Approximately 90% of epidermal growth factor receptor (EGFR) mutations are usually associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The remaining 10% defines a small, extremely heterogeneous subgroup of mutations, with a varied profile of sensitivity and response to target therapies.This retrospective observational study includes 47 patients affected by metastatic NSCLC harboring uncommon EGFR mutations (single or compound mutation). Patients were treated with EGFR-targeting TKIs or platinum-based chemotherapy as first-line treatment.Median OS resulted longer in the compound mutation group when compared to single rare mutations (33.6 vs 12 months; P = 0.473); a similar result was observed for PFS (16 vs 7.6 months; P = 0.281), although statistical significance was not reached. ORR, PFS and OS resulted similar for patients treated with first-line EGFR TKIs or chemotherapy. No difference in terms of PFS and OS was found according to the TKI administered.Compound mutations seem to be a good prognostic indicator for OS; they are also predictive of response to 1st and 2nd generation EGFR TKIs, as well as exon 19 insertions and mutations in codon 719 of exon 18. For mutations in exon 18 (not in codon 719) and exon 20 insertions, chemotherapy seems the most effective available option. The addition of immunotherapy to chemotherapy could change this approach in the next future.

Multimodal therapy for synchronous bone oligometastatic NSCLC: The role of surgery.

OBJECTIVES: The study aimed to assess the feasibility of radical surgical treatment for selected bone-oligometastatic non-small cell lung cancer (NSCLC) patients and to identify prognostic factors associated with survival. MATERIALS AND METHODS: The clinical records of 27 patients with bone synchronous oligometastatic NSCLC were retrospectively analyzed. RESULTS: Thirteen (48.1%) bone metastases were treated by surgery and 14 (51.9%) by local radiotherapy. Eighteen (66.7%) patients underwent induction chemotherapy before lung surgery, and 3 (11.1%) concurrent radiotherapy. Pulmonary surgery was a major lung resection in 23 (85.2%) cases. Intraoperative and 30-days mortality was null. Only one major (ARDS) and 10 (37.04%) mild complications (like air leakage, arrhythmia, and mucus retention) were recorded. 1-year and 5-years OS from the diagnosis and 1-year, 3- years disease-free survival (DFS) were 96%, 38%, and 66%, 30%, respectively. After stepwise Cox regression analysis, local recurrence (p = 0.05) and metachronous metastases (p = 0.04) maintained their independent prognostic value as overall survival negative determinants. Nodal upstaging (p = 0.04) and nonsurgical treatment of bone lesion (p = 0.03) turned out to be independent risk factors for shorter DFS; the vertebral localization of bone metastases showed only a remarkable trend towards significance (p = 0.06) as a risk factor for a worse DFS. CONCLUSIONS: In selected patients, surgical treatment of primary NSCLC and bone synchronous metastasis seems to be safe and feasible and rewarding survivals may be expected.

Masaoka-Koga and TNM Staging System in Thymic Epithelial Tumors: Prognostic Comparison and the Role of the Number of Involved Structures.

BACKGROUND: The aim of this study was to evaluate the Masaoka-Koga and the tumor node metastases (TNM) staging system in thymic epithelial tumors (TET) considering possible improvements. METHODS: We reviewed the data of 379 patients who underwent surgical resection for TET from 1 January 1985 to 1 January 2018, collecting and classifying the pathological report according to the Masaoka-Koga and the TMN system. The number of involved organs was also considered as a possible prognostic factor and integrated in the two staging systems to verify its impact. RESULTS: Considering the Masaoka-Koga system, 5- and 10-year overall survival (5-10YOS) was 96.4% and 88.9% in stage I, 95% and 89.5% in stage II and 85.4% and 72.8% in stage III (p = 0.01), with overlapping in stage I and stage II curves. Considering the TNM system, 5-10YOS was 95.5% and 88.8% in T1, 84.8% and 70.7% in T2 and 88% and 76.3% in T3 (p = 0.02), with overlapping T2-T3 curves. Including the number of involved structures, in Masaoka-Koga stage III, patients with singular involved organs had a 100% and 76.6% vs. 87.7% 5-10YOS, which was 76.6% in patients with multiple organ infiltration. Considering the TNM, T3 patients with singular involved structures presented a 5-10YOS of 100% vs. 62.5% and 37.5% in patients with multiple organ involvement (p = 0.07). CONCLUSION: The two staging systems present limitations due to overlapping curves in early Masaoka-Koga stages and in advanced T stages for TNM. The addition of the number of involved organs seems to be a promising factor for the prognosis stratification in these patients.

[Management of small cell lung cancer patient in the regions of Lazio, Umbria and Sardinia.] / Gestione del paziente con microcitoma nelle regioni Lazio, Umbria e Sardegna.

Small cell lung cancer (SCLC) is an aggressive disease, difficult to treat. There have been no significant therapeutic advances over platinum and etoposide chemotherapy in the last 20 years until the introduction of immunotherapy. In 2020 atezolizumab, an immune checkpoint inhibitor against PD-L1 was approved in Italy in combination with carboplatin and etoposide for the first-line treatment of patients with extensive stage disease (ES-SCLC), becoming the new standard treatment. On May 20, 2021, a virtual meeting, directed by profs. Federico Cappuzzo and Emilio Bria, was held in which 14 clinicians from different oncology centers in Lazio, Umbria and Sardinia discussed the issues of ES-SCLC patients treatment, after the advent of immunotherapy. The aim of the meeting was to share their clinical experience and to provide a series of practical indications that can support clinicians in the management of ES-SCLC patients in first-line with chemo-immunotherapy.

Large Cell Neuro-Endocrine Carcinoma of the Lung: Current Treatment Options and Potential Future Opportunities.

Large-cell neuroendocrine carcinomas of the lung (LCNECs) are rare tumors representing 1-3% of all primary lung cancers. Patients with LCNEC are predominantly male, older, and heavy smokers. Histologically, these tumors are characterized by large cells with abundant cytoplasm, high mitotic rate, and neuroendocrine immunohistochemistry-detected markers (chromogranin-A, synaptophysin, and CD56). In 2015 the World Health Organization classified LCNEC as a distinct subtype of pulmonary large-cell carcinoma and, therefore, as a subtype of non-small cell lung carcinoma (NSCLC). Because of the small-sized tissue samples and the likeness to other neuroendocrine tumors, the histological diagnosis of LCNEC remains difficult. Clinically, the prognosis of metastatic LCNECs is poor, with high rates of recurrence after surgery alone and overall survival of approximately 35% at 5 years, even for patients with early stage disease that is dramatically shorter compared with other NSCLC subtypes. First-line treatment options have been largely discussed but with limited data based on phase II studies with small sample sizes, and there are no second-line well defined treatments. To date, no standard treatment regimen has been developed, and how to treat LCNEC is still on debate. In the immunotherapy and targeted therapy era, in which NSCLC treatment strategies have been radically reshaped, a few data are available regarding these opportunities in LCNEC. Due to lack of knowledge in this field, many efforts have been done for a deeper understanding of the biological and molecular characteristics of LCNEC. Next generation sequencing analyses have identified subtypes of LCNEC that may be relevant for prognosis and response to therapy, but further studies are needed to better define the clinical impact of these results. Moreover, scarce data exist about PD-L1 expression in LCNEC and its predictive value in this histotype with regard to immunotherapy efficacy. In the literature some cases are reported concerning LCNEC metastatic patients carrying driver mutations, especially EGFR alterations, showing targeted therapy efficacy in this setting of disease. Due to the rarity and the challenging understanding of LCNEC, in this review we aim to summarize the management options currently available for treatment of LCNEC.

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy.

BACKGROUND: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate. METHODS: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses. RESULTS: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, ß-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate. CONCLUSION: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

Post-progression outcomes of NSCLC patients with PD-L1 expression ≥ 50% receiving first-line single-agent pembrolizumab in a large multicentre real-world study.

BACKGROUND: Treatment sequencing with first-line immunotherapy, followed by second-line chemotherapy, is still a viable option for NSCLC patients with PD-L1 expression ≥50%. METHODS: We evaluated post-progression treatment pathways in a large real-world cohort of metastatic NSCLC patients with PD-L1 expression ≥ 50% treated with first-line pembrolizumab monotherapy. RESULTS: Overall, 974 patients were included. With a median follow-up of 22.7 months (95%CI: 21.6-38.2), the median overall survival (OS) of the entire population was 15.8 months (95%CI: 13.5-17.5; 548 events). At the data cutoff, among the 678 patients who experienced disease progression, 379 (55.9%) had not received any further treatment, and 359 patients (52.9%) had died. Patients who did not receive post-progression therapies were older (p = 0.0011), with a worse ECOG-PS (p < 0.0001) and were on corticosteroids prior to pembrolizumab (p = 0.0024). At disease progression, 198 patients (29.2%) received a switched approach and 101 (14.9%) received pembrolizumab ByPD either alone (64 [9.4%]) or in combination with local ablative treatments (37 [5.5%]) (LATs). After a random-case control matching according to ECOG-PS, CNS metastases, bone metastases, and (previous) best response to pembrolizumab, patients receiving pembrolizumab ByPD plus LATs were confirmed to have a significantly longer post-progression OS compared to patients receiving pembrolizumab ByPD alone 13.9 months versus 7.8 months (p = 0.0179) 241 patients (35.5%) among the 678 who had experienced PD, received a second-line systemic treatment (regardless of previous treatment beyond PD). As compared to first-line treatment commencement, patients' features at the moment of second-line initiation showed a significantly higher proportion of patients aged under 70 years (p = 0.0244), with a poorer ECOG-PS (p < 0.0001) and having CNS (p = 0.0001), bone (p = 0.0266) and liver metastases (p = 0.0148). CONCLUSIONS: In the real-world scenario NSCLC patients with PD-L1 expression ≥50% treated with first-line single-agent pembrolizumab achieve worse outcomes as compared to the Keynote-024 trial. Poor post-progression outcomes are major determinants of the global results that should be considered when counselling patients for first-line treatment choices.

Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: A case-control matched analysis from a large multicenter study.

BACKGROUND: Improved outcome in tobacco smoking patients with non-small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first-line immunotherapy in patients with high PD-L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. METHODS: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first-line pembrolizumab and platinum-based chemotherapy. RESULTS: A total of 962 NSCLC patients with PD-L1 expression ≥50% who received first-line pembrolizumab and 462 NSCLC patients who received first-line platinum-based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15-1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02-1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52-1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45-1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case-control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression-free survival (PFS) (HR = 1.68 [95% CI: 1.17-2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84-2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49-0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45-0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. CONCLUSIONS: Among metastatic NSCLC patients with PD-L1 expression ≥50% receiving first-line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first-line chemotherapy.

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non-small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors.

BACKGROUND: Rapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population. MATERIALS AND METHODS: Archival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS). RESULTS: Fifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005). CONCLUSIONS: A low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.

The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures.

Non-small cell lung cancer (NSCLC) represents the perfect paradigm of 'precision medicine' due to its complex intratumoral heterogeneity. It is truly characterized by a range of molecular alterations that can deeply influence the natural history of this disease. Several molecular alterations have been found over time, paving the road to biomarker-driven therapy and radically changing the prognosis of 'oncogene addicted' NSCLC patients. Kirsten rat sarcoma (KRAS) mutations are present in up to 30% of NSCLC (especially in adenocarcinoma histotype) and have been identified decades ago. Since its discovery, its molecular characteristics and its marked affinity to a specific substrate have led to define KRAS as an undruggable alteration. Despite that, many attempts have been made to develop drugs capable of targeting KRAS signaling but, until a few years ago, these efforts have been unsuccessful. Comprehensive genomic profiling and wide-spectrum analysis of genetic alterations have only recently allowed to identify different types of KRAS mutations. This tricky step has finally opened new frontiers in the treatment approach of KRAS-mutant patients and might hopefully increase their prognosis and quality of life. In this review, we aim to highlight the most interesting aspects of (epi)genetic KRAS features, hoping to light the way to the state of art of targeting KRAS in NSCLC.

Blood serum amyloid A as potential biomarker of pembrolizumab efficacy for patients affected by advanced non-small cell lung cancer overexpressing PD-L1: results of the exploratory "FoRECATT" study.

BACKGROUND: Identifying the patients who may benefit the most from immune checkpoints inhibitors remains a great challenge for clinicians. Here we investigate on blood serum amyloid A (SAA) as biomarker of response to upfront pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with PD-L1 ≥ 50% receiving upfront pembrolizumab (P cohort) and with PD-L1 0-49% treated with chemotherapy (CT cohort) were evaluated for blood SAA and radiological response at baseline and every 9 weeks. Endpoints were response rate (RR) according to RECIST1.1, progression-free (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with ROC analysis in the P cohort. RESULTS: In the P Cohort (n = 42), the overall RR was 38%. After a median follow-up of 18.5 months (mo), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L; n = 28/42.67%) was significantly associated with higher RR (53.6 versus 7.1%; OR15, 95% CI 1.72-130.7, p = 0.009), longer PFS (17.4 versus 2.1 mo; p < 0.0001) and OS (not reached versus 7.2mo; p < 0.0001) compared with SAA > 29.9 mg/L. In multivariate analysis, low SAA positively affects PFS (p = 0.001) and OS (p = 0.048) irrespective of ECOG PS, number of metastatic sites and pleural effusion. SAA monitoring (n = 40) was also significantly associated with survival endpoints: median PFS 17.4 versus 2.1 mo and median OS not reached versus 7.2 mo when SAA remained low (n = 14) and high (n = 12), respectively. In the CT Cohort (n = 30), RR was not affected by SAA level (p > 0.05) while low SAA at baseline (n = 17) was associated with better PFS (HR 0.38, 95% CI 0.16-0.90, p = 0.006) and OS (HR 0.25, 95% CI 0.09-0.67, p < 0.001). CONCLUSION: Low SAA predicts good survival outcomes irrespective of treatment for advanced NSCLC patients and higher likelihood of response to upfront pembrolizumab only. The strong prognostic value might be exploited to easily identify patients most likely to benefit from immunotherapy. A further study (FoRECATT-2) is ongoing to confirm results in a larger sample size and to investigate the effect of SAA on immune response in vitro assays.

Collagenous colitis and atezolizumab therapy: an atypical case.

Immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti-PD-1 (programmed cell death protein 1), and PD-L1 (programmed cell death protein-ligand 1) are emerging drugs that have radically changed treatment and prognosis of different types of tumors. However, despite their considerable benefits, immune checkpoint inhibitors are associated with numerous side effects involving several organs. Gastrointestinal toxicities represent some of these most common adverse events. While clinical presentation usually ranges from mild diarrhea to life-threatening colitis, typical endoscopic and histologic findings of immune-mediated colitis often resemble those of inflammatory bowel diseases. However, less common patterns are lymphocytic colitis and, rarely, collagenous colitis. Physician and pathologists must be aware of the wide spectrum of clinical and histological findings that may be encountered in immune-related gastro-intestinal toxicities. We report a rare and atypical case of collagenous colitis occurred in a woman affected by stage IV lung adenocarcinoma, on atezolizumab therapy.

[Target therapies in translocated ALK lung cancer: treatment management in oncology center of Lazio.] / Target therapies nel tumore al polmone ALK-positivo: gestione del trattamento nei centri di oncologia del LazioIncontro di approfondimento e confronto sulla gestione dei pazienti e sulla strategia terapeutica nei carcinomi polmonari positivi al riarrangiamento di ALK.

Lung cancer is a disease extremely heterogeneous in the molecular aspect and knowing the mutational profile of patients is essential in order to initiate the most appropriate treatment. In 2018, alectinib was approved in Italy for the first-line treatment of patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), becoming a new therapeutic option for this patient group which constitutes approximately 3-7% of patients with NSCLC. On October 26th a virtual meeting was held in which 10 clinicians from various oncology centers in Lazio took part on the management of therapy of patients with Alk translocation, directed by Dr. Maria Rita Migliorino. The aim of the meeting was to share their clinical experience and to provide a series of practical that can help clinicians during treatment with target therapies in ALK-positive NSCLC.

Chemotherapy in non-small cell lung cancer patients after prior immunotherapy: The multicenter retrospective CLARITY study.

OBJECTIVES: In the most of cases, for non-small cell lung cancer (NSCLC) patients who progressed to previous immune checkpoint inhibitors (CKI) administered as first- or as second-line therapy, chemotherapy (CT) remains the only viable options in the absence of "druggable" mutations. We aimed to explore the efficacy of salvage chemotherapy after immunotherapy (SCAI) in advanced NSCLC patients. MATERIALS AND METHODS: We designed a retrospective, multicenter study, involving 20 Italian centers, with the primary objective of describing the clinical outcome of advanced NSCLC patients treated with SCAI at the participating institutions from November 2013 to July 2019. The primary endpoint of the study was represented by overall survival (OS), defined as the time from CT initiation to death. Secondary outcome endpoints of the SCAI (progression free survival, PFS, objective response rate, ORR and toxicity) and explorative biomarkers (lactate dehydrogenase, LDH, and neutrophil-to-lymphocyte ratio, NLR during immunotherapy) were also analyzed. RESULTS: In our study population of 342 NSCLC patients, SCAI obtained a median OS of 6.8 months (95 % confidence interval, CI 5.5-8.1), median PFS of 4.1 months (95 % CI 3.4-4.8) and ORR of 22.8 %. A "Post-CKI score" was constructed by combining significant predictors of OS at the multivariate analyses (sex, ECOG PS, disease control with prior immunotherapy), Harrell'C was 0.65, (95 % CI:0.59-0.71). CONCLUSIONS: Despite the late-line settings, our findings support the hypothesis that previous immunotherapy might increase the sensitivity of the tumor to the subsequent chemotherapy. The "Post-CKI score" was clinically effective in successfully discriminating three distinct prognostic subgroups of patients after the failure of CKI, representing a possibly useful tool for the tailored decision-making process of advanced treatment-line settings in NSCLC.