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.

Prevalence of Thromboembolic Events in Patients With Non-Small Cell Lung Cancer and RET Fusions.

This cohort study examines the incidence, risks, and characteristics of deep vein thrombosis, pulmonary embolism, arterial thrombosis, and stroke among patients with non­small cell lung cancer (NSCLC) and RET fusions.

Liquid Biopsies for Circulating Tumor DNA Detection May Reveal Occult Hematologic Malignancies in Patients With Solid Tumors.

PURPOSE: High-risk clonal hematopoiesis (CH) is frequently incidentally found in patients with solid tumors undergoing plasma cell-free DNA sequencing. Here, we aimed to determine if the incidental detection of high-risk CH by liquid biopsy may reveal occult hematologic malignancies in patients with solid tumors. MATERIALS AND METHODS: Adult patients with advanced solid cancers enrolled in the Gustave Roussy Cancer Profiling study (ClinicalTrials.gov identifier: NCT04932525) underwent at least one liquid biopsy (FoundationOne Liquid CDx). Molecular reports were discussed within the Gustave Roussy Molecular Tumor Board (MTB). Potential CH alterations were observed, and patients referred to hematology consultation in the case of pathogenic mutations in JAK2, MPL, or MYD88, irrespective of the variant allele frequency (VAF), or in DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1 with VAF ≥ 10%, while also considering patient cancer-related prognosis. TP53 mutations were discussed case-by-case. RESULTS: Between March and October 2021, 1,416 patients were included. One hundred ten patients (7.7%) carried at least one high-risk CH mutation: DNMT3A (n = 32), JAK2 (n = 28), TET2 (n = 19), ASXL1 (n = 18), SF3B1 (n = 5), IDH1 (n = 4), IDH2 (n = 3), MPL (n = 3), and U2AF1 (n = 2). The MTB advised for hematologic consultation in 45 patients. Overall, 9 patients of 18 actually addressed had confirmed hematologic malignancies that were occult in six patients: two patients had myelodysplastic syndrome, two essential thrombocythemia, one a marginal lymphoma, and one a Waldenström macroglobulinemia. The other three patients were already followed up in hematology. CONCLUSION: The incidental findings of high-risk CH through liquid biopsy may trigger diagnostic hematologic tests and reveal an occult hematologic malignancy. Patients should have a multidisciplinary case-by-case evaluation.

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion.

INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.

Current treatment approaches for brain metastases in ALK/ROS1/NTRK-positive non-small-cell lung cancer.

INTRODUCTION: Oncogene-addicted non-small cell lung cancer (NSCLC) patients present a high incidence of CNS metastases either at diagnosis or during the course of the disease. In this case, patients present with worse prognosis and are often excluded from clinical trials unless brain metastases are pre-treated or clinically stable. AREAS COVERED: As a result of the discovery of several oncogenic drivers in ALK/ROS1/NTRK-positive NSCLC, targeted agents have been tested in several trials. We evaluate and compare the intracranial efficacy of available targeted agents in ALK/ROS1/NTRK-positive NSCLC based on subgroup analysis from pivotal trials. EXPERT OPINION: Last-generation ALK inhibitors have shown slightly superior intracranial activity but pivotal trials do not consider the same endpoints for intracranial efficacy, therefore data are not comparable. Local treatments for BM including surgical resection, stereotactic radiosurgery (SRS) and WBRT, should be integrated with systemic therapies basing on specific criteria like presence of oligoprogression or symptomatic progression.

KRAS in NSCLC: State of the Art and Future Perspectives.

In NSCLC, KRAS mutations occur in up to 30% of all cases, most frequently at codon 12 and 13. KRAS mutations have been linked to adenocarcinoma histology, positive smoking history, and Caucasian ethnicity, although differences have been described across KRAS mutational variants subtypes. KRAS mutations often concur with other molecular alterations, notably TP53, STK11, and KEAP1, which could play an important role in treatment efficacy and patient outcomes. For many years, KRAS mutations have been considered undruggable mainly due to a high toxicity profile and low specificity of compounds. Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Despite their approval, the efficacy of these drugs is lower than expected and progression among responders has been reported. Mechanisms of acquired resistance to anti-KRAS molecules typically involves either on target secondary mutations (e.g., G12, G13, Q61H, R68S, H95, Y96C, V8L) or off-target alterations. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.

A Case of Pulmonary Sarcoidosis during First-Line Targeted Therapy with Dabrafenib Plus Trametinib in BRAF V600E-Mutated Metastatic Melanoma.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) exert a cytotoxic and immune-mediated effect on metastatic melanoma. The immune-mediated mechanism can lead to some adverse events, including panniculitis, erythema, keratitis, vitiligo-like lesions, or, more rarely, sarcoid-like skin reactions. In particular, sarcoidosis-related manifestations during melanoma treatment are characterized mainly by skin involvement and are seldom associated with chest or lymph node lesions. Overall, managing these adverse events can be very challenging from the diagnostic and therapeutic points of view. We present a case of pulmonary sarcoidosis; it is the first without skin involvement and initially only with lung presentation, diagnosed during treatment with BRAFi and MEKi for metastatic cutaneous melanoma. After about 2 years of treatment, with an oncological complete response, a histologically confirmed form of pulmonary sarcoidosis was diagnosed and initially interpreted as tumor progression. Sarcoidosis has always remained asymptomatic. After progression in the thorax and supraclavicular lymph nodes, steroid therapy with prednisone was instituted with total remission of the signs of disease. The targeted therapy has never been interrupted, and the patient still shows a complete response. This clinical case suggests that rare immune-mediated events, such as pulmonary sarcoidosis, should be considered during targeted therapy for metastatic melanoma and not only during treatment with immune checkpoint inhibitors. It also suggests that the interruption of targeted treatment should be accurately considered based on the expected risks or benefits since such immune-mediated events may have low clinical impact.

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.

A Comparison of Lenvatinib versus Sorafenib in the First-Line Treatment of Unresectable Hepatocellular Carcinoma: Selection Criteria to Guide Physician's Choice in a New Therapeutic Scenario.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy across the world. Alongside improvement in local approaches for early stages, the prognosis of patients with advanced disease remains poor. The tyrosine kinase inhibitor sorafenib was the first drug approved for advanced HCC. During the past decade, this has been extensively explored in real-life settings, such as Eastern Cooperative Oncology Group performance status 2, Child-Pugh B liver function, chronic kidney disease, HIV infection, transplant recipients and the elderly. After 10 years, the multikinase inhibitor lenvatinib was approved in first-line setting. The Phase III REFLECT trial established the non-inferiority of lenvatinib compared with sorafenib in terms of overall survival, meanwhile exploratory analysis suggests a potential benefit over sorafenib for patients with HBV chronic infection and positive alpha-fetoprotein value. Experience with lenvatinib for patients not matching the REFLECT trial criteria remains promising but still retrospective. Indeed, the treatment sequence after lenvatinib still remains a crucial issue, considering that standard second-line options were tested only in patients who progressed to sorafenib. Overall, the choice between lenvatinib and sorafenib should take into account key selection criteria from randomized trials, evidence to date in special clinical situations, the physician's experience and patient's preference. Fast approval of atezolizumab plus bevacizumab as first-line treatment for advanced HCC brought an additional element in this scenario. Undoubtedly, lenvatinib and sorafenib remain available options for patients who are not suitable or those progressed to combination immunotherapy. It is conceivable that new systemic options will contribute to design a new treatment algorithm for HCC in the near future. Meanwhile, prospective studies and biomarker analysis are needed to help physicians in the choice between lenvatinib and sorafenib.

Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab.

BACKGROUND: Few data are available about real-life cardiotoxicity associated with s.c. versus i.v. trastuzumab treatment of early-stage, HER2-positive breast cancer, and little is known about its predisposing factors. PATIENTS AND METHODS: We retrospectively reviewed data of 363 adult patients treated with adjuvant trastuzumab for HER2-positive breast cancer. Univariate statistical analysis was performed, and a multivariable logistic model was developed to identify independent risk factors of cardiac toxicity. RESULTS: Within 5 years, the overall incidence of events meeting our criteria was 11.8%, and an early discontinuation of trastuzumab was recorded in 20 patients (5.5%). No cases of congestive heart failure occurred, neither multiple events per patient were observed. A total of 184 patients received i.v. and 179 received s.c. trastuzumab. Compared with the s.c. formulation, a higher cardiotoxicity rate for the i.v. administration (15.2% vs 8.4%) was found, and particularly in those patients with cardiovascular risk factors (19.3% vs 8.7%), at the univariate and multivariate analyses. Although more patients with prior anthracycline-based chemotherapy experienced cardiac events, the association of this therapy with cardiac events was not significant. The incidence of cardiac events was not influenced by anthropometric data (e.g. body mass index) or a diagnosis of diabetes mellitus. 5-year event-free survival was 91.7% in the overall population; event-free survival rates were similar between the s.c. and the i.v. groups. CONCLUSION: Our study shows a more favorable safety profile of s.c. versus i.v trastuzumab administration. The use of s.c. trastuzumab could be advisable in at-risk patients.

Prospective Validation of the Italian Alliance Against Cancer Lung Panel in Patients With Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: The deeper knowledge of non-small-cell lung cancer (NSCLC) biology and the discovery of driver molecular alterations have opened the era of precision medicine in lung oncology, thus significantly revolutionizing the diagnostic and therapeutic approach to NSCLC. In Italy, however, molecular assessment remains heterogeneous across the country, and numbers of patients accessing personalized treatments remain relatively low. Nationwide programs have demonstrated that the creation of consortia represent a successful strategy to increase the number of patients with a molecular classification. PATIENTS AND METHODS: The Alliance Against Cancer (ACC), a network of 25 Italian Research Institutes, has developed a targeted sequencing panel for the detection of genomic alterations in 182 genes in patients with a diagnosis of NSCLC (ACC lung panel). One thousand metastatic NSCLC patients will be enrolled onto a prospective trial designed to measure the sensitivity and specificity of the ACC lung panel as a tool for molecular screening compared to standard methods. RESULTS AND CONCLUSION: The ongoing trial is part of a nationwide strategy of ACC to develop infrastructures and improve competences to make the Italian research institutes independent for genomic profiling of cancer patients.

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.

Eribulin across multiple lines of chemotherapy: a retrospective study on quality of life and efficacy in metastatic breast cancer patients.

This study evaluates efficacy, tolerability and health-related quality of life of eribulin in patients with metastatic breast cancer. Predictive and/or prognostic factors of outcome were also analyzed. Among 44 women receiving eribulin mesylate, one patient had a complete response, 22.7% a partial response and 25% a stable disease. Median overall survival and median progression-free survival were 11.8 and 4.5 months, respectively. Treatment was well tolerated; the most frequent adverse events were neutropenia (52%), leukopenia (50%), fatigue (38%) and alopecia (40%). No significant reductions of health-related quality of life parameters were observed. Disease control during previous chemotherapy lines was related with better outcome with eribulin. In conclusion, eribulin treatment should be considered in a multiple chemotherapy lines strategy in metastatic breast cancer.