Systematic review and meta-analysis of immune checkpoint inhibitors as single agent or in combination with chemotherapy in early-stage non-small cell lung cancer: Impact of clinicopathological factors and indirect comparison between treatment strategies.

BACKGROUND: In non-small cell lung cancer (NSCLC), the immune checkpoint inhibitors (ICI) revolution is rapidly moving from metastatic to early-stage, however, the impact of clinicopathological variables and optimal treatment sequencing remain unclear. METHODS: Randomized controlled trials (RCTs) in patients with early-stage NSCLC treated with ICI as single agent or in combination with platinum-based chemotherapy (PCT) were included. Primary outcomes were pathological complete response (pCR), event free survival (EFS) (neoadjuvant/perioperative), and disease-free survival (DFS) (adjuvant). Secondary outcomes were major pathological response (MPR), overall survival (OS), toxicity, surgical outcomes (neoadjuvant/perioperative); OS and toxicity (adjuvant). An additional secondary endpoint was to compare EFS and OS between neoadjuvant and perioperative strategies. RESULTS: 8 RCTs (2 neoadjuvant, 4 perioperative, 2 adjuvant) (4661 participants) were included. Neoadjuvant/perioperative ICI+PCT significantly improved pCR, EFS, OS, MPR and R0 resection compared to PCT. Adjuvant ICI significantly improved DFS compared to placebo. There was a significant subgroup interaction by PD-L1 status (χ2 = 10.72, P = 0.005), pCR (χ2 = 17.80, P < 0.0001), and stage (χ2 = 4.46, P = 0.003) for EFS. No difference according to PD-L1 status was found for pCR, with 14% of patients having PD-L1 negative tumors still experiencing a pCR. No interaction by PD-L1 status was found for DFS upon adjuvant ICI. Indirect comparison showed no difference in EFS and OS between neoadjuvant and perioperative ICI+PCT. CONCLUSIONS: PD-L1 status, pCR and stage impact on survival upon neoadjuvant/perioperative ICI. The restriction of neoadjuvant/perioperative ICI to PD-L1 + patients could preclude pCR and long-term benefit in the PD-L1- subgroup. Neoadjuvant and perioperative could be equivalent strategies.

Sex dimorphism and cancer immunotherapy: May pregnancy solve the puzzle?

In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetal-antigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal-antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a regulatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetal-maternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials.

Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?

The ability to identify the broadest range of targetable gene fusions is crucial to facilitate personalized therapy selection for advanced lung adenocarcinoma (LuADs) patients harboring targetable receptor tyrosine kinase (RTK) genomic alterations. In order to evaluate the most effective testing approach for LuAD targetable gene fusion detection, we analyzed 210 NSCLC selected clinical samples, comparing in situ (Fluorescence In Situ Hybridization, FISH, and ImmunoHistoChemistry, IHC) and molecular (targeted RNA Next-Generation Sequencing, NGS, and RealTime-PCR, RT-PCR) approaches. The overall concordance among these methods was high (>90%), and targeted RNA NGS was confirmed to be the most efficient technique for gene fusion identification in clinical practice, allowing the simultaneous analysis of a large set of genomic rearrangements at the RNA level. However, we observed that FISH was useful to detect targetable fusions in those samples with inadequate tissue material for molecular testing as well as in those few cases whose fusions were not identified by the RNA NGS panel. We conclude that the targeted RNA NGS analysis of LuADs allows accurate RTK fusion detection; nevertheless, standard methods such as FISH should not be dismissed, as they can crucially contribute to the completion of the molecular characterization of LuADs and, most importantly, the identification of patients as candidates for targeted therapies.

Case report: Successful use of mepolizumab for immune checkpoint inhibitors-induced hypereosinophilic syndrome in two patients with solid malignancies.

Hypereosinophilic syndrome (HES) represents a group of blood disorders characterized by an absolute eosinophil count (AEC) > 1.5 × 103/µl in the peripheral blood, which eventually extravasate and cause organ damage. It can be primary or secondary to infections or tumors. The infiltration of eosinophils in tissue and organs is associated with different disorders and, in some cases, with life-threatening manifestations. Albeit the pathogenesis of HES in patients with solid tumo\rs is not yet clarified; recently, HES has also been described as an immune-related adverse event in patients with solid tumors receiving immune checkpoint inhibitors. Treatment of HES is still debated, especially in patients with concomitant solid tumors, and different drugs including imatinib, hydroxyurea, interferon-ɑ, glucocorticoids, and the monoclonal antibody targeting circulating IL-5 mepolizumab have been proposed according to the underlying cause and the severity of HES. Herein, we describe, for the first time, the successful use of mepolizumab for the treatment of immune checkpoint-induced HES in two patients with metastatic solid tumor.

Intratumoral Cellular Heterogeneity: Implications for Drug Resistance in Patients with Non-Small Cell Lung Cancer.

Tailored therapies based on the identification of molecular targets currently represent a well-established therapeutic scenario in the treatment of non-small cell lung cancer (NSCLC) patients. However, while aiming to improve patients' response to therapy, development of resistance is frequently observed in daily clinical practice. Intratumoral heterogeneity is a frequent event in NSCLC, responsible for several critical issues in patients' diagnosis and treatment. Advances in single-cell sequencing technologies have allowed in-depth profiling of tumors and attributed intratumoral heterogeneity to genetic, epigenetic, and protein modification driven diversities within cancer cell populations. This review highlights current research on the biological role of tumor heterogeneity and its impact on the development of acquired resistance in NSCLC patients.

History of Extensive Disease Small Cell Lung Cancer Treatment: Time to Raise the Bar? A Review of the Literature.

Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the last 40 years. With the advent of immunotherapy, this scenario has finally changed. Our review aims to provide an overview of the primary studies on the actual therapeutic strategies available for ED-SCLC patients, and to highlight emerging evidence supporting the use of immunotherapy in SCLC patients.

Complete testicular remission after chemotherapy in a patient with advanced seminoma: is the testicle a real 'sanctuary'? A case report and review of the literature.

Testicular cancer is relatively uncommon, but at the same time, it is the most common solid tumor in men between the ages of 20 and 34 years. Seminoma represents the most frequently encountered germ cell tumors. Because orchiectomy is usually performed before chemotherapy, little is known about the effect of systemic chemotherapy on primary testicular tumors. Furthermore, the testis has always been considered a sanctuary site, an immune-privileged site in which inadequate exposure of the tumor to chemotherapy may occur. We report the case of a young patient with advanced seminoma with a complete testicular response after four cycles of cisplatin-based chemotherapy. Then, we performed a systematic review of the literature reporting the studies published to date on the topic.

Baseline PET as prognostic index in diffuse large B-cell lymphoma and grade IIIb follicular lymphoma: a retrospective study of a single-center experience.

BACKGROUND: International guidelines support performing baseline positron emission tomography (PET) in lymphoma. Metabolic tumor volume (MTV) measurement has been proposed as a good measurement of disease burden. We investigated if MTV at baseline PET can be predictive of complete response (CR) to first line standard chemotherapy in diffuse large B-cell lymphoma (DLBCL) and in follicular lymphoma (FL) grade IIIb. METHODS: We retrospectively analyzed data on 54 consecutive patients with DLBCL and FL grade IIIb treated in our institution. Dedicated software automatically estimated the SUVmax of the most active lesion and the MTV of the entire lesion burden using an isocontour threshold method set at 42% (MTV42) and 28% (MTV28) of the SUVmax. In addition, the ratio value (MTV28/MTV42) was calculated. Every group of lesions was evaluated separately. All patients were treated with R-CHOP-21. We performed a univariate and a multivariate logistic regression analysis to explore any possible association between PET parameters and CR. RESULTS: At the univariate logistic regression analysis, patients with a MTV28 lower than the median value (173.1) had an odds ratio (OR) of 4 (95% CI: 0.94-16.9) of obtaining a CR in comparison to patients with a MTV 28 higher than the median value; patients with a MTV42 lower than the median value (i.e. 85.6) had an OR of 3.63 (95% CI: 0.85-15.34) of obtaining a CR in comparison to patients with a MTV 42 equal or higher than the median value. Using MTV28/MTV42 value with median as cut-off instead of MTV28, patients with a MTV28/MTV42 lower than the median value (i.e. 1.81) had an OR of 4.26 (95% CI: 0.72-25.07) and of 7.54 (95% CI: 0.70-80.91) of obtaining a CR in comparison to patients with a MTV28/MTV42 equal or higher than the median value in the two models, respectively. CONCLUSIONS: The results of our study suggest that MTV could be a useful tool to predict response to R-CHOP in patients affected with DLBCL and FL grade IIIb and that a multi-parameters evaluation should be considered.

Dabrafenib and trametinib induced pancreatitis: a case report and review of the literature.

Approximately 50% of melanomas are characterized by BRAF mutation (V600E in 90% of cases), that predicts more aggressive behaviour. This mutation is the target of dabrafenib, an anti-BRAF tyrosine-kinase inhibitor (TKI), that together with trametinib, anti-MEK TKI, is approved for first-line treatment of metastatic melanoma due to significant benefit in overall and progression-free survival. Most common treatment-related adverse events are pyrexia, chills, fatigue, rash, nausea, vomiting, and diarrhoea. This case report aims to present another less common adverse event of combined anti-BRAF and anti-MEK treatment. Our patient, after 4 months on target-therapy, experienced sudden deep abdominal pain. At the initial work-out at the emergency department, increase in serum lipase was detected and radiological findings were consistent with acute pancreatitis. Admitted to the hospital, other causes were ruled out and target-therapy was discontinued with symptoms improvement. Radiological and clinical follow-up was performed and a diagnosis of drug-induced pancreatitis was made. After few days of medical support with analgesia and antibiotic, the patient felt better and was discharged; target-therapy was permanently interrupted. Searching the literature, not so many cases of iatrogenic pancreatitis are described with this TKI combination, therefore, we have reported it as a rare but life-threatening adverse event that should be investigated whenever conceivable.

EGFR T790M detection rate in lung adenocarcinomas at baseline using droplet digital PCR and validation by ultra-deep next generation sequencing.

BACKGROUND: Routine testing of baseline EGFR T790M mutation may have important clinical impact but many discordant data have been reported regarding the diagnostic, prognostic and predictive role of this marker. In this study we aimed to assess T790M frequency in 164 untreated EGFR-mutated NSCLCs using methods with different sensitivity as well as to analyze the relationship between baseline T790M mutation status, patient's clinicopathologic features and tyrosine kinase inhibitors (TKI) treatment outcomes. METHODS: We compared the diagnostic performance, sensitivity and specificity of three methods, namely MALDI-TOF mass spectrometry (MS), Allele-Specific Real Time PCR (AS-PCR), droplet digital PCR (ddPCR). Ultra-deep next generation sequencing (NGS) validation of T790M-mutant NSCLCs was performed using SiRe® panel. RESULTS: Baseline T790M occurred in 17% of the tumors. Intermediately sensitive techniques such as MALDI-TOF MS (detection limit of T790M ≥5%) allow to detect T790M in 2% of cases exhibiting mutant-allele fractions ranging from 11.5% to 17%. Median overall survival (OS) in these patients was poor (7.3 months) and progression free survival (PFS) was of 3.3 months in patients treated with a 1st generation EGFR TKI. The remaining T790M-positive cases showed very low mutant-allele fractions ranging from 0.07% to 0.38% and required highly sensitive methods such as ddPCR and NGS to be identified. All these cases showed a concurrent sensitizing EGFR mutation (mainly exon 19 deletion), and clinicopathological features similar to those observed in EGFR mutant cancers. Median OS of these patients was 27 months while median PFS after TKI treatment was 20 months. CONCLUSIONS: Routine test of baseline EGFR T790M may have an important role in the prediction to EGFR TKI therapy response and should be performed using highly sensitive and quantitative methods, such as ddPCR and NGS, in order to reliably distinguish NSCLCs with high or very low T790M mutant-allele fraction.