Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments ...usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.
Abstract
Background
We previously showed that therapy with anti–checkpoints T-lymphocyte-associated protein 4 (anti–CTLA-4) or antiprogrammed cell death protein 1 (anti–PD-1) agents was more ...effective for men as compared with women. However, because the sex-dimorphism of the immune system is complex, involving multiple elements of immune responses, it is possible that women could derive larger benefit than men from strategies other than therapy with immune checkpoint inhibitors (ICIs) alone. Here we investigated whether women could derive larger benefit than men from the combination of chemotherapy and anti-PD-1 or anti-PD-L1.
Methods
We performed two meta-analyses. The first included all randomized controlled trials (RCTs) testing anti-PD1 and anti–PD-L1 plus chemotherapy vs chemotherapy to assess different efficacy between men and women. The second included all RCTs of first-line systemic treatment in advanced non-small cell lung cancer testing anti–PD-1/PD-L1 given either alone or combined with chemotherapy to assess the different efficacy of these two immunotherapeutic strategies according to patients’ sex. For each RCT included in the two meta-analyses, first, a trial-specific ratio of hazard ratios (HRs) was calculated from the ratio of the reported hazard ratios in men and in women; second, these trial-specific ratios of hazard ratios were combined across trials using a random-effects model to obtain a pooled hazard ratios ratio. A pooled HRs ratio estimate lower than 1 indicates a greater treatment effect in men, and higher than 1 a greater effect in women.
Results
Eight RCTs were included in the first meta-analysis. The pooled overall survival hazard ratios (OS-HRs) comparing anti–PD-1/PD-L1 plus chemotherapy vs chemotherapy was 0.76 (95% confidence interval CI = 0.66 to 0.87) for men and 0.48 (95% CI = 0.35 to 0.67) for women. The pooled ratio of the overall survival hazard ratios reported in men vs women was 1.56 (95% CI = 1.21 to 2.01), indicating a statistically significant greater effect for women. Six RCTs were included in the second meta-analysis: three tested an anti-PD-1 alone, whereas three RCTs tested anti-PD-1/PD-L1 plus chemotherapy. The pooled overall survival hazard ratios were 0.78 (95% CI = 0.60 to 1.00) in men and 0.97 (95% CI = 0.79 to 1.19) in women for anti–PD-1 alone, compared with 0.76 (95% CI = 0.64 to 0.91) in men and 0.44 (95% CI = 0.25 to 0.76) in women for anti–PD-1/PD-L1 plus chemotherapy. The pooled ratio of overall survival hazard ratios was 0.83 (95% CI = 0.65 to 1.06) for anti–PD-1 alone, indicating a greater effect in men, and 1.70 (95% CI = 1.16 to 2.49) for anti–PD-1/PD-L1 plus chemotherapy, indicating a greater effect in women.
Conclusion
Women with advanced lung cancer derived a statistically significantly larger benefit from the addition of chemotherapy to anti–PD-1/PD-L1 as compared with men.
Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed ...melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient's possible response to treatment or development of toxicities.
Purpose of Review
To review evidence on the efficacy and safety of combined BRAF-targeted therapy and immune checkpoint inhibitors in patients with BRAF-mutated metastatic melanoma.
Recent Findings
...Programmed death-1 pathway inhibitors administered with BRAF/MEK inhibitors showed promising anti-tumour activity in BRAF-mutated advanced melanoma and were investigated for safety and efficacy in three large international clinical trials. Although, in two out of those three randomized phase III studies, progression-free survival (PFS) did not reach statistical significance, results showed that duration of response (DOR) and overall survival (OS) were improved using combined therapy, sustaining the scientific rationale for its use at least in a subset of metastatic melanomas. However, the frequent occurrence of autoimmunity-induced toxicities should be considered since it is limiting the continuity and the wide application of these regimens.
Summary
Novel treatment modalities combining targeted therapy with checkpoint inhibitors require further clinical investigation and elucidation of their effect on the immune system and cancer cell modulation.
We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune ...response and immune evasion in patients with NSCLC.
We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti-PD-1/anti-PD-L1 drugs.
As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell-excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti-PD-1/PD-L1 drugs.
We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
Metastatic vulvar melanoma is a rare and aggressive disease and survival is usually poor. Vulvar melanomas harbor BRAF V600 mutations only infrequently; consequently, target therapy is a rare ...therapeutic option and immunotherapy usually has only a weak effect. On the other hand, KIT mutations are rare in cutaneous melanomas, but relatively frequent in mucosal melanomas, particularly in vulvar-vaginal melanomas, and can be a therapeutic target. Herein, we report a clinical case of a patient with metastatic vulvar melanoma, harboring an exon 17 c-KIT mutation, treated with avapritinib (BLU-285) – a highly potent and selective oral kinase inhibitor designed to treat imatinib-resistant gastro-intestinal stromal tumors (GIST) by targeting KIT/PDGFRα activation loop mutants (exons 17/18). After failure of the combination of ipilimumab + nivolumab first and then nivolumab alone, the patient received avapritinib 300 mg/daily for central nervous system (CNS), lymph-nodal, right adrenal gland, lung, and subcutaneous metastases. Best response was partial remission, according to RECIST 1.1 criteria. Time to treatment progression was 11 months. Main toxicities were grade 2 cutaneous vasculitis that required avapritinib discontinuation, and grade 2 uveitis of unknown origin, treated by vitrectomy and empiric antibiotic and antiviral therapy due to negative cultural tests. Uveitis was detected at the time of progression and therapy was definitively discontinued. In conclusion, avapritinib proved to be effective even in the presence of a pretreated disease, a high tumor burden, and brain metastases. In our experience, treatment was feasible and toxicity manageable. Considering the lack of effective therapies and the poor outcome of the disease, determination of c-KIT mutations should be performed routinely in cases of metastatic mucosal melanoma.
To provide evidence explaining the poor association between pCR and patients’ long-term outcome at trial-level in neoadjuvant RCTs for breast cancer (BC), we performed a systematic-review and ...meta-analysis of all RCTs testing neoadjuvant treatments for early-BC and reporting the hazard ratio of DFS (HRDFS) for the intervention versus control arm stratified by pathological response type (i.e., pCR yes versus no).
The objective was to explore differences of treatment effects on DFS across patients with and without pCR.
We calculated the pooled HRDFS in the two strata of pathological response (i.e., pCR yes versus no) using a random-effects model, and assessed the difference between these two estimates using an interaction test.
Ten RCTs and 8496 patients were included in the analysis.
Patients obtaining pCR in the intervention-arm had a higher, although not statistically significant, risk of DFS-event as compared with patients obtaining pCR in the control-arm: the pooled HRDFS for the experimental versus control arm was 1.23 (95%CI, 0.91–1.65). On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR: the pooled HRDFS was 0.86 (95%CI, 0.78–0.95).
Treatment effect on DFS was significantly different according to pathological response type (interaction test p: 0.014).
We reported new evidence that contributes to explaining the poor surrogacy value of pCR at trial-level in neoadjuvant RCTs for early-BC.
•Pathological complete response (pCR) has been shown to be associated with long-term outcome at patient level but not at trial-level in neoadjuvant RCTs for breast cancer (BC).•One explanation could be that new neoadjuvant treatment regimens achieving substantially higher pCR rates might exert a dissociated effect on primary tumors versus micrometastases.•In this meta-analysis of recent RCTs testing neoadjuvant treatments for early-BC patients, there was a numerically higher risk of DFS-event for patients obtaining pCR in the intervention-arm as compared with those obtaining pCR in the control-arm.•On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR.
We aimed to provide a comprehensive overview of the link between vitamin D and non-melanoma skin cancer (NMSC). For this purpose, we conducted a systematic literature review (updated to 3 February ...2021) and meta-analysis of the studies reporting on the association between vitamin D intake (from diet and supplements) and blood concentration, polymorphisms of the vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes, and the risk of NMSC. Random effects meta-analysis models were fitted to merge study-specific risk estimates into summary relative risk (SRR) and corresponding 95% confidence intervals (CI). Twenty-four studies altogether were included. There was a suggestive association between increasing serum/plasma vitamin D concentration and NMSC risk (SRR for highest vs. lowest concentration 1.67, 95%CI 0.61–4.56), although with large heterogeneity across studies (I2 = 91%). NMSC risk was associated with highest vitamin D intake in observational studies but not in clinical trials. Finally, there was no significant association between any polymorphism of the VDR and VDBP genes and NMSC risk. In conclusion, no strong relationship between vitamin D metabolism and NMSC risk appears to exist according to our systematic review and meta-analysis, although some findings are worthy of further investigation.
As diverse therapeutic options are now available for advanced melanoma patients, predictive markers that may assist treatment decision are needed. A model based on baseline serum lactate ...dehydrogenase (LDH), peripheral blood relative lymphocyte counts (RLC) and eosinophil counts (REC) and pattern of distant metastasis, has been recently proposed for pembrolizumab-treated patients. Here, we applied this model to advanced melanoma patients receiving chemotherapy (
116) or anti-CTLA-4 therapy (
128). Visceral involvement, LDH and RLC were associated with prognosis regardless of treatment. Instead, when compared to chemotherapy-treated patients with REC < 1.5%, those with REC ≥ 1.5% had improved overall survival when receiving anti-CTLA-4 Hazard Ratio (HR) = 0.56 (0.4-0.93) but not chemotherapy HR = 1.13, (0.74-1.74), and the treatment-by-REC interaction was significant for both overall (
= 0.04) and progression free survival (
= 0.009). These results indicate baseline REC ≥ 1.5% as a candidate predictive biomarker for benefit from anti-CTLA-4. Further studies are needed to confirm these findings in patients receiving immune-modulating agents.
Small-cell lung cancer (SCLC) transformation from EGFR mutant adenocarcinoma is a rare entity that is considered to be a new phenotype of SCLC. While transformation from adenocarcinoma (ADC) with ...EGFR exon 19 deletions and exon 21 L858R point mutations has been described, to our knowledge, no cases of transformation to SCLC from exon-18-mutated ADC have been reported. We reported a clinical case of a patient with exon-18-EGFR-transformed SCLC, and we performed a systematic review of the literature.
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