Immune-Related Adverse Event Likelihood Score Identifies "Pure" IRAEs Strongly Associated With Outcome in a Phase I-II Trial Population.

BACKGROUND: Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process. METHODS: In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate. RESULTS: Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (n = 143), HC IRAE (n = 24), or LC IRAE (n = 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all P < .01). CONCLUSION: ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.

MET in Non-Small-Cell Lung Cancer (NSCLC): Cross 'a Long and Winding Road' Looking for a Target.

Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the 'druggable' molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.

Fast Mimicking Diets and Other Innovative Nutritional Interventions to Treat Patients with Breast Cancer.

The impact of nutritional patterns on the risk of breast cancer (BC) is well investigated in the oncology literature, including the type of diets and caloric intake. While obesity and elevated body mass index are well-reported critical risk factors of BC occurrence, there is an expanding area of oncology assessing the impact of caloric intake and nutritional patterns in patients with cancer. Caloric restriction and fast mimicking alimentary regimens have been consistently reported to improve survival outcomes based on preclinical models. Moreover, emerging clinical evidence has paved the way for new metabolic approaches for the treatment of BC, in addition to the established therapeutic arsenal or as alternative options. In this chapter, our aim is to discuss the principal strategies of metabolic manipulation through nutritional interventions for patients with BC as an innovative area of cancer therapy.

Combination immunotherapy strategies for triple-negative breast cancer: current progress and barriers within the pharmacological landscape.

INTRODUCTION: Triple-negative breast cancer (TNBC) is a breast cancer subtype characterized by poorer prognosis. Despite that TNBC can display immunogenic features, anti-PD(L)1 monotherapy strategies have resulted in disappointing results, underscoring the need to optimize their use in TNBC. Among many, combining immunotherapy with other agents to exploit the synergistic effect of different drugs has been explored. Such a combination approach led to the approval of immune checkpoint inhibitors (ICIs) plus chemotherapy in both metastatic and early setting. Nevertheless, primary or secondary resistance to ICIs remains a major hurdle to overcome, with a major need to explore novel combination strategies. AREAS COVERED: This review summarizes the biological rationale, current evidence, and ongoing clinical trials of immunotherapy combined with novel immunotherapeutics, chemotherapy, targeted compounds, and antibody-drug conjugates. EXPERT OPINION: The treatment landscape of TNBC is in continuous changes. ICIs are now part of the clinical practice; however, several unmet needs still remain, including the need to overcome resistance and prolong benefit of ICIs. Exploiting synergism between different agent has emerged as an attractive strategy to extend the benefit obtained with ICIs. The goal of future research will be to unveil the mechanisms underlying resistance to ICIs and to identify better biomarkers for patient selection.

SARS-CoV-2 vaccine in patients with thymic epithelial tumours with and without active or pre-existing autoimmune disorders: Brief report of a TYME network safety analysis.

BACKGROUND: International guidelines recommend severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine for patients with cancer. A substantial risk of developing vaccine-related autoimmune toxicities could be hypothesised for patients with thymic epithelial tumours (TETs) due to their high risk of autoimmune disorders (ADs). Moreover, a cross-reaction between SARS-CoV-2 spike protein antibodies and various tissue proteins has been shown, and antibodies against nucleoproteins showed overlaps in the autoimmune cross-reaction with antibodies to spike protein. Due to the rarity of TETs, no data addressing this hypothesis are available. METHODS: Patients with TETs who received SARS-CoV-2 vaccine, treated in 4 referral centres of the Italian Collaborative Group for ThYmic MalignanciEs (TYME) network between February 2021 and September 2021, were interviewed through a standardised 15-items questionnaire in order to describe the safety of SARS-CoV-2 vaccine in patients affected by TETs. RESULTS: Data from 245 doses of vaccine administered to 126 patients (41 = thymic carcinoma, 85 = thymoma; 38 with AD, of which 26 with active AD) were collected. Nine patients had a previous COVID-19-positive swab. No cases of AD reactivation or worsening of a pre-existing AD were seen in the study population. A new diagnosis of myasthenia gravis likely unrelated to the vaccine was made in two patients after the vaccination. Sixty-four patients (51%) experienced a total of 103 adverse events, all G1/G2, most commonly fatigue, new or worsening muscle pain and chills. None AE required patients' hospitalisation. CONCLUSIONS: SARS-CoV-2 mRNA vaccines appear to be safe in patients with TET, even in case of active or pre-existing AD.

Systemic Treatment of Ductal Carcinoma In Situ of the Breast.

Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer (BC), whose diagnosis significatively increased with the diffusion of BC screening programs. DCIS actually represents roughly 20% of new BC diagnoses (1). About 70% of DCIS shows positivity for hormone receptor (HR), while HER2 is overexpressed in 25-30% of the cases (2,3). Concerning the systemic approach, the only one that should be considered for HR-positive DCIS is adjuvant endocrine therapy (ET), according to NCCN guidelines (4). In fact, the excellent prognosis of this neoplasm does not justify the utilization of more aggressive treatment strategies, such as HER2- directed therapies or chemotherapy. Here we discuss the results of the most important clinical trials enrolling DCIS patients in the adjuvant and in the preoperative setting; in addition, we report the chemoprevention studies utilizing ET which demonstrated a reduction of the risk of DCIS development. On balance, the choice to undertake or not an adjuvant ET, which is often burdened by adverse events that could impact on the quality of life of the patients and on their adherence to the therapy, should be discussed with the patient, taking into account that no survival advantage has been demonstrated so far.

First line treatment of BRAF mutated advanced melanoma: Does one size fit all?

In the last decade, immunotherapy and target therapy have revolutionized the prognosis of patients with BRAF-V600 mutation-positive metastatic melanoma. To date, three different combinations of BRAF/MEK inhibitors have been approved for this population, showing comparable efficacy and unique toxicity profiles. Several immune-checkpoint inhibitors, including pembrolizumab, nivolumab and the combination of nivolumab plus ipilimumab, are also available options for untreated metastatic melanoma patients. A novel approach has emerged by combining immune-checkpoint inhibitors and targeted agents, based on preclinical hints of synergy, prompting clinical results from large randomized trials. Specifically, the triplet of atezolizumab, vemurafenib and cobimetinib has been recently approved by FDA for patients with untreated BRAF-mutant metastatic melanoma. With a wide variety of available treatment options in this setting, it is paramount to establish criteria to select the most effective and safe frontline tailored approaches, for each patient. Results from ongoing studies are awaited, to maximise the benefits in survival outcomes and quality of life for patients, balancing adverse events and clinical benefit. The purpose of this review is to summarize the current landscape of standard and experimental treatment strategies for the first line treatment of patients with BRAF-mutated advanced melanoma and discuss the best patient-centered tailored strategies in the first-line setting.

Margetuximab for the treatment of HER2-positive metastatic breast cancer.

INTRODUCTION: No specific standard treatment is currently recommended for HER2-positive advanced breast cancer (BC) patients progressing to dual HER2 blockade and to trastuzumab emtansine (TDM-1). However, several novel anti-HER2 agents are emerging and rapidly revolutionizing this setting. Among these, the FC-engineered monoclonal antibody margetuximab has recently demonstrated to slightly improve progression-free survival (PFS) compared with trastuzumab, when combined with chemotherapy for pretreated HER2-positive advanced BC. AREAS COVERED: The present review article recapitulates the clinical development of margetuximab, critically discussing its implications in the current landscape of BC treatment algorithms. EXPERT OPINION: The clinical role of Margetuximab can only be interpreted in view of the rapidly evolving treatment landscape for pretreated HER2-positive advanced BC. Indeed, the recently approved anti-HER2 agents tucatinib and trastuzumab deruxtecan currently represent appealing options for the post-TDM1 setting, while margetuximab may have a role after progression to the abovementioned agents, in case of a future approval. Regardless of its clinical uptake, it should be noted that the development of margetuximab has relevantly improved our biological understanding of HER2-positive BC, highlighting the implication of patient's genotype in determining treatment outcomes, as well as the relevance of antibody-dependent cellular cytotoxicity (ADCC) in the context of HER2-blockade.