Molecular tumor board in patients with metastatic breast cancer.

PURPOSE: Comprehensive genomic profiling is becoming increasingly important in the management of patients with metastatic breast cancer (mBC). Real-world clinical outcomes from applying molecular tumor boards (MTBs) recommendations in this context remain limited. Accordingly, we conducted a retrospective, single-institution analysis to evaluate the clinical impact of discussing patients affected by mBC at the MTB. METHODS: Clinicogenomic data of patients affected by mBCs referred to the European Institute of Oncology MTB between August 2019 and December 2023 were reviewed. Genomic alterations were classified by ESCAT framework. Clinical outcomes of patients showing actionable alterations and receiving molecular-matched therapy (MMT) were compared to those receiving standard therapy (ST). RESULTS: Ninety-six patients were included. Following MTB discussion, genetic counseling was recommended in 27% (n = 26) of patients, while additional molecular analyses were requested in 25% (n = 24) cases. Fifty-six patients (58%) displayed at least one actionable alteration. For patients with available follow-up (n = 50), 32 (64%) received MMTs and 18 (36%) ST. No differences in real-world progression-free survival (rwPFS) (4.07 months [95% CI 2.14-8.28] vs. 3.12 months [95% CI 1.51-NE], P = 0.8) and 12-month overall survival (OS) (58% [95%CI 43-78] vs. 57% [95%CI 34-97), P = 0.9) were observed between the MMT- and ST-group. Level I ESCAT alterations yielded longer rwPFS (5.82 months [95% CI 3.12-8.41]) compared to ESCAT II (2.14 months [95%CI 1.61-NE]) and ESCAT III (2.10 months [95% CI 2.04-NE]; P = 0.03). Twenty-four percent of patients showed a PFS2/PFS1 ratio > 1.3 from MMT. CONCLUSION: Molecular tumor boards can provide additional treatment options for patients affected by mBC. Besides treatment recommendations, MTBs also have the utility to assess the validity of discussed genomic reports and to identify alterations worthy of genetic counseling.

Deleterious alterations in homologous recombination repair genes and efficacy of platinum-based chemotherapy in biliary tract cancers.

BACKGROUND: Platinum-based chemotherapy represents the standard first-line treatment for biliary tract cancers (BTC). Deficits in genes involved in the homologous recombination (HR) and DNA damage response (DDR) may confer higher sensitivity to platinum agents. METHODS: We retrospectively included patients affected by BTC from 2 Italian institutions. Inclusion criteria consist of the receipt of platinum-based chemotherapy in the metastatic setting and the availability of comprehensive genomic profiling using next-generation sequencing (NGS). Patients were included in the HRD-like group if demonstrated oncogenic or likely oncogenic alterations in HR-/DDR-genes. Clinical endpoints were compared between the HRD-like group and the non-HRD-like group. RESULTS: Seventy-four patients were included, of whom 25 (33%) in the HRD-like group and 49 (66%) in the non-HRD group. With a median follow-up of 26.04 months (interquartile-range [IQR] 9.41-29.27) in the HRD-like group and of 22.48 months (IQR 16.86-40.53) in the non-HRD group, no PFS difference emerged, with a mPFS of 5.18 months in the HRD-like group compared to 6.04 months in the non-HRD group (hazard ratio [HR], 1.017, 95% CI 0.58-1.78; P = .95). No differences were observed in DCR (64% [95 CI 45%-83%] vs 73% [95 CI 61%-86%]; P = .4), and CBR (45% [95% CI 28%-73%] vs 50% [95% CI, 37%-68%]; P = .9) between the HRD-like group and non-HRD groups, respectively. Median OS did not statistically differ between the HRD-like group and non-HRD group (26.7 vs 18.0 months, respectively; HR, 0.670, 0.33 to 1.37, P = .27). CONCLUSION: HR-/DDR-genes, when assessed with regular tumor-only NGS panels, provide limited clinical validity to identify patients with BTC more likely to benefit from platinum-based chemotherapy.

Effect of age on safety and efficacy of novel cancer drugs investigated in early-phase clinical trials.

BACKGROUND: Elderly patients are underrepresented in clinical trials, particularly in early-phase studies. Our study assessed the safety and efficacy of novel anti-cancer treatments investigated in early-phase clinical trials, comparing outcomes between younger and elderly patients. METHODS: This retrospective study analyzed data from patients enrolled in phase I/II trials at our center between January 2014 and April 2021. We evaluated clinicopathologic characteristics, toxicity, and clinical efficacy, categorizing patients into younger (≤ 65 years) and elderly (> 65 years) groups. RESULTS: 419 patients were included with a median age of 56 years. Among these, 107 (26 %) were older than 65 years. Predominant cancers included breast (48 %), lung (10 %), and melanoma (5 %). Patients were treated in 64 trials, predominantly receiving immunotherapy-based (47 %) or targeted therapy-based (45 %) treatment. Elderly presented with poorer ECOG performance status (P = 0.001) and had fewer prior therapy lines (P = 0.01) than younger patients. Grade ≥ 3 adverse events (AEs) were similar across age groups (31 % younger vs 33 % elderly; P = 0.7), including in combination therapy scenarios. However, elderly patients experienced more AEs with antibody-drug conjugates compared to younger counterparts (56 % vs 14 %, P = 0.036) and were more likely to discontinue treatment due to toxicity (15 % vs 7 %; P = 0.011). No significant age-related differences in response rates and survival outcomes were observed across treatment modalities, except for immunotherapy-based regimens for which elderly patients exhibited higher response rates, disease control rates, and prolonged progression-free survival. CONCLUSIONS: Our findings suggest that elderly exhibit comparable safety and efficacy outcomes to younger patients in early-phase clinical trials for new cancer drugs. This underscores the importance of including elderly patients in phase I/II trials to ensure the generalizability of study results and mitigate age-related disparities in cancer treatment access.

The evolving landscape of metastatic HER2-positive, hormone receptor-positive Breast Cancer.

Therapeutic agents targeting Human Epidermal Growth Factor Receptor 2 (HER2) demonstrated to positively impact the prognosis of HER2-positive breast cancer. HER2-positive breast cancer can present either as hormone receptor-negative or positive, defining Triple-positive breast cancer (TPBC). TPBC demonstrate unique gene expression profiles, showing reduced HER2-driven gene expression, as recapitulated by a higher proportion of Luminal-type intrinsic subtypes. The different molecular landscape of TPBC dictates distinctive clinical features, including reduced chemotherapy sensitivity, different patterns of recurrence, and better overall prognosis. Cross-talk between HER2 and hormone receptor signaling seems to be critical to determine resistance to HER2-directed agents. Accordingly, superior outcomes have been achieved with the use of endocrine therapy, representing the first subtype-specific pharmacological intervention unique to this subgroup. Additional targeted agents capable to tackle resistance mechanisms to anti-HER2, hormone agents, or both might further improve the efficacy of treatments, such as PI3K/AKT/mTOR inhibitors, particularly in a biomarker-enriched setting, and CDK4/6-inhibitors, with preliminary data suggesting a role of PAM50 subtyping to predict higher benefits in luminal tumors. Finally, the distinct biology of triple-positive tumors may yield the rationale for considering combinations within antibody-drug conjugate regimens. Accordingly, in this review, we summarized the current evidence and rationale for considering TPBC as a different entity, in which distinct therapeutical approaches leveraging on the different biological profile of TPBC may result in superior anticancer regimens and improved patient-centric outcomes.

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis.

BACKGROUND: Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. METHODS: To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. CLINICAL REPORT AND RESULTS: We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered. CONCLUSION: uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

Cancers of Unknown Primary Origin: Real-World Clinical Outcomes and Genomic Analysis at the European Institute of Oncology.

BACKGROUND: Cancer of unknown primary origin (CUP) poses a significant challenge due to poor clinical outcomes and limited treatment options. As such, further definition of clinicopathological factors and genomic profile to better adapt treatment strategies is required. METHODS: Medical records were interrogated to retrospectively include CUP with available clinical and genomics data at the European Institute of Oncology. Next-generation sequencing (NGS) included targeted panels. Statistical analyses were conducted with R Software 4.2.2. RESULTS: A total of 44 patients were included. With a median follow-up of 39.46 months (interquartile range [IQR] 35.98-47.41 months), median PFS (mPFS) to first-line regimen was 3.98 months (95% CI 3.22-5.98), with a clinical benefit rate of 26% (95% CI 14%-49%), and disease control rate (DCR) limited to 48.28%. Most patients (26 of 31, 83.87%) received platinum-doublet chemotherapy, with no statistically significant difference between first-line treatment regimens. Median OS (mOS) was 18.8 months (95% CI 12.3-39.9), with a 12-month OS rate of 66% (95% CI 50%-85%). All patients received comprehensive genomic profiling (CGP). For 11 patients, NGS was unsuccessful due to low sample quantity and/or quality. For the remaining, TP53 (n = 16, 48%) and KRAS (n = 10, 30%) represented the most altered (alt) genes. No microsatellite instability was observed (0 of 28), while 6 of 28 (21.43%) tumors carried high TMB (≥10 mutation per megabase). Eight of 33 tumors (24.2%) displayed at least one actionable alteration with potential clinical benefit according to ESCAT. Only 2 of them received targeted therapy matched to genomic alterations, with a combined mPFS of 2.63 months (95% CI 1.84-not evaluable) as third-line regimens. Six patients received anti-PD1/PD-L1 therapy, showing a meaningful mPFS of 13 months (95% CI 2.04-not evaluable). CONCLUSION: CUP exhibits poor prognosis with limited benefits from standard treatment regimens. A significant proportion of CUPs carry actionable alterations, underscoring the importance of genomic profiling to gather additional treatment opportunities. In addition, immunotherapy might represent a valuable treatment option for a subset of CUP. Finally, accurate definition of sequencing methods and platforms is crucial to overcome NGS failures.

Beyond PD(L)-1 Blockade in Microsatellite-Instable Cancers: Current Landscape of Immune Co-Inhibitory Receptor Targeting.

High microsatellite instability (MSI-H) derives from genomic hypermutability due to deficient mismatch repair function. Colorectal (CRC) and endometrial cancers (EC) are the tumor types that more often present MSI-H. Anti-PD(L)-1 antibodies have been demonstrated to be agnostically effective in patients with MSI-H cancer, but 50-60% of them do not respond to single-agent treatment, highlighting the necessity of expanding their treatment opportunities. Ipilimumab (anti-CTLA4) is the only immune checkpoint inhibitor (ICI) non-targeting PD(L)-1 that has been approved so far by the FDA for MSI-H cancer, namely, CRC in combination with nivolumab. Anti-TIM3 antibody LY3321367 showed interesting clinical activity in combination with anti-PDL-1 antibody in patients with MSI-H cancer not previously treated with anti-PD(L)-1. In contrast, no clinical evidence is available for anti-LAG3, anti-TIGIT, anti-BTLA, anti-ICOS and anti-IDO1 antibodies in MSI-H cancers, but clinical trials are ongoing. Other immunotherapeutic strategies under study for MSI-H cancers include vaccines, systemic immunomodulators, STING agonists, PKM2 activators, T-cell immunotherapy, LAIR-1 immunosuppression reversal, IL5 superagonists, oncolytic viruses and IL12 partial agonists. In conclusion, several combination therapies of ICIs and novel strategies are emerging and may revolutionize the treatment paradigm of MSI-H patients in the future. A huge effort will be necessary to find reliable immune biomarkers to personalize therapeutical decisions.

Evaluation of the Geographical Accessibility of Genome-Matched Clinical Trials on a National Experience.

BACKGROUND: Molecular-driven oncology allows oncologists to identify treatments that match a cancer's genomic profile. Clinical trials are promoted as an effective modality to deliver a molecularly matched treatment. We explore the role of geographical accessibility in Italy, and its impact on patient access to clinical trials. MATERIAL AND METHODS: We retrospectively reviewed molecular data from a single-institutional case series of patients receiving next-generation sequencing testing between March 2019 and July 2020. Actionable alterations were defined as the ones with at least one matched treatment on Clinicaltrials.gov at the time of genomic report signature. We then calculated the hypothetical distance to travel to reach the nearest assigned clinical trial. RESULTS: We identified 159 patients eligible for analysis. One hundred and one could be potentially assigned to a clinical trial in Italy, and the median distance that patients needed to travel to reach the closest location with a suitable clinical trial was 76 km (interquartile range = 127.46 km). Geographical distribution of clinical trials in Italy found to be heterogeneous, with Milan and Naples being the areas with a higher concentration. We then found that the probability of having a clinical trial close to a patient's hometown increased over time, according to registered studies between 2015 and 2020. CONCLUSIONS: The median distance to be travelled to the nearest trial was generally acceptable for patients, and trials availability is increasing. Nevertheless, many areas are still lacking trials, so efforts are required to increase and homogenize the possibilities to be enrolled in clinical trials for Italian patients with cancer.

Baseline Tumor Size as Prognostic Index in Patients With Advanced Solid Tumors Receiving Experimental Targeted Agents.

BACKGROUND: Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. METHODS: We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. RESULTS: A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P < .001), including among those receiving immunotherapy (12 vs. 7.5 months, P = .005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P = .002) and OS (20.5 vs. 9.9 months, P < .001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P < .001) and OS (21.2 vs. 6.7 months, P < .001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P = .57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P = .30), OS (19.3 vs. 11.8 months, P = .20), and ORR (33% vs. 28%, P = .78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P = .03) and OS (P < .001) but not with ORR (P = .11). CONCLUSIONS: Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT.

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.

Variant allele frequency: a decision-making tool in precision oncology?

Precision oncology requires additional predictive biomarkers for targeted therapy selection. Variant allele frequency (VAF), measuring the proportion of variant alleles within a genomic locus, provides insights into tumor clonality in somatic genomic testing, yielding a strong rationale for targeting dominant cancer cell populations. The prognostic and predictive roles of VAF have been evaluated across different studies. Yet, the absence of validated VAF thresholds and a lack of standardization between sequencing assays currently hampers its clinical utility. Therefore, analytical and clinical validation must be further examined. This Review summarizes the evidence regarding the use of VAF as a predictive biomarker and discusses challenges and opportunities for its clinical implementation as a decision-making tool for targeted therapy selection.

A demand-offer critical analysis of current drug development. Phase I drugs versus TCGA sequencing data.

BACKGROUND: Phase I clinical trials have become increasingly critical to regulatory approvals of novel agents. In phase I drug development, a global problem of unknown magnitude is the multiplicity of similar drugs being investigated against the same target, colloquially known as the 'me too' phenomenon. METHODS: Ranging from December 2020 to December 2022 we annotated phase I clinical trials present on clinicaltrials.gov. Public databases were queried for annotation of investigational agents (IAs). Extensive literature research and data mining were performed to annotate agents not present in public databases. The Cancer Genome Atlas (TCGA) pan-cancer sequencing cohort was used to perform second-level analyses to evaluate tumour types with a higher number of IA matches. RESULTS: A total of 1054 unique drug targets were identified. The most frequent IA classes were: cell products (1223), small-molecule inhibitors (1110), antibodies (733), and vaccines (346). Only a minority (8.9%) of phase I IAs were explored against a target without a competitive agent; 7% of agents shared targets with 2-3 other agents. Unfortunately, the majority (84%) shared targets with at least four other agents. Using data from the TCGA pan-cancer sequencing potentially underserved histologies were identified. Analysis of alteration-IA matches revealed potentially frequent and unexplored alterations in many tumour types. CONCLUSIONS: The majority of IAs (86%) shared targets with at least three other agents. We argue that these duplicative efforts could be redirected toward unmet needs instead.

The emerging role of PI3K inhibitors for solid tumour treatment and beyond.

Phosphoinositide 3-kinases (PI3Ks) play a central role in tumourigenesis with recurrent activating mutations of its p110α subunit (PIK3CA) identified in several tumours. Although several PI3K inhibitors are approved for haematological malignancies, only alpelisib was approved in solid tumours and for the treatment of PIK3CA-related overgrowth spectrum (PROS) syndrome. Traditional PI3K inhibitors inhibit both wild-type and mutant PI3K with almost equal potency, thus limiting their efficacy due to on-target toxicity. Since the initiation of phase I clinical trials investigating next generation allosteric mutant and isoform selective PIK3CA inhibitors, there has been a surge in interest in PIK3CA targeting in solid tumours. Preclinical characterisation of these compounds showed that maximal mutant protein inhibition fails to elicit metabolic and glucose homoeostasis dysregulation, one of the dose limiting toxicities of both selective and pan PI3K inhibitors. While extreme selectivity can be hypothesised to grant activity and safety advantage to these novel agents, on the other hand reduced benefit can be speculated for patients harbouring multiple or rare PIK3CA mutations. This review summarises the current understanding of PI3K alterations and the state-of-the-art treatment strategies in PI3K driven solid tumours, while also exploring the potential intrinsic and acquired resistance mechanisms to these agents, and the emerging role of mutant selective PIK3CA inhibitors.

Molecular tumour board at European Institute of Oncology: Report of the first three year activity of an Italian precision oncology experience.

BACKGROUND: Precision oncology aims to improve clinical outcomes by personalising treatment options for patients with cancer. Exploiting vulnerabilities identified in a patient's cancer genome requires reliable interpretation of a huge mole of alterations and heterogeneous biomarkers. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) allows evidence-based evaluation of genomic findings. Molecular tumour boards (MTBs) convey the required multi-disciplinary expertise to enable ESCAT evaluation and strategical treatment choice. MATERIALS AND METHOD: We retrospectively reviewed the records of 251 consecutive patients discussed by European Institute of Oncology MTB between June 2019 and June 2022. RESULTS: One-hundred eighty-eight (74.6%) patients had at least one actionable alteration. After MTB discussion, 76 patients received molecularly matched therapies (MMTs) while 76 patients received standard of care. Patients receiving MMT displayed higher overall response rate (37.3% versus 12.9%), median progression-free survival (mPFS 5.8 months, 95% confidence interval [CI] 4.1-7.5 versus 3.6 months, 95% CI 2.5-4.8, p = 0.041; hazard ratio 0.679, 95% CI 0.467-0.987) and median overall survival (mOS 35.1 months, 95% CI not evaluable versus 8.5 months, 95% CI 3.8-13.2; hazard ratio 0.431, 95% CI 0.250-0.744, p = 0.002). Superiority in OS and PFS persisted in multivariable models. Among 61 pretreated patients receiving MMT, 37.5% of patients had PFS2/PFS1 ratio ≥1.3. Patients with higher actionable targets (ESCAT tier I) had better OS (p = 0.001) and PFS (p = 0.049), while no difference was observed in lower evidence levels. CONCLUSIONS: Our experience shows that MTBs can yield valuable clinical benefit. Higher actionability ESCAT level appears to be associated with better outcomes for patients receiving MMT.

Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies.

Cancers are composed of transformed cells, characterized by aberrant growth and invasiveness, in close relationship with non-transformed healthy cells and stromal tissue. The latter two comprise the so-called tumor microenvironment (TME), which plays a key role in tumorigenesis, cancer progression, metastatic seeding, and therapy resistance. In these regards, cancer-TME interactions are complex and dynamic, with malignant cells actively imposing an immune-suppressive and tumor-promoting state on surrounding, non-transformed, cells. Immune cells (both lymphoid and myeloid) can be recruited from the circulation and/or bone marrow by means of chemotactic signals, and their functionality is hijacked upon arrival at tumor sites. Molecular characterization of tumor-TME interactions led to the introduction of novel anti-cancer therapies targeting specific components of the TME, such as immune checkpoint blockers (ICB) (i.e., anti-programmed death 1, anti-PD1; anti-Cytotoxic T-Lymphocyte Antigen 4, anti-CTLA4). However, ICB resistance often develops and, despite the introduction of newer technologies able to study the TME at the single-cell level, a detailed understanding of all tumor-TME connections is still largely lacking. In this work, we highlight the main cellular and extracellular components of the TME, discuss their dynamics and functionality, and provide an outlook on the most relevant clinical data obtained with novel TME-targeting agents, with a focus on T lymphocytes, macrophages, and cancer-associated fibroblasts.

The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046.

TPX-0046 is designed to overcome resistance to FDA approved RET inhibitors Selpercatinib and Pralsetinib. Early prediction of resistance mechanisms to investigational drugs may facilitate subsequent drug and trial designs. This study aims to predict potential mutations inducing resistance to TPX-0046. We conducted an in-silico analysis of TPX-0046 macrocyclic structure and predicted the binding mode on RET. We used as reference literary examples of resistance mechanisms to other macrocyclic inhibitors (Lorlatinib on ALK/ROS1) to construct RET secondary resistance mutations. We conducted docking simulations to evaluate impact of mutations on TPX-0046 binding. TPX-0046 binding mode on RET appears to not be influenced by Solventfront G810X mutation presence. Bulky Gatekeeper V804X mutations affect predicted TPX-0046 binding mode. Mutations in Beta 7 strand region L881F and xDFG S891L impair TPX-0046 docking. Our findings suggest that development of second generation RET inhibitors focused mainly on Solventfront G810X mutations granting resistance to selective RET inhibitors Selpercatinib and Pralsetinib. If these findings are confirmed by identification of Gatekeeper V804X mutations in patients progressing to TPX-0046, explanation of acquired resistance and loss of benefit will be easier These findings might accelerate development of third generation RET inhibitors, as well as clinical trial design in precision oncology settings.

Safety of COVID-19 mRNA Vaccines in Patients with Cancer Enrolled in Early-Phase Clinical Trials.

Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population. Patients enrolled in early-phase clinical trials receive novel treatments with unknown efficacy and safety profiles. Studies on the safety of COVID-19 vaccines in these patients are urgently required. This is a retrospective, real-world, cohort study of patients receiving anticancer treatments and COVID-19 vaccines between 1 February and 25 June 2021 at the Division of New Drugs Development for Innovative Therapies of the European Institute of Oncology. One hundred thirteen patients were enrolled, 40 in early-phase clinical trials, and 20 under novel immunotherapy agents. Nearly three-quarters of the patients experienced at least one adverse event (AE) after the first dose (1D) (74.3%) and second dose (2D) (72.6%). Most of the AEs were local (67.3% 1D and 61.9% after 2D), while 31.8% (1D) and 38.1% (2D) of the patients had systemic AEs. No AEs above grade 2 were observed. Therefore, COVID-19 vaccines appear to be safe in patients enrolled in early-phase clinical trials, including patients receiving novel immunotherapy compounds. All cancer patients should be prioritized for COVID-19 vaccination, regardless of ongoing treatments or enrollment in early-phase trials.

Selective FGFR/FGF pathway inhibitors: inhibition strategies, clinical activities, resistance mutations, and future directions.

Introduction: Fibroblast growth factor receptor (FGFR)/fibroblast growth factor (FGF) is a pathway characterized by recurring alterations in cancer. Its dysregulations enhance cancer cell proliferation, survival, migration and invasion, as well as angiogenesis and immune evasion.Areas covered: FGFR/FGF selective inhibitors belong to a broad class of drugs with some being approved for specific indications and others under investigation in ongoing phase I and II clinical trials. In this review, all available clinical data from trials on selective FGFR/FGF inhibitors as well as described resistance mutations and mechanisms are presented. FGFR/FGF pathway inhibitors are classified according to the mechanism they employ to dampen/suppress signaling and to the preferred FGFR binding mode when X-ray crystal structure is available.Expert opinion: Data presented suggests the general actionability of FGFR1,2,3 mutations and fusions across histologies, whereas FGFR1,2,3 amplifications alone are poor predictors of response to tyrosine kinase inhibitors. Overexpression on immunohistochemistry (IHC) of FGF19, the stimulatory ligand of FGFR4, can predict response to FGFR selective inhibitors in hepatocellular carcinoma. Whereas IHC overexpression of FGFR1,2,3 is not sufficient to predict benefit from FGFR inhibitors across solid tumors. FGFR1,2,3 mRNA overexpression can predict response even in absence of structural alteration. Data on resistance mutations suggests the need for new inhibitors to overcome gatekeeper mutations.

Prognostic impact of early tumor shrinkage and depth of response in patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the new standard of care in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Since tumor response dynamic parameters already shown a strong association with survival outcomes in patients with mCRC treated with first-line therapy, we investigated the association of early tumor shrinkage (ETS) and depth of response (DoR) in patients with MSI-H/dMMR mCRC treated with ICIs. METHODS: This is a retrospective, multicenter, cohort study in patients with dMMR and/or MSI-high mCRC treated with ICIs (anti-PD-1/PD-L1 with or without anti-CTLA-4 agents) with measurable disease and at least one post-baseline radiological disease reassessment. The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. A maximally selected statistics method in a Cox regression model for progression-free survival (PFS) was used to determine the optimal cut-offs for ETS and DoR. RESULTS: We included a total of 169 patients: 116 (68.6%) were treated with anti-PD-1 monotherapy, whereas 53 (31.4%) with anti-PD-1 plus anti-CTLA-4 agents. Patients with primary progressive disease (N=37, 21.9%), experienced an extremely poor overall survival (OS) and were evaluated separately. In patients with clinical benefit, we observed a significant association between ETS and DoR with both OS and PFS, and we identified a relative reduction of at least 1% as the optimal cut-off for ETS and a relative reduction of at least 50% as the optimal cut-off for DoR. CONCLUSIONS: ETS and DoR are important prognostic factors in patients with MSI-high mCRC treated with ICIs that might be useful to design treatment intensification/deintensification strategies. A prospective validation of both is warranted.

The Pan-Immune-Inflammation Value in microsatellite instability-high metastatic colorectal cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) yielded unprecedented efficacy in patients with microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). Since the Pan-Immune-Inflammation Value (PIV) is a blood-based biomarker with prognostic usefulness in mCRC, it might predict clinical outcomes and primary resistance to ICIs. METHODS: We retrospectively analysed the association of PIV and its early modulation at 3/4 weeks after treatment initiation with the outcomes of MSI-high mCRC patients receiving anti-programmed death-(ligand)1 (PD-[L]1) +/- anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. PIV cut-offs were determined using the maximally selected rank statistics. RESULTS: A total of 163 patients were included. In the multivariable models for overall survival (OS) and progression-free survival (PFS), both high (>492) baseline PIV (OS: adjusted [a] HR, 3.00; 95% CI, 1.49-6.04, p = 0.002; PFS: aHR, 1.91; 95% CI, 1.06-3.44, p = 0.031) and early PIV increase ≥+30% (OS: aHR, 3.21; 95% CI, 1.65-6.23, p < 0.001; PFS: aHR, 2.25; 95% CI, 1.30-3.89, p = 0.003) confirmed an independent prognostic impact. After stratifying patients according to baseline PIV and ICI regimen, OS and PFS were significantly worse in subjects with high PIV receiving anti-PD-1/PD-L1 monotherapy. Early PIV increase was an independent predictor of clinical benefit (aOR, 0.23; 95% CI, 0.08-0.66; p = 0.007), whereas a trend was observed for baseline PIV (aOR, 0.33; 95% CI, 0.10-1.07; p = 0.065). CONCLUSION: PIV is a strong predictor of outcomes in MSI-high mCRC patients receiving ICIs. Prospective validation of these results is required to establish its role as a stratification factor for personalised combination strategies.