Comprehensive genome profiling (CGP) is expected to widen the scope of cancer drug options by identifying the genes involved in carcinogenesis. However, a few patients can access recommended treatments following CGP. Herein, we report a case in which pemigatinib, a selective fibroblast growth factor receptor (FGFR) inhibitor, was used as last-line therapy to treat a patient with advanced gastric cancer exhibiting FGFR2 genomic alterations, as determined by CGP testing. The patient (male, 52 years old) was diagnosed with advanced gastric cancer (cStage IV, cT4aN3M1 [LYM], por, HER2 0, microsatellite stable) and received docetaxel + cisplatin + S-1 (7 cycles), irinotecan + ramucirumab (11 cycles), and nivolumab (3 cycles), but experienced progressive disease (PD). Subsequently, FoundationOne Liquid CDx testing was conducted, revealing FGFR2 rearrangement and amplification; however, no clinical trials on genotype-matched therapies for FGFR2 alterations were available. After three cycles of TAS-102, the patient experienced PD and provided consent for the off-label use of pemigatinib. The Cancer Genomics Medical Committee of our hospital approved the self-funded treatment. The patient had markedly decreased CEA and CA19-9 levels after treatment initiation, but experienced PD after five courses. Over the treatment course, grade 1 hyperphosphatemia and onychomadesis were observed. To the best of our knowledge, this is the first reported case of pemigatinib therapy employed in a patient with advanced gastric cancer exhibiting FGFR2 gene alterations. This case could serve as a notable example of tumor-agnostic therapy to broaden treatment options for gastric cancer patients with rare genetic alterations.

Due to the considerable technological progress in molecular and genetic diagnostics as well as increasing insights into the molecular pathogenesis of diseases, there has been a fundamental paradigm shift in the past two decades from a \"one-size-fits-all approach\" to personalized, molecularly informed treatment strategies. Personalized medicine or precision medicine focuses on the genetic, physiological, molecular, and biochemical differences between individuals and considers their effects on the development, prevention, and treatment of diseases. As a pioneer of personalized medicine, the field of oncology is particularly noteworthy, where personalized diagnostics and treatment have led to lasting change in the treatment of cancer patients in recent years. In this article, the significant change towards personalized treatment concepts, especially in the field of personalized oncology, will be discussed and examined in more detail.
UNASSIGNED: Aufgrund des erheblichen technologischen Fortschritts in der molekularen und genetischen Diagnostik sowie zunehmender Erkenntnisse über die molekulare Pathogenese von Krankheiten hat in den letzten zwei Jahrzehnten ein grundlegender Paradigmenwechsel stattgefunden – von einem „One-size-fits-all-Ansatz“ hin zu personalisierten, molekular informierten Therapiestrategien. Die personalisierte Medizin oder Präzisionsmedizin konzentriert sich auf die genetischen, physiologischen, molekularen und biochemischen Unterschiede zwischen Individuen und berücksichtigt deren Auswirkungen auf die Entwicklung, Prävention und Behandlung von Krankheiten. Als Vorreiter der personalisierten Medizin ist v. a. der Bereich der Onkologie zu nennen, wo personalisierte Diagnostik und Therapie die Behandlung von Krebspatient:innen in den letzten Jahren nachhaltig verändert haben. In diesem Artikel wird der signifikante Wandel hin zu personalisierten Therapiekonzepten, insbesondere im Bereich der personalisierten Onkologie, ausführlich diskutiert und näher beleuchtet.

BACKGROUND: Pembrolizumab, an anticancer immunotherapy agent, has received multiple approvals since its first approval by the U.S. Food and Drug Administration (FDA) in 2014. Limited data exist on its real-world use and shifts post tumor-agnostic approval in 2017 for the treatment of patients with any microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) solid tumors. This study analyzes pembrolizumab\'s pre and post-tumor-agnostic approval use among older U.S. adults, revealing its evolving role in oncology practice.
METHODS: Using the Surveillance, Epidemiology and End Results (SEER)-Medicare data (2014-2019), we examined the cancer sites of pembrolizumab recipients before and after tumor-agnostic approval. Cancer sites were classified based on the timing of site-specific approvals (before/after tumor-agnostic approval) or no site-specific approval, and inclusion in MSI-H/dMMR clinical trials.
RESULTS: The total number of pembrolizumab recipients increased from 4221 in the pre-agnostic period to 20 479 in the post-agnostic period. Pembrolizumab was used for a broad range of cancer types, including cancers that had no FDA-approved site-specific indications at the time of use (25.8% in pre- and 24.6% in post-agnostic periods). The proportion of pembrolizumab recipients receiving pembrolizumab for cancers with site-specific approvals before tumor-agnostic approval decreased from 77.3% to 70.8%. The proportion of pembrolizumab recipients receiving pembrolizumab for cancers that gained site-specific approvals following tumor-agnostic approval almost doubled (6.8% to 13.0%). The proportion of pembrolizumab recipients with cancers included in MSI-H/dMMR trials also doubled (12.3% to 25.5%) following tumor-agnostic approval.
CONCLUSIONS: Pembrolizumab use has expanded over time among older adults with cancer, extending beyond those with FDA-approved site-specific indications.

The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

BACKGROUND: An increasing number of trials indicate that treatment outcomes in cancer patients with metastatic disease are improved when targeted treatments are matched with druggable genomic alterations in individual patients (pts). An estimated 30-80% of advanced solid tumors harbor actionable genomic alterations. However, the efficacy of personalized cancer treatment is still scarcely investigated in larger, controlled trials due to the low frequency and heterogenous distribution of druggable alterations among different histologic tumor types. Therefore, the overall effect of targeted cancer treatment on clinical outcomes still needs investigation.
METHODS: ProTarget is a national, non-randomized, multi-drug, open-label, pan-cancer phase 2 trial aiming to investigate the anti-tumor activity and toxicity of currently 13 commercially available, EMA-approved targeted therapies outside the labeled indication for treatment of advanced malignant diseases, harboring specific actionable genomic alterations. The trial involves the Danish National Molecular Tumor Board for confirmation of drug-variant matches. Key inclusion criteria include a) measurable disease (RECIST v.1.1), b) ECOG performance status 0-2, and c) an actionable genomic alteration matching one of the study drugs. Key exclusion criteria include a) cancer type within the EMA-approved label of the selected drug, and b) genomic alterations known to confer drug resistance. Initial drug dose, schedule and dose modifications are according to the EMA-approved label. The primary endpoint is objective response or stable disease at 16 weeks. Pts are assigned to cohorts defined by the selected drug, genomic alteration, and tumor histology type. Cohorts are monitored according to a Simon\'s two-stage-based design. Response is assessed every 8 weeks for the first 24 weeks, then every 12 weeks. The trial is designed similar to the Dutch DRUP and the ASCO TAPUR trials and is a partner in the Nordic Precision Cancer Medicine Trial Network. In ProTarget, serial fresh tumor and liquid biopsies are mandatory and collected for extensive translational research including whole genome sequencing, array analysis, and RNA sequencing.
CONCLUSIONS: The ProTarget trial will identify new predictive biomarkers for targeted treatments and provide new data and essential insights in molecular pathways involved in e.g., resistance mechanisms and thereby potentially evolve and expand the personalized cancer treatment strategy.
METHODS: 16, 09-MAY-2022.
BACKGROUND: ClinicalTrials.gov Identifier: NCT04341181. Secondary Identifying No: ML41742. EudraCT No: 2019-004771-40.

Precision medicine is increasingly important in cancer treatment. Tumor-agnostic therapies are used regardless of tumor entity because they target specific biomarkers in tumors. In Germany, the benefit assessment of oncological pharmaceuticals has traditionally been entity specific. Thus, the assessment of tumor-agnostic therapies leaves stakeholders with various challenges. Our aim was to systematically identify challenges and possible solutions for the benefit assessment of therapies in tumor-agnostic indications using a 2-step sequential qualitative approach.
To identify relevant challenges, we conducted qualitative interviews with different stakeholders who were involved in previous benefit assessments of tumor-agnostic therapies in Germany. To identify possible solutions for these challenges, we systematically searched MEDLINE, Embase, and the websites of European health technology assessment bodies for relevant literature.
We identified 9 categories of challenges of which the following were deemed particularly relevant: the absence of direct comparative studies, challenges regarding the use of basket studies and indirect comparisons, challenges in determining the appropriate comparative therapy in a tumor-agnostic indication, and challenges on the system side. Seven categories of solutions were identified, including an increased use of real-world evidence, making conditional decisions in the context of systematic reassessments, splitting the field of application, and finding (new) ways to design and analyze basket studies.
A range of possible solutions, which can help to meet the identified challenges in Germany, have been found. Future research should investigate the acceptance and feasibility of these solutions.

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis.
METHODS: Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood.
UNASSIGNED: Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs.
BACKGROUND: The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

DNA repair mechanisms are essential for maintaining cellular homeostasis. Malfunction of these repair mechanisms leads to cellular DNA mutations, carcinogenic transformation, and cell death. These same defects also create vulnerabilities that are relatively specific to cancer cells, and which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The targeted therapy based on inhibiting the DNA damage response (DDR) opens a new therapeutic landscape for patients with deficient DDR. Currently there are two DNA repair mechanisms that are used as targets for molecular therapies: Mitsmach Repair (MMR) and Homologous Recombination Repair (HRR). These molecular targets allow for immunotherapy treatments based on \"checkpoint inhibitors\" (ICIs) drugs and \"PARP inhibitor\" (PARPi) drugs in different solid tumors. In this review we will describe the state of the art of this interesting mechanism and explain the options for treatment based on these alterations. Moreover, many clinical trials are currently underway exploring better treatment options for dMMR and HRD patients with different solid tumours.

This study tackles several challenges of evaluating histology-independent treatments using entrectinib as an example. Histology-independent treatments are provided based on genetic marker(s) of tumors, regardless of the tumor type. We evaluated the lifetime cost-effectiveness of testing all patients for NTRK fusions and treating the positive cases with entrectinib compared with no testing and standard of care (SoC) for all patients.
The health economic model consisted of a decision tree reflecting the NTRK testing phase followed by a microsimulation model reflecting treatment with either entrectinib or SoC. Efficacy of entrectinib was based on data from basket trials, whereas historical data from NTRK-negative patients were corrected for the prognostic value of NTRK fusions to model SoC.
\"Testing\" (testing for NTRK fusions, with subsequent entrectinib treatment in NTRK-positive patients and SoC in NTRK-negative patients) had higher per-patient quality-adjusted life-years (QALYs) and costs than \"No testing\" (SoC for all patients), with a difference of 0.0043 and €732, respectively. This corresponded to an incremental cost-effectiveness ratio (ICER) of €169 957/QALY and, using a cost-effectiveness threshold of €80 000/QALY, an incremental net monetary benefit of -€388. When excluding the costs of genetic testing for NTRK fusions, the ICER was reduced to €36 290/QALY and the incremental net monetary benefit increased to €188.
When treatment requires the identification of a genetic marker, the associated costs and effects need to be accounted for. Because of the low prevalence of NTRK fusions, the number needed-to-test to identify patients eligible for entrectinib is large. Excluding the testing phase reduces the ICER substantially.

Alterations in short-repetitive DNA sequences, known as microsatellite instability (MSI), can reflect deficiencies in Mismatch Repair (MMR) system which represents a major player in DNA integrity maintenance. The incidence of MSI-H/dMMR has been shown to be variable depending on the tumor type. Several studies confirmed that dMMR/MSI status, although less frequent than PD-L1 expression, may better predict response to immune-checkpoint inhibitors (ICIs) in patients with solid tumors. In October 2016, the FDA granted pembrolizumab as breakthrough therapy for the treatment of non-CRC, MSI-H/dMMR tumors, providing, for the first time, a tumor-agnostic indication. In the next future, the tissue-agnostic evaluation of MSI-H/dMMR could become the common denominator for the immunotherapy treatment of patients with different advanced solid tumors, in order to select patient subgroups which may benefit from this therapy. In this Review we provided an overview of the main clinical studies describing the association between MSI-H/dMMR tumors and immunotherapy response.