BACKGROUND
Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed.


METHODS
In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy.


RESULTS
A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions.


CONCLUSIONS
The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.).

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions.

Abstract Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with &amp;gt;70-fold selecti­vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non–small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. Significance: PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293 

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer

Histone methyltransferases (HMTs) play a critical role in gene post-translational regulation and diverse physiological processes, and are implicated in a plethora of human diseases, especially cancer. Increasing evidences demonstrate that HMTs may serve as a potential therapeutic target for cancer treatment. Thus, the development of HMTs inhibitor have been pursued with steadily increasing interest over the past decade. However, the disadvantages such as insufficient clinical efficacy, moderate selectivity, and propensity for acquired resistance have hindered the development of conventional HMT inhibitors. New technologies and methods are imperative to enhance the anticancer activity of HMT inhibitors. In this review, we first review the structure and biological functions of the several essential HMTs, such as EZH2, G9a, PRMT5, and DOT1L. The internal relationship between these HMTs and cancer is also expounded. Next, we mainly focus on the latest progress in the development of HMT modulators encompassing dual-target inhibitors, targeted protein degraders and covalent inhibitors from perspectives such as rational design, pharmacodynamics, pharmacokinetics, and clinical status. Lastly, we also discuss the challenges and future directions for HMT-based drug discovery for cancer therapy. 

Small molecules targeting selected histone methyltransferases (HMTs) for cancer treatment: Current progress and novel strategies

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed. 

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes

Simple Summary Medulloblastoma is the most prevalent intracerebellar pediatric brain tumor, accounting for approximately 20% of all childhood brain tumors and over 60% of embryonal brain tumors. MYC-driven medulloblastoma has extreme metastatic potential and is often resistant to multipronged treatment. PRMT5 plays a key role in cell functions and processes in MYC-driven medulloblastoma by stabilizing the MYC protein. RMT5 inhibitors can potentially disrupt MYC’s function, impeding tumor progression and offering a target therapeutic approach to treat MYC-amplified medulloblastoma. Here, we highlight the challenges that must be addressed in future drug development. Abstract MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such as glioblastoma and medulloblastoma. PRMT5 regulates oncogenes, including MYC, that are often deregulated in medulloblastomas. However, the role of PRMT5-mediated post-translational modification in the stabilization of these oncoproteins remains poorly understood. The potential impact of PRMT5 inhibition on MYC makes it an attractive target in various cancers. PRMT5 inhibitors are a promising class of anti-cancer drugs demonstrating preclinical and preliminary clinical efficacies. Here, we review the publicly available preclinical and clinical studies on PRMT5 targeting using small molecule inhibitors and discuss the prospects of using them in medulloblastoma therapy.

PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma

Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Abstract Purpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Patients and Methods: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Results: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. Conclusions: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development. 

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

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Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.