agerafenib (RXDX-105) / Roche, Daiichi Sankyo - LARVOL DELTA

TA0953/HM06, a Novel RET-specific Inhibitor Effective in Extracranial and CNS Disease Models of NSCLC with RETfusions (IASLC-WCLC 2022) - P1/2 | " TAS0953/HM06 was more effective than RET multi-kinase inhibitors (cabozantinib, RXDX105, vandetanib), and equipotent to selpercatinib and pralsetinib, at inhibiting growth of patient-derived (8) and isogenic (2) cell lines harboring different RET fusions (IC50<0.1µM)... Our data show that TAS0953/HM06 is effective at inhibiting growth in vitro and in vivo of preclinical models driven by RET fusions. TAS0953/HM06 was more effective than selpercatinib at decreasing CNS disease and extending survival, at a dose that produced comparable suppression of tumor growth in extracranial disease models. TAS0953/HM06 represents a promising new therapeutic option for patients with RET fusions including those with brain metastasis and those resistant to first-generation selective RET inhibitors."

CNS Disorders • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CCND1 • RET

RET rearrangements define a new and rare molecular subtype of metastatic colorectal cancer (mCRC) (ESMO-GI 2017) - P1; "A patient receiving FOLFOX-panitumumab experienced disease progression as best response, while treatments with unselective RET inhibitors such regorafenib or sunitinib achieved short-lasting clinical benefit. RET rearrangements define a new and rare molecular subtype of mCRCs associated with unfavorable prognosis, and specific clinicopathological and molecular features. Except for lack of significant association with right sidedness, the present findings in RET rearranged mCRC resemble those previously reported for ALK, ROS1 and NTRK positive cases. Since sensitivity to available treatment options, including anti-EGFRs, may be very limited, targeted approaches with RET specific inhibitors such as RXDX-105 should be a priority for future research."

Colorectal Cancer

A Phase 1b study of RXDX-105, a VEGFR-sparing potent RET inhibitor, in RETi-naïve patients with RET fusion-positive NSCLC (ESMO 2017) - P1; "RXDX-105 has demonstrated antitumor activity across multiple fusion partners in RET-positive NSCLC pts with a manageable safety profile. However, responses were not observed in pts whose tumors harbored a KIF5B-RET fusion, consistent with previous evidence with other agents, suggesting that this RET fusion may be less susceptible to RET inhibition."

Clinical • Late-breaking abstract • P1 data • Hematological Malignancies • Non Small Cell Lung Cancer

Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy. (PubMed, J Thorac Oncol) - "Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy."

Journal • Endocrine Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma

Chylothorax and chylous ascites during RET tyrosine kinase inhibitor therapy. (ASCO 2022) - " A pan-cancer cohort of 7517 pts treated with at least 1 of 17 MKIs and selective RET TKIs and an independent cohort of 96 pts treated with the selective RET TKIs, selpercatinib or pralsetinib, were identified. Across cohorts, chylous effusions were identified in 22 pts and were most common with selpercatinib (7%; 15/217), followed by the MKIs agerafenib (4%; 1/24), cabozantinib (0.3%; 3/918), and lenvatinib (0.3%; 3/1185)... Chylous effusions can emerge on treatment with certain MKIs or selective RET TKIs. Recognition of this potential side effect is key to prevent misattribution of worsening effusions to progressive malignancy and to motivate a better understanding of its biology and management."

Endocrine Cancer • Genito-urinary Cancer • Lung Adenocarcinoma • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Soft Tissue Sarcoma • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

"RET inhibition with RXDX-105 resulted in responses only in non–KIF5B–RET-containing cancers, no wonder it was discontinued.." (@RenoHemonc)

Oncology • KIF5B

[VIRTUAL] Hypersensitivity reactions (HR) to selpercatinib in RET fusion+ non-small cell lung cancer (NSCLC) patients (pts) following immune checkpoint inhibition (CPI) (ESMO 2020) - P1/2 | "Background Selpercatinib (LOXO-292), a highly selective and potent RET inhibitor, has significant antitumor activity with a favorable safety profile in pts with advanced RET-altered tumors, regardless of prior treatment (tx). Immune-related toxicities have been reported with vemurafenib, crizotinib, osimertinib, and RXDX-105 for prior CPI-treated pts...Funding: Eli Lilly and Company, Loxo Oncology at Lilly. Clinical trial identification: NCT03157128."

Checkpoint inhibition • Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

RET inhibition in novel patient-derived models of RET-fusion positive lung adenocarcinoma reveals a role for MYC upregulation. (PubMed, Dis Model Mech) - "Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105...Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies."

Clinical • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CCDC6 • KIF5B • RET

Novel KIF5B-RET+ NSCLC cell lines demonstrate differential responses to RET inhibitors (AACR 2018) - "MTS proliferation assays have revealed that the CUTO22 cell line is very sensitive to the highly specific RET inhibitor, CEP-32496/RXDX-105, and the multi-kinase inhibitor ponatinib. Both the Kif5b-Ret+ and Trim24-Ret+ Ba/F3 cell lines are highly sensitive to multiple RET inhibitors. In conclusion, these data suggest that RET inhibitors successfully inhibit the target protein, but not downstream signaling, suggesting that KIF5B-RET may have unique co-alterations or reliance on alternative pathways to promote growth and proliferation."

Preclinical • Non Small Cell Lung Cancer

Continued Access to RXDX-105 (clinicaltrials.gov) - P1; N=3; Completed; Sponsor: Memorial Sloan Kettering Cancer Center; Active, not recruiting ➔ Completed

Clinical • Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRAF

Ignyta: ENA 2016 (Ignyta) - "5 out of 9 RET inhibitor-naïve patients with RET fusion-positive tumors have a RECIST response, 4 confirmed (1 CR, 3 PR) and 1 unconfirmed response (uPR), for a preliminary ORR of 56%"

P1 data • Oncology

RXDX-105: Anticipated expiry of patent in US related to composition-of-matter in 2030 (Ignyta) - Annual Report 2016

Patent expiry • Oncology

RXDX-105: "Of these, 8 patients harbored RET fusions partners other than KIF5B: CCDC6, EML4, and PARD3" (Ignyta) - ESMO 2017: "ORR of 75% (95% CI: 34.9% - 96.8%) in patients with non-KIF5B-RET fusions"; "Additionally, 1 patient had SD for ~6 cycles"; "Median DOR has not been reached, with the longest DOR at 10.2 months"

P1 data • Non Small Cell Lung Cancer • Oncology

Ignyta: Jefferies Healthcare Conference 2016 (Ignyta) - Anticipated interim data from P1b “basket study” (NCT01877811) for advanced solid tumors in Q4 2016

Anticipated P1 data • Oncology

Ambit Biosciences and Teva announce clearance of an Investigational New Drug (IND) application for CEP-32496, a novel BRAF(V600E) inhibitor (Ambit Biosciences) - Ambit Biosciences & Teva Pharmaceutical Industries Limited announced the clearance of an IND with the FDA for CEP-32496, a novel BRAF (V600E) kinase inhibitor

IND approval • Oncology

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105. (PubMed, Cancer Discov) - "Interestingly, the ORR varied significantly by the gene fusion partner (p<0.001, Fisher's exact test): 0% (95% CI 0% - 17%, n=0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI 30% - 93%, n=6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range 5 to 18+ months)."

Journal • P1 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • Thoracic Cancer

Ignyta: J.P. Morgan Healthcare Conference (35th Annual J.P. Morgan Healthcare Conference, Ignyta) - Anticipated data update from P1b “basket study” (NCT01877811) in solid tumors in H2 2017

Anticipated P1 data • Oncology

Ignyta: J.P. Morgan Healthcare Conference (35th Annual J.P. Morgan Healthcare Conference, Ignyta) - Anticipated data update from P1b “basket study” (NCT01877811) in solid tumors in H2 2017

Anticipated P1 data • Oncology

Ignyta: Jefferies Healthcare Conference 2016 (Ignyta) - "RXDX-105 Exposure Has Reached Levels Expected To Be Efficacious in RET and BRAF Driven Tumors"; "RXDX-105 Preliminary Anti-Tumor Activity"; "Treatment-Emergent Adverse Events in All Phase 1 Patients: Generally well-tolerated. All AEs reversible with dose reduction or holiday, No treatment-related AEs ≥ Grade 4"

P1 data • Oncology

Ignyta announces selection of recommended phase 2 dose and initiation of phase 1b Basket trial of RXDX-105 (Businesswire) - "Ignyta...announced the selection of a recommended Phase 2 dose (RP2D) and initiation of the Phase 1b portion of its Phase 1/1b clinical trial of RXDX-105, the company’s orally available, small molecule multikinase inhibitor with potent activity against such targets as RET and BRAF. The Phase 1b portion of the study utilizes a basket design focusing on patients with solid tumors that contain molecular alterations of RET or BRAF."

New P1 trial • Oncology

Small molecule inhibitor agerafenib effectively suppresses neuroblastoma tumor growth in mouse models via inhibiting ERK MAPK signaling. (PubMed, Cancer Lett) - "More importantly, agerafenib exhibited a favorable toxicity profile, potently suppressed tumor growth, and prolonged survival in NB mouse models. In conclusion, our preclinical data suggest that agerafenib might be an effective therapeutic agent for NB treatment, both as a single-agent and in combination with chemotherapy."

Journal • Preclinical

RXDX105 (IASLC-LCTT 2020) - No abstract available

Study of RXDX-105, Potent RET Inhibitor in Patients With Advanced Lung Cancer and Other Solid Tumors (clinicaltrials.gov) - P1; N=143; Completed; Sponsor: Ignyta, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Jun 2019 ➔ Feb 2019

Clinical • Trial completion • Trial completion date

Continued Access to RXDX-105 (clinicaltrials.gov) - P1; N=3; Active, not recruiting; Sponsor: Memorial Sloan Kettering Cancer Center; Recruiting ➔ Active, not recruiting; Trial completion date: Dec 2019 ➔ Dec 2020; Trial primary completion date: Dec 2019 ➔ Dec 2020

Clinical • Enrollment closed • Trial completion date • Trial primary completion date

RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. (PubMed, Ann Oncol) - P1; "RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc...In the multivariable model, RET rearrangements were still associated with shorter OS [HR: 2.97; 95% CI, 1.25-7.07; P=0.014], while primary tumor location, RAS and BRAF mutations and MSI status were not. Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management."

Journal • MSi-H Biomarker