Item 8.01 Other Events
On December 1, 2016,
the Company announced data from its ongoing Phase 1/1b study of RXDX-105, the Companys VEGFR-sparing, potent RET inhibitor at the 2016 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium in Munich, Germany.
As of the November 2016, data cut-off, the findings showed:
Safety
A total of 91 patients with a range of solid
tumors have been treated in the Phase 1/1b clinical trial, with 55 patients treated in the Phase 1 study and 36 patients treated in the Phase 1b study.
RXDX-105 continues to demonstrate a safety profile similar to what has been previously reported: across both studies, the most common treatment-related
adverse events (>10% incidence) were rash (31%), fatigue (22%), diarrhea (20%), nausea (18%), hypophosphatemia (14%), vomiting (14%), muscle spasms (13%), and decreased appetite (10%).
The majority of treatment-related adverse events were Grade 1 or 2, and were reversible with dose modification.
The most common Grade 3 treatment-related adverse events (>5% incidence) were rash (9%), hypophosphatemia (7%), and ALT increase (6%).
One patient experienced a Grade 3 drug reaction with eosinophilia and systemic symptoms, in which the patient recovered with drug discontinuation. One patient
experienced Grade 3 rash complicated by fatal alveolar hemorrhage. No other treatment-related Grade 4 or higher events were observed.
Toxicities commonly
associated with VEGFR inhibition, such as hypertension, hypothyroidism, proteinuria, and neurotoxicity, were rarely observed (<5%).
Efficacy
Of the 36 patients treated in the Phase 1b study, 35 had RET or BRAF molecular alterations.
Nine RET inhibitor-naïve patients (n = 8 in the Phase 1b cohort; n = 1 in the Phase 1 cohort) with RET fusion-positive tumors were treated at a daily
dose of 275 mg or 350 mg in the fed state, and were evaluable for response.
A preliminary ORR of 56% was observed in patients with RET fusion-positive
solid tumors who were RET inhibitor-naïve (five out of nine treated patients had a RECIST response).
1
Of the five patients demonstrating a RECIST response, one patient with metastatic colorectal cancer (mCRC)
achieved a complete response; three patients, all with non-small cell lung cancer (NSCLC), achieved a partial response; and one patient with NSCLC had an unconfirmed partial response.
Among the seven patients with RET fusion-positive NSCLC who were RET inhibitor-naïve, three achieved a partial response and one achieved an unconfirmed
response (a second scan had not been obtained at the date of data cutoff), for a preliminary ORR of 57%.
Duration of response to RXDX-105 ranged from 2+
to 7+ months, with all responder patients currently continuing on treatment in active response; median duration of response, therefore, has not yet been determined.
Additionally, a previously disclosed Phase 1 patient with RET-mutated M918T medullary thyroid cancer had a confirmed partial response and continues on
treatment after ten cycles.
These data confirm that RXDX-105 is active across a range of different histologies, with confirmed RECIST responses now
observed in medullary thyroid cancer, NSCLC, and mCRC, and across a range of RET molecular alterations, including the M918T point mutation, and CCDC6-, EML4-, and PARD3-RET fusions.
Among the remaining patients treated in Phase 1b who were either RET fusion-positive and received prior RET inhibitor treatments (n = 4) or had BRAF molecular
alterations (n = 23), durable disease control but no objective responses have been observed to date.