Daraxonrasib

Based on findings in animals, daraxonrasib can cause fetal harm when administered to pregnant women. There are no available data on daraxonrasib use in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of daraxonrasib to pregnant female mice during the period of organogenesis resulted in adverse developmental outcomes including mortality, alterations to growth, and structural abnormalities at exposures ≥2.5 times the recommended dose based on AUC. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no data on the presence of daraxonrasib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with daraxonrasib and for 1 week after the last dose.

Carcinogenesis

Carcinogenesis studies have not been conducted with daraxonrasib.

Mutagenesis

Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.

Impairment of Fertility

No fertility studies have been conducted with daraxonrasib. In general toxicology studies in mice and monkeys, there were no remarkable findings in male or female reproductive organs.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population of daraxonrasib described in the WARNINGS AND PRECAUTIONS section reflects exposure to daraxonrasib 300 mg once daily in 241 patients with pancreatic adenocarcinoma enrolled in RASolute 302 and 184 patients with pancreatic adenocarcinoma enrolled in the open-label trial RMC-6236-001.

Metastatic Pancreatic Adenocarcinoma

The safety of daraxonrasib was evaluated in RASolute 302. Patients with metastatic pancreatic adenocarcinoma received either daraxonrasib 300 mg once daily (N=241) or physician's choice of standard of care (SOC) chemotherapy regimens (N=214). Among patients who received daraxonrasib, 52% were exposed for 6 months or longer and 2% were exposed for greater than one year.

Serious adverse reactions occurred in 30% of patients treated with daraxonrasib. Serious adverse reactions occurring in ≥2% of patients treated with daraxonrasib were diarrhea (3.7%), pyrexia (3.3%), sepsis (2.9%), fatigue (2.1%), and hemorrhage (2.1%).

Adverse reactions leading to permanent discontinuation of daraxonrasib occurred in 2.9% of patients, including two patients who discontinued due to rash (0.8%).

Adverse reactions leading to dose interruptions occurred in 69% of patients who received daraxonrasib. Adverse reactions which required dose interruptions in ≥5% of patients were rash (27%), stomatitis (20%), fatigue (9%), diarrhea (8%), vomiting (8%), nausea (7%), and pyrexia (6%).

Adverse reactions leading to dose reductions occurred in 37% of patients who received daraxonrasib. Adverse reactions which required dose reductions in ≥5% of patients were rash (18%), stomatitis (8%), and diarrhea (5%).

The most common (≥20%) adverse reactions in patients treated with daraxonrasib were rash, diarrhea, stomatitis, nausea, fatigue, vomiting, abdominal pain, edema, decreased appetite, and hemorrhage.

Table 1 and Table 2 summarize adverse reactions and laboratory abnormalities in RASolute 302, respectively.

Table 1. Adverse Reactions (≥10%) in Patients Who Received Daraxonrasib in RASolute 302:

^* Graded per NCI CTCAE Version 5.0.
^† Chemotherapy: mFOLFIRINOX, gemcitabine and nab-paclitaxel, FOLFOX, or nal-IRI+5-FU/LV.
^‡ Includes multiple related terms.

Other clinically important adverse reactions occurring in less than 10% of patients who received daraxonrasib in RASolute 302 included renal-limited thrombotic microangiopathy (0.4%).

Table 2. Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received Daraxonrasib in RASolute 302*:

^* The denominator used to calculate the percentage varied from 234 to 237 in the daraxonrasib arm and from 207 to 208 in the SOC chemotherapy arm, based on the number of patients with a baseline value and at least one post-baseline value.
^† Graded per NCI CTCAE Version 5.0.