Hello, and thank you for joining me today. As we all know, one of the most important developments in solid tumor oncology and perhaps ever in pancreatic cancer is the approval of daraxonrasib, a Pan-RAS inhibitor for patients with metastatic pancreatic cancer. There's been much talk and a lot of focus about RAS inhibitors and their mechanism of action, but today we're going to focus on understanding and managing the dermatologic side effects associated with this therapy.

From a GI oncology APP standpoint, we can learn from our experience with panitumumab-associated skin toxicities in the STEP trial, utilizing prophylactic sunscreen, moisturizer, antibiotics, and topical steroids. Although these drugs act differently in the rash signaling pathway, disruption of this pathway in normal skin can contribute to similar dermatologic side effects.

With daraxonrasib, dermatologic toxicity occurred in 86% of patients in the initial clinical trials, 10% experiencing grade three toxicity. Manifestations of the dermatologic toxicities include rash, itching, dry skin, skin fissuring and ulceration, and paronychia. Median time to onset for these toxicities is pretty quick, usually about 13 days. Rash resulted in dose interruptions in approximately 27% of patients, and dose reductions in 18% of patients, highlighting why prophylactic management is paramount in managing these side effects. Daraxonrasib prophylaxis includes using sunscreen of at least an SPF of 30 daily and educating patients to avoid prolonged direct sun exposure. Patients should also be educated to use a daily fragrance-free cleanser and moisturizing cream. They should avoid using harsh skin cleansers or acne products.

Prophylactic antibiotics, similar to what we do with panitumumab prophylaxis, includes using doxycycline 100 milligrams BID, or minocycline 50 milligrams BID for at least the first eight weeks. Also included is the recommendation for topical steroids, which are also to be used twice daily, including a low potency steroid to the face such as hydrocortisone 2.5%, and a low to medium potency topical steroid to the trunk such as triamcinolone 0.1%. There are additional topical steroids to consider if the scalp is involved such as betamethasone dipropionate 0.05% lotion, or fluocinolone 0.01% oil, and those are also to be used twice daily.

Other adjunctive measures may be needed such as antihistamines for itching, treatment of super and post infection involving any of the pustular lesions, and using thick emollients or petroleum jelly to protect the skin from painful fissures or dryness. When patients do develop the rash despite prophylaxis, daraxonrasib can usually be continued in mild grade one reactions. Grade two skin reactions often require escalation of the topical steroids to a higher potency such as using the triamcinolone that we recommend to the trunk. You can use that to the face for about two weeks. You can add additional antibiotics, and patients might require a brief treatment interruption.

For more severe reactions, daraxonrasib should be held, and on top of previous interventions might also require a brief oral corticosteroid taper in addition to a dermatologic consult. Grade four skin reactions require permanent discontinuation. The key as an oncology APP is to help patients understand that dermatologic reactions should be anticipated and expected on treatment with daraxonrasib, and these should be managed prophylactically rather than waiting for the toxicities to occur and then trying to manage them after the fact. Doing it this way not only helps patients stay on therapy, but minimizes side effects and improves their quality of life.