A critical reason patients stop ADC treatments is the burden of side effects like skin toxicity or GI issues, not just disease progression. This underscores the urgent need to develop ADCs with better safety profiles, enabling patients to stay on effective therapy longer.

When using the AKT inhibitor capivasertib, preventing rash is more effective than treating it. A recommended strategy for physicians unfamiliar with the drug is to prescribe twice-daily non-drowsy antihistamines proactively for the first 6-8 weeks, as the rash is difficult to manage once it appears.

The distinct side effect profiles of pan-RAS inhibitors (rash, mucositis) and G12D-specific inhibitors (GI issues) are driving separate clinical strategies. The G12D drugs' better combinability with chemotherapy contrasts with pan-RAS agents, which may be better suited for monotherapy due to toxicity from blocking normal RAS.

Long-term data from the DEFI trial shows continuing niragasestat beyond one year increases overall response rates from 34% to 46%. Counterintuitively, the incidence and severity of common side effects like diarrhea and nausea tend to diminish after the first year of treatment.

The Phase 2 TRAIT study suggests starting adjuvant abemaciclib at a lower dose and escalating over several weeks significantly reduces early discontinuations due to side effects like diarrhea. This strategy helps more patients get through the initial high-toxicity period and remain on the effective dose for the full two-year course.

The side effect profile of capivasertib is front-loaded. Key toxicities like diarrhea and rash appear quickly, leading to the majority (63%) of drug discontinuations occurring within the first three months. This highlights a critical window for proactive management and patient education to improve adherence.

Data from the SOLAR-1 trial showed that adding prophylactic antihistamines for patients taking alpelisib cut the incidence of all-grade rash in half and reduced high-grade rash by 40%. This has become a standard practice for mitigating dermatologic toxicity with this class of drugs.

The TRAIL trial found starting abemaciclib at a low dose (50mg) and escalating every two weeks drastically improves tolerability. This approach reduced Grade 3 diarrhea from 7.8% in the pivotal trial to just 3.3% and lowered early discontinuation rates, allowing more patients to reach the full therapeutic dose and stay on treatment.

Real-world use of capivaseratib reveals more challenging rash and diarrhea than trial data may suggest. The speaker recommends proactive management with non-sedating antihistamines starting the day *before* therapy and prophylactic loperamide. This strategy, combined with dose reductions that don't compromise PFS, is key for patient tolerance.