While pirtobrutinib works after covalent BTK inhibitors, no data shows covalent inhibitors work after pirtobrutinib failure. This uncertainty about future options makes clinicians cautious about using it as an initial therapy, especially for younger CLL patients who will need multiple treatments over their lifetime.

Non-covalent BTK inhibitors like pirtobrutinib are currently approved for use after covalent BTK inhibitors fail. Moving them to the frontline setting, as studied in BRUIN-313, disrupts the established treatment pathway and creates uncertainty for managing relapsed disease, as the standard 'next step' is removed.

Pirtobrutinib is the first BTK inhibitor to show a rate of atrial fibrillation equivalent to a chemoimmunotherapy control arm in a randomized trial. This uniquely safe cardiovascular profile makes it a strong first-line candidate for older Chronic Lymphocytic Leukemia (CLL) patients or those with significant heart-related comorbidities.

Developers often test novel agents in late-line settings because the control arm is weaker, increasing the statistical chance of success. However, this strategy may doom effective immunotherapies by testing them in biologically hostile, resistant tumors, masking their true potential.

The BRUIN-313 trial successfully compared pirtobrutinib to bendamustine-rituximab (BR). However, BR is no longer the frontline standard of care. This 'straw man' comparator makes it difficult to position pirtobrutinib against current preferred treatments like other BTK inhibitors or venetoclax regimens, limiting immediate clinical applicability.

Despite strong single-agent trial results, experts believe the field is shifting away from continuous monotherapy. The most significant future impact for pirtobrutinib will likely be as a backbone of fixed-duration combination therapies with drugs like venetoclax, aiming for deeper remissions without indefinite treatment.

Even with positive results from two registrational Phase 3 trials, experts note a potential regulatory hurdle. The FDA has shown increasing concern over studies with a low proportion of patients from North America, a characteristic of these trials, potentially complicating an otherwise strong case for approval based on clinical merit.

The ongoing Phase III trial for Sigvotatug Vedotin compares it against docetaxel, the current standard for second-line NSCLC. Docetaxel is known for modest efficacy and significant side effects, creating a major opportunity for the new drug to demonstrate superiority and rapidly become the new clinical standard.

Clinicians are hesitant to use newer, potentially safer non-covalent BTK inhibitors before established covalent inhibitors. While it's known that non-covalents work after covalents fail, the reverse is unproven, creating a one-way treatment path that reserves these newer agents for later lines of therapy.