The phase 2 SKIPPirr trial (NCT05663866) has demonstrated the effectiveness of prophylactic dexamethasone in reducing immune-related reactions (IRRs) in patients with non-small cell lung cancer (NSCLC) treated with amivantamab and lazertinib. The trial explored four different prophylactic strategies, with dexamethasone at 8 mg showing the most promise by reducing the IRR rate from 67.4% to 22.5%.
SKIPPirr Trial Results
The SKIPPirr study evaluated dexamethasone at 4 mg and 8 mg, montelukast at 10 mg, and methotrexate at 25 mg as prophylactic measures. Only dexamethasone at 8 mg successfully passed both stages of the Simon's 2-stage design and proceeded to the expansion stage, enrolling 24 additional patients. This regimen involved administering dexamethasone 8 mg twice daily for two days before and one day before amivantamab infusion.
Konstantinos Leventakos, MD, PhD, from the Mayo Clinic, highlighted the significance of these findings, noting the critical role of pharmacists in managing the complex dosing regimens. The results suggest that proactive measures can significantly improve the tolerability of amivantamab-based treatments.
PALOMA-3 Trial and Subcutaneous Amivantamab
The phase 3 PALOMA-3 trial (NCT05388669) compared subcutaneous amivantamab plus lazertinib with intravenous (IV) amivantamab. Results indicated that subcutaneous administration led to a lower IRR rate (13% vs. 66%) and showed non-inferior progression-free survival (PFS) and overall survival (OS). The subcutaneous regimen involved 1600 mg weekly for four weeks, then every two weeks.
The trial met its co-primary endpoints of pharmacokinetics at a median follow-up of 7 months. These findings suggest that subcutaneous amivantamab could offer a more convenient and better-tolerated alternative to IV administration.
COCOON Trial and Dermatologic Management
Recognizing the broader spectrum of toxicities associated with amivantamab, the phase 2 COCOON trial (NCT06120140) is investigating enhanced dermatologic management strategies in patients receiving first-line amivantamab plus lazertinib. This trial addresses the dermatologic adverse events beyond IRRs, aiming to improve overall patient experience and treatment adherence.
Expert Perspectives on Proactive Management
Experts at the Mayo Clinic emphasized the importance of a multidisciplinary approach to managing amivantamab-related toxicities. Mohammed Shanshal, MB, BCh, MD, highlighted the need to minimize allergic adverse events and immediate toxicities to facilitate dose escalation and improve patient compliance, potentially leading to better PFS and OS.
Tassos Dimou, MD, stressed that supportive care, including antibiotics, creams, and shampoos, remains crucial despite advancements in IRR management. He also pointed out the time toxicity for both patients and the care team, underscoring the need for efficient and easy-to-implement strategies.
Dr. Leventakos noted the importance of having a dedicated thoracic oncology pharmacist to navigate the complexities of these regimens, particularly in trials like COCOON and SKIPPirr. He also raised the question of how these data might influence the sequencing of therapies, particularly in the first-line setting.
Kaushal Parikh, MD, questioned whether single-agent osimertinib could still play a role in frontline treatment for select patients, suggesting further investigation into ctDNA monitoring to potentially spare some patients from more intensive therapies.
