The Leclaza-Rybrevant combination therapy has emerged as the new standard of care for lung cancer treatment and is now being actively implemented in South Korea's clinical settings.

As results indicate improvements in progression-free survival (PFS) as well as overall survival (OS) compared to Tagrisso (osimertinib, AstraZeneca), Janssen has initiated patient programs at major hospitals.

Then, can this globally emerging standard option be rapidly integrated into clinical settings? Analysis suggests the key factors for successful adoption are effective side effect management and the resolution of cost barriers.

According to industry sources on March 31, the MARIPOSA Phase 3 study results presented at the European Lung Cancer Congress (ELCC 2025) in Paris have established combination therapy as a global standard.

The study demonstrated that, compared to Tagrisso monotherapy, the combination therapy extended OS by more than one year, offering outstanding clinical benefits. Attention is shifting to how quickly this combination therapy can be adopted in clinical settings.

In addition, the interim analysis of the 'Cocoon' clinical trial, also presented at ELCC 2025, deserves particular attention, as it may provide solutions to typical side effects associated with combination therapies, such as skin rash and periungual inflammation.

The Cocoon study was designed for 200 patients with treatment-naïve metastatic non–small cell lung cancer (NSCLC) with EGFR mutations. In the interim analysis, 138 patients were included, with participants divided into a standard-of-care (SOC) group and a prophylactic management group, both receiving the combination therapy.

The study's prophylactic group designated to receive 'Cocoon therapy' received a comprehensive prevention strategy including ▲Oral administration of doxycycline or minocycline at 100 mg for weeks 1 to 12 ▲Application of a clindamycin lotion to the scalp from weeks 13 to 52 ▲Chlorhexidine cleansing of the nails ▲Use of ceramide-based moisturizers on the body and face. The SOC (standard-of-care) group was managed reactively with ltreatments, such as topical steroids or antibiotics, as needed based on local clinical practices.

The primary endpoint was the incidence of Grade ≥ 2 skin adverse events within 12 weeks after treatment initiation. At the interim analysis, over 70% of all patients had completed the 12‑week assessment. In the prophylactic 'Cocoon therapy' group, the incidence of Grade ≥ 2 skin adverse events was 38.6%, more than half that observed in the SOC group (76.5%).

As a result, only 21% of patients in the prophylactic group required a dosage reduction of the combination therapy due to side effects, compared to SOC group (31%). Similarly, treatment discontinuation due to adverse events occurred in only 11% of patients in the prophylactic group versus 19% in the SOC group.

Notably, for skin-related adverse events, only 7% of patients in the prophylactic group needed to reduce the dosage of Leclaza or Rybrevant compared to 19% in the SOC group, with discontinuation rates of 1% versus 4%, respectively.

Patients who discontinued treatment due to adverse reactions were 11% versus 19%, which was nearly half.

Overall, the study results demonstrate that the Cocoon therapy offers an effective solution for managing the skin-related side effects that have long been a significant concern with the combination therapy. Analysis suggests that it could potentially improve treatment continuity.

Professor Byoung Chul Cho, Director of the Lung Cancer Center at Yonsei Cancer Hospital, said, "With the overall survival results for the combination therapy presented at ELCC 2025, there is a common view among experts that this therapy could be selected as the preferred therapy in the NCCN guidelines given its significant clinical benefit. Given these impressive clinical outcomes, the drug must manage the side effects effectively."

"The Cocoon study has provided a viable approach for managing skin rashes," Professor Cho added, "In clinical practice when a combination therapy improves survival by one year over the current standard of care, we cannot dismiss it simply because it requires more intensive side effect management. With the drug's proven efficacy, further discussion is needed on adopting this more effective combination therapy."

As for clinical practices in South Korea, the biggest hurdle for Leclaza-Rybrevant combination therapy is related to its cost.

Leclaza monotherapy has been reimbursed with the National Health Insurance coverage since last year. However, Lecalza in combination with other drugs is still non-reimbursed.

Professor Sun Min Lim (Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Hospital), said, "Although the therapy is legally available since it has received domestic approval, the high cost makes it difficult to consider," adding, "Based on clinical data, treatment isn't limited to just one year. Patients may need to be treated for up to 50 months, a significant burden from the patient's perspective."

Meanwhile, Janssen has initiated patient programs at major hospitals capable of utilizing the combination therapy, starting mid-March.

Janssen has confirmed that the company will cover 72% of the drug price of Leclaza–Rybrevant combination therapy for the first 12 vials and 20% for each vial from the 13th onward.

For Leclaza, the drug price is refunded to patients according to a risk-sharing agreement negotiated by Yuhan with the regulatory authorities last year. As a result, only Rybrevant's cost is supported through patient assistance programs.

Professor Cho said, "Although there are price hurdles, compared to other options, the Leclaza-Rybrevant combination therapy preserves a chemotherapy option for future resistance," adding, "In comparison to treatments that are advanced from first-line therapy, it offers the advantage of providing viable second- and third-line treatment options for patients."

Doctors voice that policy reforms are needed to address the increasing prevalence of combination therapies.

In fact, over the past five years, 54 combination therapy for anticancer drugs have been approved, of which 26 involve combinations between two new drugs, similar to the Leclaza-Rybrevant combination therapy.

The healthcare authorities have explained that reimbursement discussion is underway, considering the approvals of various anticancer combination therapies, the overall sequencing of treatment lines, and the number of administrations.

Kim Gook-hee, Head of the Pharmaceutical Benefits Department at HIRA, said, "Anticancer drugs are clearly defined from the approval documentation regarding regimen and treatment sequence, and reimbursement criteria are set accordingly," adding, "However, with the recent surge in combination therapies, there are concerns about whether this approach can be maintained and whether all such combinations should be covered under reimbursement."

Kim added, "For anticancer drugs, discussions are already underway in the Cancer Drug Review Committee considering the regimen, treatment line, and overall survival period," adding, " Although side effects have decreased, we must also comprehensively consider the toxicity issues that can arise when anticancer drugs are combined."