At the 2024 European Society for Medical Oncology Asia Congress (ESMO ASIA 2024), during the Preferred Oral Presentations on Thoracic Oncology, Professor Yi-Long Wu from Guangdong Provincial People's Hospital presented the positive results of the PACIFIC-5 Phase III trial (Abstract No: LBA6). This study evaluated the efficacy of durvalumab consolidation therapy in unresectable Stage III non-small cell lung cancer (NSCLC) patients who remained progression-free after concurrent (cCRT) or sequential chemoradiotherapy (sCRT). Oncology Frontier invited Prof. Wu to provide an in-depth interpretation of the findings and highlight key points from this landmark study.PACIFIC-5: Validation of Immunotherapy Consolidation Benefits
Does PACIFIC-5 confirm the benefits of immunotherapy consolidation from PACIFIC? Are the outcomes consistent between cCRT and sCRT subgroups?
Prof. Wu: At this year’s ESMO ASIA, I presented the positive Phase III trial results at the congress, the PACIFIC-5 trial data. Following its presentation on the opening day during the thoracic oncology session, the results garnered widespread attention.
Some may question why PACIFIC-5 was conducted given the proven efficacy of durvalumab consolidation therapy after cCRT in the original PACIFIC trial and GEMSTONE-301’s validation of this approach post-sCRT. The reasoning lies in two key aspects:
- Diverse Radiotherapy Practices: For unresectable Stage III NSCLC, treatment strategies differ, with 40–80% of patients receiving cCRT across countries (80% in the US, 40% in the UK, and 50% in China). While PACIFIC established the efficacy of durvalumab after cCRT, the critical question remained: Can patients unable to undergo cCRT also benefit from durvalumab consolidation following sCRT? GEMSTONE-301 answered this question in a Chinese population, while PACIFIC-5 addresses it in a global context, including patients from China, Russia, Eastern Europe, South Asia, and Southeast Asia, thereby addressing the demographic limitations of PACIFIC’s primarily Caucasian cohort.
- Confirmation of PACIFIC Results: For cCRT-treated patients, the benefits of durvalumab consolidation therapy have only been confirmed in the PACIFIC trial. A second international study was necessary to validate these findings.
PACIFIC-5 achieved its primary objective, delivering positive results. This trial randomized patients post-cCRT or sCRT in a 2:1 ratio to receive durvalumab or placebo as maintenance therapy. Unlike PACIFIC, which limited durvalumab treatment to one year, PACIFIC-5 continued therapy until disease progression. Concerns over overtreatment were mitigated by the recognition that sCRT patients often relapse quickly and may require extended maintenance therapy.
PACIFIC-5 initially included all-comer patients, regardless of EGFR/ALK mutation status. During the study, mounting evidence revealed the lack of benefit from immunotherapy in EGFR/ALK-positive NSCLC patients, leading to a refined analysis focusing on EGFR/ALK-negative patients (modified intention-to-treat, mITT). The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review (BICR) in the mITT population.
In the mITT cohort, durvalumab significantly improved PFS compared to placebo, with a median PFS of 14 months versus 6.5 months (HR=0.75, P=0.038), extending PFS by 7.5 months. While overall survival (OS) data remain immature, the OS hazard ratio (HR) of 0.83 suggests a survival benefit trend. Importantly, PFS benefits were consistent across both cCRT and sCRT subgroups.
Clinical Implications of PACIFIC-5 for Asian Patients
What guidance does PACIFIC-5 provide for clinical practice, considering the differences in treatment response among various ethnic groups?
Prof. Wu: GEMSTONE-301 demonstrated the benefits of sugemalimab consolidation therapy post-cCRT or sCRT in unresectable Stage III NSCLC, leading to its approval in China. PACIFIC-5, as a global study with a fully positive outcome, offers significant potential for regulatory approval in China and possibly in the US or EU, pending mature OS data.
PACIFIC-5’s OS has already reached 38 months, comparable to PACIFIC’s OS data, reinforcing the significant survival benefits of this approach. The PACIFIC-5 regimen is likely to gain broad recognition and adoption in clinical practice.
Management of EGFR-Mutant NSCLC Post-TKI Failure
At the ESMO ASIA session on “Managing EGFR-Mutant NSCLC,” discussions included treatment options following first-line EGFR-TKI failure. Could you share your insights?
Prof. Wu: Managing EGFR-mutant NSCLC post-TKI failure is complex, with multiple evolving strategies. Initially, treatment selection was mutation-driven, paving the way for fourth-generation TKIs. However, progress in fourth-generation TKI development has been slow.
An alternative focus is addressing resistance mechanisms, such as MET amplification. Studies targeting MET amplification have shown promise, with results expected next year.
Additionally, novel treatment modalities like antibody-drug conjugates (ADCs) and bispecific antibodies have achieved impressive outcomes. HER3 and TROP2 are emerging ADC targets, demonstrating excellent efficacy in EGFR-TKI-resistant patients.
Treatment approaches for EGFR-TKI-resistant NSCLC are diversifying, including ADCs or bispecific antibodies for all-comer populations and targeted therapies like MET-TKI combined with EGFR-TKI for specific resistance mechanisms. The future holds increasing options and optimism for patients.
Reflections on ESMO ASIA 2024
What are your thoughts on ESMO ASIA 2024, and which thoracic oncology findings stood out to you?
Prof. Wu: Although ESMO ASIA 2024 was condensed into three days, it offered unique and insightful content. As a past CSCO president, I was involved in discussions leading to the inception of ESMO ASIA over a decade ago, and I served as the inaugural scientific chair. ESMO ASIA now has its distinct identity, focusing on summarizing annual oncology advances with a particular emphasis on therapies tailored to Asian populations.
During the thoracic oncology session, aside from PACIFIC-5, another noteworthy study was the Beamion LUNG-1 trial, evaluating a HER2 tyrosine kinase inhibitor (TKI) for HER2-mutant advanced/metastatic NSCLC. At a 120 mg dose, it achieved a 71% response rate, challenging ADCs in the second-line setting.
Further, the combined analysis of TROPION-Lung01 and TROPION-Lung05 revealed promising efficacy and manageable safety of the TROP2 ADC Dato-DXd in pretreated EGFR-mutant NSCLC patients.
Given the unique genetic and clinical profiles of Asian patients, such as higher frequencies of oncogenic driver mutations, dedicated analyses for this population are essential. ESMO ASIA continues to provide vital data for optimizing cancer care for Asian patients.
Yi-Long Wu, MD, PhD
- Professor of Oncology, Guangdong Provincial People’s Hospital
- IASLC Distinguished Scientist Awardee
- Vice President, Chinese Medical Doctor Association
- President, Guangdong Medical Doctor Association
- Chief Expert, Guangdong Provincial People’s Hospital
- Honorary Director, Guangdong Lung Cancer Institute
- Chair, Chinese Thoracic Oncology Group (CTONG)
- Globally Highly Cited Scientist in Clinical Medicine (2018–2024)
- Former President, Chinese Society of Clinical Oncology (CSCO)
