Konkuk University Medical Center researchers have reported interim results from the NeoLazBAL study, a phase 2 clinical trial, indicating that Leclaza, a third-generation EGFR-targeted anticancer drug, can downstage inoperable lung cancer in 55% of patients with EGFR gene mutations detected via lung lavage fluid biopsy. This enables a significant proportion of patients to become eligible for surgical resection.
The study, led by Professor Lee Kye-young, enrolled patients with suspected lung cancer who had EGFR gene mutations identified in lung lavage fluid biopsies. Participants received Leclaza for nine weeks, followed by re-staging and surgery. Adjuvant therapy with Leclaza was administered for three years post-surgery for patients at stage 2 or higher, or those at high risk of recurrence.
The trial also assessed the accuracy of diagnosing lung cancer using lung lavage fluid biopsy and the sensitivity of detecting EGFR genetic mutations. The primary goals were to determine if Leclaza pretreatment could induce downstaging, eliminate micrometastases, convert inoperable cases to operable ones, and ultimately reduce postoperative recurrence rates, thereby increasing lung cancer cure rates.
According to Professor Lee, data analysis following surgery revealed promising treatment performance. Of the 128 patients screened via bronchoscopy and lung lavage fluid biopsy, 48 tested positive for EGFR mutations. Forty patients consented to Leclaza treatment, and 34 underwent surgical resection after the nine-week upfront therapy.
The results showed partial remissions in 55.8% (19 of 34) of patients, with no cases of lung cancer progression observed during the neoadjuvant treatment phase. Surgical tissue pathology confirmed lung adenocarcinoma in all 34 patients, validating the diagnostic accuracy of lung lavage fluid biopsy for EGFR mutation-positive NSCLC without the need for traditional biopsies.
EGFR genetic testing demonstrated a 97.1% concordance of gene subtypes in 33 out of 34 patients. Among 44 patients with negative lavage fluid biopsies who underwent surgery for suspected early-stage lung cancer, 10 were found to be EGFR mutation-positive, yielding a final sensitivity of 77.3% for lavage fluid biopsy in stage I NSCLC.
Professor Lee noted that the sensitivity of lung lavage fluid biopsy in identifying EGFR mutation-positive patients was reduced in cases with low SUBmax values, indicative of exosome non-shedders with low cancer activity index in stage 1A disease. However, imaging findings alone may suffice for surgical decisions in these instances. Conversely, in stage I EGFR-mutant lung cancer with a high cancer activity index, upfront Leclaza treatment may induce downstaging and reduce recurrence rates.
Surgical procedures included lobectomy (90.3%), wedge resection (6.2%), and segmentectomy (3.1%). Complete resection (R0 resection) was achieved in 97.5% of patients, while one patient had microscopic residual cancer cells (R1 resection) and received Leclaza post-surgery to prevent recurrence.
Pathologic control outcomes showed a primary pathologic response (MPR) rate of 18.2%, consistent with other neoadjuvant studies involving EGFR-targeted agents. While neoadjuvant therapy with EGFR-targeted agents is not yet standard of care due to the higher pathologic response rates (50-60%) seen with recent immunochemotherapy regimens, this study indicates a potential role for Leclaza in downstaging.
Professor Lee suggested that increasing the duration of upfront treatment, combining Leclaza with chemotherapy or immunochemotherapy, or using combinations like Rybrevant (amivantamab) and Leclaza might improve the MPR rate. The research team has received approval to recruit an additional 20 patients for further study.
The development of lung lavage fluid biopsy offers a promising early lung cancer diagnostic method, addressing the challenges associated with traditional tissue biopsies. This approach allows for the diagnosis of lung adenocarcinoma with targets such as EGFR, KRAS, ALK, and ROS1 by identifying target genes in lung lavage fluid. The team is also researching early lung cancer diagnostics for untargeted lung cancer using methylated DNA, NGS, proteomics, and exosomal small RNAs.
