Survival Benefit with KEYTRUDA® After Locally Ablative Therapy (LAT) for Oligometastatic NSCLC

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

It is estimated that approximately 7% of patients with NSCLC present with a limited number of metastatic foci (oligometastatic). Several retrospective studies have shown that the use of Locally Ablative Therapy (LAT) to all sites of disease in oligometastatic NSCLC is associated with a significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), when compared with historical data. Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. Therefore, incorporating immunotherapy along with LAT has been an area of active research. In the PACIFIC trial, consolidation therapy with PD-L1 inhibitor IMFINZI® (Durvalumab), following chemoradiation, significantly improved PFS and OS among patients with locally advanced NSCLC suggesting that there is a strong biological rationale for the use of immunotherapy in patients with minimal residual disease state.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. The primary objective of this study was to evaluate whether the addition of KEYTRUDA® after Locally Ablative Therapy (LAT) improves outcomes among patients with oligometastatic NSCLC, compared with historical data.

The authors conducted a single arm Phase II trial at an academic referral cancer center, and 51 eligible patients with oligometastatic NSCLC (no more than 4 metastatic sites) were enrolled. Enrolled patients had oligometastatic disease at diagnosis (synchronous disease) or who developed oligometastatic disease after initial definitive therapy (metachronous disease). There was no limit on the number of prior therapies, although patients could not have received prior therapy with a Programmed Death 1 (PD-L1) inhibitor. Any form of Locally Ablative Therapy (LAT) was acceptable and LATs included Surgery, Chemoradiotherapy, Stereotactic radiotherapy, and/or Interventional ablation. Forty five of the 51 patients enrolled received KEYTRUDA® within 4 to 12 weeks of completing LAT. Patients received KEYTRUDA® 200 mg IV every 21 days, for 8 cycles and were allowed to continue therapy for a total of 16 cycles in the absence of progressive disease or untoward toxicities. The median age was 64 years and patients were eligible regardless of their PD-L1 or molecular target status. Thirty-two patients had adequate tissue for assessment of PD-L1 status, and 29 patients had adequate tissue for assessment of CD8 T-cell infiltration. In patients undergoing testing, 34% had results positive for PD-L1 (1% or more) and 52% had CD8 T-cell infiltration of greater than 2.5%. Patients received a median of 11 cycles of KEYTRUDA®.

The two Primary efficacy end points were Progression Free Survival (PFS) from the start of Locally Ablative Therapy (PFS-L) and PFS from the start of KEYTRUDA® therapy (PFS-P). This study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included Overall Survival, Safety, and Quality of Life, as measured by the Functional Assessment of Cancer Therapy–Lung (FACT-L) instrument.

After a median follow-up of 23.2 months for surviving patients, the median PFS from the start of Locally Ablative Therapy (PFS-L) was 19.1 months, which was a statistically significant improvement from the historical median of 6.6 months (P=0.005). The median PFS from the start of KEYTRUDA® therapy (PFS-P) was 18.7 months. The mean Overall Survival rate at 12 months was 90.9% and at 24 months was 77.5%. The Progression Free Survival from the start of Locally Ablative Therapy (PFS-L) was not influenced by PD-L1 expression or CD8 T-cell tumor infiltration. Quality of Life as measured by the FACT-L scores at cycles 8 and 16 were not significantly different from FACT-L scores at baseline.

The authors concluded that KEYTRUDA® after Locally Ablative Therapy for oligometastatic NSCLC was associated with a clinically and statistically significant improvement in Progression Free Survival, compared with historical data, without a decrement in Quality of Life. They added that the Overall Survival data is encouraging but will require further follow up. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer: A Phase 2 Trial. Bauml JM, Mick R, Ciunci C, et al. JAMA Oncol. Published online July 11, 2019. doi:10.1001/jamaoncol.2019.1449