Surgical resection is the most effective treatment for early-stage non-small cell lung cancer (NSCLC), but in many cases, surgery alone is not enough. Despite advances in surgical techniques and radiation technology, up to 75 percent of patients will develop metastatic disease.1 The addition of adjuvant chemotherapy can improve five-year disease-free survival (DFS) 5 to 15 percent;2,3 however, long-term survival after treatment for early-stage NSCLC remains a significant challenge, especially in comparison with the improvements that have been made in other solid tumors, such as breast and colon cancer. Identification of a therapeutic regimen that successfully reduces recurrence rates after surgical resection of early-stage NSCLC could improve many lives.
Significant advances have been made in the treatment of metastatic NSCLC, particularly with the addition of immune checkpoint inhibitors, such as pembrolizumab, an anti-programmed death (PD)-1 antibody that works by releasing the brakes on the immune system, resulting in T-cell activation and tumor cell death. In metastatic NSCLC without a targeted therapy option (for example, epithelial growth factor receptor [EGFR] mutations or anaplastic lymphoma kinase [ALK] fusion), pembrolizumab +/- chemotherapy is now the first-line standard of care.4-6 For patients with unresectable stage III NSCLC, durvalumab (anti-PD-L1 antibody), is now standard of care treatment after concurrent chemotherapy + radiation, with an 11 percent improvement in disease-free survival at two years and an increase in median progression-free survival from 5.6 months to 17.2 months.7 Fortunately, these therapies typically are well-tolerated, even when received regularly for extended periods of time.
The question then becomes: if these regimens are showing promising results for patients with advanced disease, can they be used to improve survival in early-stage, resectable NSCLC patients? Promising data for short-course neoadjuvant checkpoint blockade were presented at the 2019 American Society of Clinical Oncology meeting, demonstrating a major pathologic response of 24 percent for patients with stage I–IIIA resectable NSCLC, treated with three cycles of checkpoint blockade.8 Other ongoing studies are evaluating checkpoint inhibitors after completion of postoperative chemotherapy and enroll only after completing adjuvant chemotherapy. Although a sequential approach represented a logical next step in adjuvant therapy, there has been considerable success in the metastatic setting, safely administering immune therapy drugs with chemotherapy. This more aggressive strategy may have the most potential in patients with minimal disease burden, such as the surgically resected population.
ALCHEMIST trial
Integration of Immunotherapy into Adjuvant Therapy For Resected NSCLC: ALCHEMIST CHEMO-IO is the first trial to enroll patients to concurrent chemotherapy with checkpoint inhibitor in the adjuvant setting and is the first to enroll patients to a sequential arm (chemotherapy followed by checkpoint inhibitor) before
receiving any chemotherapy (see Figure 1). In this trial, patients with stage IB–IIIA NSCLC treated with definitive surgical resection will be randomized to one of three arms: platinum doublet chemotherapy alone, platinum doublet followed by pembrolizumab (anti-PD-1 therapy), or platinum doublet with concurrent pembrolizumab followed by pembrolizumab. This novel trial, following complete resection of stage IB-IIIA NSCLC, requires EGFR and ALK status for eligibility and PD-L1 for stratification. The three-arm design will allow an opportunity to compare both the sequential arm and concurrent arm with standard of care chemotherapy. There also will be an opportunity to compare the two experimental arms with each other.
Figure 1. Schema: ALCHEMIST CHEMO-IO
