Tumor genotyping has had an enormous impact on the management of advanced non-small cell lung cancer (NSCLC). Today, tumor genotyping for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements is widely accepted as a standard of care for advanced non-squamous NSCLC in order to identify patients for treatment with EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, or ALK TKIs, such as crizotinib. Furthermore, genotyping to identify other rare but targetable genotypes (such as ROS1 rearrangements, BRAF V600E mutations, and so on) is increasingly performed. It has become clear that one way to achieve durable disease control for advanced NSCLC, with minimal toxicity, is to identify a gene target and to treat it with a potent targeted agent.
Though widely used and extremely effective, these potent targeted agents are not part of our curative management of NSCLC. Several randomized studies have investigated the role of EGFR TKIs in resected NSCLC, but none have studied these agents specifically in the group known to gain the most benefit—cancers harboring EGFR mutations. The BR.19 trial randomized 503 patients with resected NSCLC to gefitinib versus placebo; however, only 15 of those patients were identified as having EGFR mutations.* The Randomized Double-blind Trial in Adjuvant NSCLC with Tarceva (RADIANT) trial randomized 973 patients with resected NSCLC positive for EGFR by immunohistochemistry or fluorescence in situ hybridization to erlotinib versus placebo, and 161 of those had EGFR mutations—disease-free survival (DFS) was more favorable in the erlotinib arm (HR 0.6), but no difference in overall survival was evident.† One single-arm study, the SELECT trial, studied adjuvant erlotinib in resected EGFR-mutant NSCLC and found it to be a feasible therapy, with 40 percent of patients requiring a dose reduction and 69 percent of patients completing more than 22 months of treatment (of the 24 months intended). The two-year DFS rate was 89 percent, which was better than expected for resected NSCLC.‡
Given that adjuvant TKI in genotype-defined NSCLC populations is feasible and may improve outcomes, the National Clinical Trials Network and National Cancer Institute (NCI) joined together to design a clinical trial platform that would facilitate definitive studies of adjuvant targeted therapies in biomarker-selected NSCLC patients. This platform was named ALCHEMIST—Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials. The ALCHEMIST program comprises three studies at present: one overall screening study (A151216) to perform tumor genotyping and collect tissue and data for correlative studies, and two treatment trials that randomize EGFR-mutant NSCLC (A081105) or ALK-rearranged NSCLC (E4512) to two years of adjuvant TKI (erlotinib for EGFR, crizotinib for ALK) versus placebo (see Figure 1). The effort balances an important clinical aim and an important translational research goal: (1) to study whether adjuvant targeted therapies can improve overall survival in resected NSCLC, and (2) to perform advanced genomics on a large cohort of resected NSCLCs and to correlate these findings with detailed clinical annotation.
Figure 1. ALCHEMIST schema
Surgical involvement is critical to the success of the ALCHEMIST screening study. This study has two aims: (1) to perform EGFR and ALK genotyping, which may lead to enrollment in the ALCHEMIST-EGFR and ALCHEMIST-ALK studies; and (2) to collect high-quality formalin-fixed, paraffin-embedded tissue to allow advanced genomics at the NCI. Patients may provide consent for the screening trial at any time in their care (before or after operation, or during adjuvant chemotherapy or radiation), so long as the patients remain in-window for treatment on the two treatment trials (see Table 1). Ideally, patients should be enrolled before resection so that an extra tumor block can be collected for the study, ensuring adequate tissue for clinical genotyping and advanced genomics. The eligible patient population for ALCHEMIST screening is patients with resectable or resected NSCLC, node-positive (IIA-IIIA) or high-risk node-negative disease (IB with size ≥ 4cm), non-squamous histology, who did not receive neoadjuvant therapy.
Table 1. Eligibility windows for ALCHEMIST trials
|Adjuvant treatment given||Eligibility window for ALCHEMIST-screening||Eligibility window for ALCHEMIST-EGFR or -ALK|
|No adjuvant therapy||75 days after surgery||90 days after surgery|
|Adjuvant chemotherapy only||165 days after surgery||180 days after surgery|
|Adjuvant chemotherapy and radiation||225 days after surgery||240 days after surgery|
For patients enrolled postoperatively, sites may either submit a tumor block or a combination of standard slides and thick-cut “scrolls” for analysis. All patients also must have a tube of blood collected and complete an epidemiological questionnaire. Those patients who are ineligible for the EGFR or ALK treatment trials are followed on the ALCHEMIST screening study every six months for five years. If a biopsy is performed at the time of recurrence, a portion of this sample should be submitted to the NCI for further genomics. Importantly, the EGFR and ALK genotyping results are returned directly to the site within 14 business days; however, the advanced genomics at the NCI is considered investigational. Thus, while these data will be shared publicly when analysis is completed, they will not be provided to sites for clinical use.
Surgeons and medical oncologists both will enroll patients in the screening study, and medical oncologists will enroll eligible EGFR- or ALK-positive patients in the two treatment trials. Both trials will accept patients who have completed standard adjuvant therapy. Adjuvant chemotherapy and/or radiation therapy is permissible but not required prior to enrollment in the treatment trial. Both treatment studies are placebo-controlled trials that study two years of adjuvant TKI versus two years of placebo. Because U.S. medical oncologists are experienced with the two targeted therapies being studied (erlotinib for EGFR, crizotinib for ALK), it is expected that toxicity and compliance will not be major issues. The primary endpoint of both studies is an improvement in overall survival; patients are allowed to receive any therapy at time of recurrence, including crossing over from placebo to TKI.
The ALCHEMIST platform is intended to allow room for growth in the number of adjuvant treatment trials supported by the screening protocol. At present, an additional treatment trial is in development to study adjuvant therapy with a PD1 inhibitor, which also will involve expanding the ALCHEMIST screening study to include squamous NSCLC. The surgeons involved in the study anticipate that the effort will continue to grow in the future to accommodate emerging agents. In this way, the ALCHEMIST trial offers an infrastructure that can answer a range of scientific questions over the coming years, all with the aim of improving the overall treatment of resected and potentially curable NSCLC.
For more information about ALCHEMIST, contact Colleen Watt from the Alliance for Clinical Trials in Oncology at firstname.lastname@example.org.
*Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non–small-cell lung cancer: Results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326.
†Shepherd FA, Alkorti NK, Eberhardt WEE, et al. Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial. J Clin Oncol. 2014;32:5s (suppl; abstr 7513.)
‡Pennell NA, Neal JW, Chaft JE, et al. SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. J Clin Oncol. 2014;32:5s, (suppl; abstr 7514).