Discussing ALCHEMIST with Dr. Shakun Malik

Discussing ALCHEMIST with Dr. Shakun Malik

Regulatory Agency Perspective
Dec 18, 2017
Posted: December 2017

Patients with completely resected early-stage non-small cell lung cancer (NSCLC) have approximately a 50% chance of experiencing disease recurrence following standard treatment. In 2014, the NCI initiated a group of randomized clinical trials, called the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST), to test adjuvant treatments to prevent cancer recurrence in patients with early-stage NSCLC.

At the time of its launch, Shakun Malik, MD, Head of Thoracic Cancer Therapeutics, Cancer Therapy Evaluation Program, Division of Cancer Treatment & Diagnosis at the NCI, described the Institute’s aspirations in a statement saying, “We believe that the findings from ALCHEMIST will not only help answer an important question about the addition of targeted therapies in earlier stage disease but will also help us in understanding the prevalence and natural history of these genomic changes in earlier stage lung cancer.”1

In terms of overall screening, ALCHEMIST has been a major undertaking. The ultimate goal is to test the tumor tissue of between 6,000 and 8,000 resected patients. “Although we are slower than anticipated in accruing patients, we are steadily screening about 100 patients per month,” said Dr. Malik in a recent discussion with IASLC Lung Cancer News.

Tumor tissue from patients with nonsquamous NSCLC who participate in ALCHEMIST are first screened for genomic EGFR mutations and ALK translocations. Individuals with EGFR-driven NSCLC are offered enrollment in a trial testing the EGFR inhibitor erlotinib (A081105), and those whose tumors have ALK rearrangements are offered enrollment in a trial of crizotinib (E4512). Patients whose tumors have neither EGFR or ALK abnormalities or whose tumors have squamous histology—a group comprising about 80% of all enrolled patients—are eligible for enrollment in the ALCHEMIST Immunotherapy trial (EA5142; ANVIL).

Patients enrolled in the immunotherapy study are randomized to receive 240 mg of nivolumab intravenously every 2 weeks or to observation. Nivolumab is an immune checkpoint pathway inhibitor that binds the programmed cell death-1 receptor (PD-1) and prevents its activation via the ligand PD-L1, and it is currently approved by the FDA for use in individuals with metastatic NSCLC whose disease has progressed on or after chemotherapy. This drug has demonstrated benefits in those patients with metastatic NSCLC tumors without EGFR or ALK abnormalities, and therefore is offered in ALCHEMIST as an adjuvant treatment for patients whose tumors do not have EGFR or ALK abnormalities.

The participants in the immunotherapy trial will receive treatment for up to 1 year, as opposed to patients in the EGFR and ALK trials who currently receive treatment for up to 2 years. Dr. Malik explained this discrepancy in protocols, saying that, “There are no data at this time of the optimal duration of these therapies. Since immunotherapies work even after patient has stopped receiving them and are given intravenously, most of the trials are designed for them to be stopped after 1 year, and ALCHEMIST is following the same rationale.”

The ALCHEMIST immunotherapy trial also employs central immunohistochemical testing for the presence of the immune checkpoint protein PD-L1 in tumor samples. Unlike the presence or absence of EGFR and ALK abnormalities, the presence or absence of PD-L1 expression is used for data stratification only, not to determine eligibility. Dr. Malik noted that this is because “the data thus far does not support the conclusion that patients with low levels of immune checkpoint proteins do not clinically benefit from immunotherapies.”

In addition to specific mutations present in tissue, the designers of ALCHEMIST also intend to provide more complete and detailed genomic data in the context of NSCLC. Dr. Malik noted that, “In addition to tumor tissue, we have also collected patients’ blood samples in order to conduct studies of the clinical significance of circulating tumor-free DNA (cfDNA) at a later time,” with respect to overall survival and disease-free survival as well as evaluating the concordance of cfDNA with tumor tissue-based biomarkers. ✦

1. NIH announces the launch of 3 integrated precision medicine trials [news release]. Bethesda, MD: National Cancer Institute Press Office; August 18, 2014. https://www.cancer.gov/news-events/press-releases/2014/ALCHEMISTlaunch. Accessed October 25, 2017.

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