Despite advances in surgical technique, radiation therapy, and chemotherapy regimens, survival for non-small cell lung cancer (NSCLC) remains uniformly low. Most patients in the U.S. have advanced stage lung disease at time of diagnosis and are not amenable to surgical treatment. When the cancer has spread outside the confines of the lung, five-year survival is reported to be 4 percent.* For patients with earlier stages of disease (disease confined to the lung, or with nodal disease not including the mediastinum) treated with multimodal therapy, survival is better, but remains poor at 55 percent at five years.*
For patients with either nodal disease or primary tumors greater than 4 cm, adjuvant chemotherapy with a doublet regimen of two agents, including either cisplatin or carboplatin is recommended after surgical resection. Unfortunately, the lung adjuvant cisplatin evaluation, also known as LACE, meta-analysis determined the absolute benefit of traditional chemotherapy added to surgical resection to be 5.4 percent.† Efforts to improve these results have not resulted in significant change within the last two decades.
Alchemists, including Sir Isaac Newton, searched for the magical substance—the philosopher’s stone—to transform lead to gold, and to create the elixir of immortality. Today, thoracic oncologists are searching for the optimal regimen to treat an often incurable disease.
Unlike the alchemists of old, who had an incomplete understanding of the building blocks of matter, our understanding of the molecular drivers of cancer has had a dramatic effect on the management of more advanced-stage lung cancer. Highly specific agents that target epidermal growth factor receptor (EGFR) mutations, such as erlotinib, and anaplastic lymphoma kinase (ALK) gene rearrangements, such as crizotinib, are now available. By directly attacking and abrogating the abnormal cell signaling cascade, targeted therapy is emerging as the chemotherapeutic method of choice. Unfortunately, only an estimated 10 percent to 15 percent of patients with NSCLC adenocarcinoma have EGFR mutations, and only 5 percent to 6 percent of patients have ALK gene rearrangements. For patients without these mutations, immunotherapy is emerging as a potential option.
The programmed death (PD)-L1 and PD-L2 ligand is present in some tumors, allowing the tumor to evade the immune system by suppressing activated T-cells. A number of different cancers have responded well to PD-1 inhibition, preventing the immunosuppressive interaction of the tumor cell and the T-cell. Nivolumab is a monoclonal antibody against PD-1 that has demonstrated efficacy in advanced-stage lung cancer, both in squamous and adenocarcinoma, regardless of PD-L1 expression on the tumor cell.‡
Figure 1. Overall schema of ALCHEMIST
ALCHEMIST studies may yield revolutionary therapy options
In 2014, the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or ALCHEMIST, opened. The goals of the trials are to identify the prevalence of EGFR and ALK mutations in patients who are eligible for adjuvant chemotherapy, and to evaluate the benefit of targeted chemotherapy in the adjuvant setting. Patients with stage IB (>4cm) through IIIA disease are eligible. Depending on EGFR or ALK mutational status, patients are randomized to targeted drug therapy (erlotinib for EGFR mutant tumors or crizotinib for ALK-rearranged tumors) versus placebo. With emerging data on the role of PD-1 mediated immunotherapy, in 2016, a third arm was added to the study, which permits the inclusion of patients without ALK or EGFR mutations and randomizes them to nivolumab versus placebo. Patients with squamous cell NSCLC—as well as patients with adenocarcinoma NSCLC who are ALK and EGFR mutation-negative—are now eligible for inclusion in this landmark trial due to the addition of this third arm evaluating adjuvant immunotherapy in this setting.
A total of 1,060 sites are accruing patients in this nationwide trial. At press time, 1,517 patients were enrolled. The goal is to enroll 8,300 patients. Also as of press time, screening for EGFR and ALK mutations had resulted in 86 patients with EGFR mutations able to be randomized to erlotinib versus placebo, and 29 patients with ALK rearrangements able to be randomized to crizotinib versus placebo. The goal of this study is to accrue 450 patients to each of these treatment arms of the ALCHEMIST trials, with a goal of accruing 714 patients in the immunotherapy adjuvant treatment arm.
The ALCHEMIST trials have the potential to revolutionize adjuvant therapy for patients with operable lung cancer. With the addition of the immunotherapy arm to this trial, all patients with operable NSCLC adenocarcinoma and squamous histology can and should have the opportunity to participate. We know that the current standard of care of cisplatin-based chemotherapy offers little benefit in the adjuvant setting. The addition of targeted therapy in the context of a tumor having a specific mutation—or immunotherapy to prevent the escape of tumor cells from our natural immune defenses—may improve long-term survival in patients with NSCLC.
*Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD. Available at: seer.cancer.gov/csr/1975_2013/. Accessed January 23, 2017.
†Pignon JP, Tribodet H, Scagliotti GV, et al. LACE Collaborative Group. Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559.
‡Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. New Engl J Med. 2015;373(2):123-135.