Some pretty good evidence suggests that chemotherapy that works in advanced disease probably works even better in early-stage disease.”
—Fadlo R. Khuri, MD
We are all well aware of the disappointing results from targeted therapies to date in studies unselected for mutation status…. It is clearly time to revisit our major success with stage IV disease if driver mutations or other biologic rationale are present.
—Kathy S. Albain, MD
Some pretty good evidence suggests that chemotherapy that works in advanced disease probably works even better in early-stage disease,” said Fadlo R. Khuri, MD, Chair, Department of Hematology and Medical Oncology at Winship Cancer Institute in Atlanta, in summarizing results from trials of patients with early-stage non–small cell lung cancer (NSCLC). Dr. Khuri presented the evidence and prospects for progress with targeted therapies at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.
The need for effective adjuvant treatment is great and growing. More than 50% of patients with resectable tumors (except stage IA) experience recurrent disease despite optimal surgery, Dr. Khuri reported. “Recurrence of disease is attributed to the presence of micrometastatic disease at diagnosis,” he noted, underlining the “clear need to eradicate micrometastasis in addition to surgery.” Low-dose computed tomography screening for lung cancer, he added, “will lead to more patients who are diagnosed with early-stage disease.”
Low-dose computed tomography screening “will be implemented in the setting of some very salient progress in recent years,” Dr. Khuri said. “We know now that adjuvant chemotherapy improves survival in early-stage lung cancer,” he added, citing several studies.
The International Adjuvant Lung Cancer Trial1 found that following complete resection, patients diagnosed with stage I to III who were randomly assigned to cisplatin-based chemotherapy had significantly higher 5-year survival and disease-free survival than those randomized to observation. Similarly, in the National Cancer Institute of Canada Clinical Trials Group and the National Cancer Institute of the U.S. Intergroup JBR.10 trial,2 overall and relapse-free survival were significantly prolonged among patients with completely resected stage IB or II NSCLC who were randomly assigned to vinorelbine plus cisplatin vs observation. Analysis of the Lung Adjuvant Cisplatin Evaluation (LACE)3 data “definitively shows that if you look at the body of the data in their totality, adjuvant chemotherapy does save lives in this setting,” Dr. Khuri stated.
Be Wary of Extrapolation
Dr. Khuri cautioned against directly extrapolating data from studies with advanced disease for use in patients with early-stage disease. “One such extrapolation that I see a little too frequently in the community setting,” he said, involves taking data from [Eastern Cooperative Oncology Group (ECOG)] 4599,4 which showed that adding bevacizumab (Avastin) to chemotherapy with paclitaxel and carboplatin improved median survival to 12.3 months vs 10.3 months for chemotherapy alone. Patients in that study, however, had recurrent or advanced NSCLC (stage IIIB or IV).
“I would respectfully say that we should probably wait for the results from ECOG 1505,” he said, “before we jump to treat everyone with bevacizumab, which is costly and potent but not lacking in toxicities.” ECOG 1505 is comparing four cycles of chemotherapy with cisplatin and either pemetrexed (Alimta), docetaxel, vinorelbine, or gemcitabine to one of those four chemotherapy regimens plus bevacizumab for 1 year. Patients have resected stage IB to IIIA NSCLC, with no prior chemotherapy and no planned radiotherapy. Accrual was completed in September 2013.
Targeting Genomic Drivers
“We probably have more identifiable, validated driver mutations in lung cancer than in most other diseases,” Dr. Khuri noted. Trials with erlotinib have shown improvement in disease-free survival among NSCLC patients with epidermal growth factor receptor (EGFR) mutations.
Secondary analysis of the RADIANT study5 presented at the 2014 ASCO Annual Meeting by Karen Kelly, MD, Professor of Medicine and Associate Director for Clinical Research at the University of California Davis Comprehensive Cancer Center (and Chair of the Thoracic Oncology Symposium), found that patients with stage IB to IIIA NSCLC and EGFR mutations who were randomly assigned to erlotinib had about an 18-month improvement in disease-free survival vs those receiving placebo.
In the phase II SELECT study,6 also presented at this year’s ASCO Annual Meeting, 2-year disease-free survival among patients with stage I to III NSCLC was 89% among patients with EGFR mutations receiving erlotinib, including 96% among those with stage I disease. Among the questions that need to be considered, Dr. Khuri noted, is: What is the meaning of improved disease-free survival in the absence of overall survival in the adjuvant setting?
Translocations in the anaplastic lymphoma kinase (ALK) gene are associated with 4% to 5% of NSCLC cancers. “We have seen some very striking data on the ALK fusion gene,” Dr. Khuri noted, and the ALK inhibitor crizotinib (Xalkori) has been approved by the U.S. Food and Drug Administration for patients with ALK-positive locally advanced or metastatic NSCLC. “The question is,” Dr. Khuri said, “Can we translate [these findings] from late-stage disease to early-stage disease?”
ALCHEMIST Study Support
Dr. Khuri urged support of ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials). “This is a very important study in that it will randomize patients based on their mutations. Rather than treat patients willy-nilly with EGFR mutations, ALK translocations, and vascular tumors, with crizotinib, gefitinib (Iressa), erlotinib, or bevacizumab, I think it is very important to push for this study. This is a study that has a very strong chance of demonstrating definitively the role of selected targeted therapy,” Dr. Khuri stated.
ALCHEMIST is testing the following hypothesis: “Treatment based on genotype will significantly improve cure rates in patients with earlier-stage (IB–IIIA) nonsquamous tumors that have been completely resected.”
“We are all well aware of the disappointing results from targeted therapies to date in studies unselected for mutation status,” explained Kathy S. Albain, MD, Professor of Medicine and Dean’s Scholar, Loyola University Chicago Stritch School of Medicine, and Director of the Breast and Thoracic Oncology Programs at Cardinal Bernardin Cancer Center. “It is clearly time to translate our major success with stage IV disease, if a driver mutation or other biologic rationale is present, into earlier-stage presentations,” she said in an overview of ALCHEMIST and targeted therapies in early-stage NSCLC provided at the symposium as a steering committee member.
Series of Integrated Trials
ALCHEMIST is actually a series of integrated trials, with a screening trial to identify genetic mutations in patients with early-stage NSCLC and, at the start, two treatment trials. “Patients can be screened either pre- or postoperatively; if after surgery, there need to be negative margins with a complete resection, standard nodal sampling, and adjuvant therapy given as per physician choice,” Dr. Albain said. Among the challenges is the “potential adverse interaction of prior adjuvant chemotherapy and/or radiotherapy with targeted therapy,” Dr. Albain said. “Fortunately, the trials will be large enough in ALCHEMIST to study outcomes of those with prior therapy vs those who go on the trial without any prior adjuvant systemic therapy.”
Tissue from resected NSCLC tumors will be tested for EGFR gene mutations and ALK gene rearrangement. Patients with ALK rearrangement will be randomly assigned to crizotinib at 250 mg twice daily or placebo for 2 years. Patients with EGFR mutations will be randomly assigned to erlotinib at 150 mg daily or placebo for 2 years. Overall survival is the primary endpoint for both trials.
Investigators plan to screen 6,000 to 8,000 patients over 5 or 6 years to identify 378 for the ALK-based trial and 430 for the EGFR-based trial. The drugs are being supplied by pharmaceutical company partners—Pfizer for the crizotinib trial and Astellas for the erlotinib trial. A third ALCHEMIST trial being proposed would involve an immune checkpoint inhibitor of the programmed cell death 1 (PD-1)
Impact of Early Discontinuation
Potential early discontinuation of the oral agents being tested in ALCHEMIST “will be a challenge to overcome to optimize efficacy,” Dr. Albain said in an interview with The ASCO Post. “In the RADIANT adjuvant trial, for example, only half the patients were able to [complete their erlotinib therapy].” (Updated data presented at the meeting showed that 47% of the patients received the prescribed duration of therapy.) “These agents have toxicity, and you need to have a team behind you supporting these patients,” she noted.
ALCHEMIST has provisions for dose reductions built in, “as well as the supportive measures for rash and some of the other toxicities,” she said. In addition, “patients will be recovering from thoracotomies” and the deconditioning to the body that entails will require careful attention to toxicity management and adherence to daily dosing, Dr. Albain pointed out.
“The duration of treatment proposed in ALCHEMIST is somewhat empiric, just as it has been in in the majority of trials of adjuvant oral therapy across tumor types. So, I would say that we should consider very early on addressing duration of these agents as a research question in parallel with the efficacy studies,” Dr. Albain said.
“We have learned this lesson with tamoxifen duration in breast cancer, but it took decades to learn that longer durations than originally thought to be adequate provide better survival,” she added.
Up and Running
“The genomic research component of ALCHEMIST addresses all patients, not just those who have the particular driver mutations of interest at the start,” Dr. Albain said. All patients will be followed for up to 5 years. “So this then establishes a rich resource for future research endeavors with detailed genomic characterization, clinical annotation, as well as epidemiologic and long-term outcomes data.”
ALCHEMIST was “just launched in the fall,” Dr. Albain noted. “There are sites that are up and running, but it is extremely early.” ALCHEMIST is open to all sites that participate in the NCI National Clinical Trials Network (NCTN) or NCI Community Oncology Research Program (NCORP). For more information on enrollment, visit www.ctsu.org or www.cancer.gov. ■
Disclosure: Drs. Khuri, Kelly, and Albain reported no potential conflicts of interest.
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2. Winton T, et al: N Engl J Med 352:2589-2597, 2005.
3. Pignon JP, et al: J Clin Oncol 26:3552-3559, 2008.
4. Sandler A, et al: N Engl J Med 355:2542-2550, 2006.
5. Kelly K, et al: 2014 ASCO Annual Meeting. Abstract 7501. Presented June 2, 2014.
6. Pennell NA, et al: SELECT. 2014 ASCO Annual Meeting. Abstract 7514. Presented June 1, 2014.