Targeting Tumors Early: Trials Push Novel Agents to Forefront

Andrew D. Smith
Published: Monday, Feb 11, 2013
Dr. Ramaswamy Govindan

Ramaswamy Govindan, MD

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors such as erlotinib or gefitinib have produced significant benefits for many patients with non-small cell lung cancer (NSCLC) whose tumors exhibit EGFR mutations, with some studies documenting response rates of nearly 75% for those with certain aberrations.1

So what could these agents do if they were pitted not against late-stage NSCLC but against early-stage tumors? Could they improve outcomes or increase survival rates?

These drugs have not been well studied in earlier-stage NSCLC, particularly after complete surgical resection, but that’s about to change. The Alliance for Clinical Trials in Oncology, a cooperative group funded by the National Cancer Institute, will test erlotinib in patients with resected NSCLC whose tumor cells harbor EGFR mutations. Results will take years, but if the targeted medications work, the trial could rewrite standards of care for 10%-15% of patients with NSCLC.

The Alliance trial epitomizes a major trend in cancer research: testing targeted cancer medications not as last-ditch treatments, but against early-stage tumors.

The few trials completed to date have returned mixed results, but new discoveries about tumor biology suggest to many researchers that targeted therapies, when used in appropriate early-stage patients, might significantly boost cure rates and extend lives, particularly when used together with, rather than instead of, today’s standard treatments.

“The focus of targeted therapies has been generally in the setting of advanced incurable metastatic disease. We have to change our mindset. We should be assessing the role of targeted therapies in carefully selected patient populations in the earlier-stage ‘curative’ settings, ” said Ramaswamy Govindan, MD, a professor in Medical Oncology at Washington University School of Medicine in St. Louis, Missouri, in an interview.

Govindan has been developing plans for a trial in which 400 patients with stage I NSCLC would receive either the current standard of care—often surgery alone—or surgery followed by erlotinib. Patients with stage II and stage III tumors, following surgery, would be treated with postoperative platinum-based adjuvant chemotherapy followed by placebo (standard arm), or postoperative platinum-based adjuvant chemotherapy followed by erlotinib (experimental arm).

Similar clinical trials in patients with other tumor types are taking place around the globe (Table). The Breast International Group and the North Central Cancer Treatment Group recruited 8381 women in 50 countries to evaluate the effects of adding lapatinib to trastuzumab as a first-line treatment in early-stage HER2-positive breast cancer in the ALTTO trial.2 Cancer Research UK is enrolling 1970 patients to study two targeted medications, the immunomodulatory agent lenalidomide and the proteasome inhibitor bortezomib, against newly diagnosed myeloma.3 And, the NCI-backed Radiation Therapy Oncology Group is seeking to recruit 950 patients with pancreatic adenocarcinoma to test whether adding erlotinib to chemotherapy and, in some cases, other treatments, improves survival following R0 or R1 resection.

Table. Selected Early-Phase Studies of Targeted Therapies2-4

Description Patients (N) Tumor Types Phase Objectives Projected Completiona
2-design ALTTO trial comparing adjuvant lapatinib and trastuzumab alone and in combination, sequenced with neoadjuvant surgery and chemotherapy and two concurrent chemotherapy optionsb 8381 Nonmetastatic, primary HER2+ breast cancer III DFS, OS, cohort analyses for cMYC, PTEN, p95 HER2 domain July 2013
Induction chemotherapy with either thalidomide or lenalidomide, followed by consolidation therapy with bortezomib if needed, and maintenance therapy of lenalidomide with or without vorinostat if appropriate 1970 Newly diagnosed symptomatic multiple myeloma III OS, PFS, response rates September 2017
4-arm trial of gemcitabine with or without erlotinib, followed by the same chemotherapy with or without radiation and capecitabine or fluorouracil 950 Pancreatic cancer stages I/II III OS, DFS, role of KRAS mutations August 2020
DFS indicates disease-free survival; OS, overall survival; PFS, progression-free survival.
aEstimated final data collection for primary outcome measure. (NCT00490139, NCT01554852, NCT01013649).
bLapatinib-alone arm closed in August 2011 after the Independent Data Monitoring Committee reported in an interim analysis that it crossed the futility barrier.

Changing Expectations

When targeted therapies first arrived more than a decade ago, optimists predicted the agents would hone in on cancer cells so effectively that they would entirely cure many patients, on their own, with minimal side effects.

Initial tests against tumors that resisted all other medications frequently showed remarkable results. Patients improved considerably, but full cures were very rare, even when medications appeared perfectly matched to individual patient cancers. Remissions ended and patients died.

Research into tumor DNA suggested an explanation. Cancer mutates aggressively. A patient’s initial cancer cells—and the overwhelming majority of all the cancer cells in his body—might be fully susceptible to a targeted medication, but almost all patients have some mutated cells that survive it. Those multiply and create the medication-resistant tumors that kill the patient.

Investigators from Johns Hopkins and Harvard University recently led a study that supports this theory.5 The Johns Hopkins scientists analyzed blood samples taken regularly from 28 patients with advanced colorectal cancers who were enrolled in a trial of the monoclonal antibody panitumumab.

They found that nine of the 24 patients with wildtype KRAS genes exhibited KRAS mutations detectable in the blood within five to six months of beginning therapy. Then the investigators, along with mathematicians from Harvard, used models to calculate that those KRAS mutations likely originated prior to the initiation of treatment with panitumumab.

Dr. Luis Alberto Diaz

Luis Alberto Diaz, MD

“If the cancer isn’t developing resistance, if it’s only surviving because it has had enough time to randomly develop resistant mutations before treatment began, then earlier treatment really does have a better chance of success. And this is likely true for all targeted medications,” said Luis Alberto Diaz, MD, associate professor of Oncology and director of the Swim Across America laboratory at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, Maryland.

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Medical Crossfire®: How to Use Liquid Biopsies Throughout the Lung Cancer Treatment Continuum OnlineJan 31, 20191.5
35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
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