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.
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.
2-design ALTTO trial comparing adjuvant lapatinib and trastuzumab alone and in combination, sequenced with neoadjuvant surgery and chemotherapy and two concurrent chemotherapy optionsb
Nonmetastatic, primary HER2+ breast cancer
DFS, OS, cohort analyses for cMYC, PTEN, p95 HER2 domain
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
Newly diagnosed symptomatic multiple myeloma
OS, PFS, response rates
4-arm trial of gemcitabine with or without erlotinib, followed by the same chemotherapy with or without radiation and capecitabine or fluorouracil
Pancreatic cancer stages I/II
OS, DFS, role of KRAS mutations
DFS indicates disease-free survival; OS, overall survival; PFS, progression-free survival.
aEstimated final data collection for primary outcome measure. ClinicalTrials.gov (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.
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.
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.
Even then, at very early stages, some cancers will have mutated enough to confer resistance to treatment by any single targeted agent, which is why many doctors expect targeted medications to enhance rather than replace existing tools. According to this logic, the way to maximize cure rates is to hit tumors as soon as they are spotted—when mutations and resistance are minimal—with several treatment types.
If all goes well, at least one of the treatments will prove fatal to every cell mutation. Even when some cancer escapes, less of it will remain and remissions should last longer.
This general line of reasoning explains why most of the new trials involve adding targeted medications to existing treatments for early-stage cancer rather than testing the targeted therapies on their own. (The ALTTO breast cancer study, which intended to test lapatinib alone as well as lapatinib plus trastuzumab, has abandoned the lapatinib-only group because of poor early results.2)Completing those studies, however, and moving targeted therapies to the front line of early-stage cancer treatment will likely take longer, in most cases, than winning initial approvals to use them against late-stage cancers.
Many targeted cancer therapies secured those first approvals in record time, thanks not only to expedited FDA review but also to the dire nature of late-stage cancers. The patients involved were often weeks from death, so researchers could see almost immediately whether experimental drugs extended life. A full trial might last only a few months and track one primary variable: lifespan.
Studying treatments for early-stage cancer is inherently more difficult. In many cases, existing treatments help patients survive for years, which means that researchers must study large groups of patients to know whether or not changes in survival times stem from experimental therapies. Moreover, they need to study those groups for long periods, sometimes several years, to note differences in survival outcomes.
To illustrate the difficulty of changing standards for early-stage cancer treatment, consider the initial findings of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-40 clinical trial, reported at the 2011 American Society of Clinical Oncology Annual Meeting.6
Different neoadjuvant chemotherapy regimens were evaluated with and without bevacizumab for 1206 patients with operable, HER2-negative tumors at stages I-IIIA. Bevacizumab, when added to preoperative chemotherapy, increased the pathologic complete response rate (34.5% vs 28.4%; P = .027) and the clinical complete response rates (64.3% vs 55.8%; P = .007).
Harry D. Bear, MD, PhD
Harry D. Bear, MD, PhD, who chairs the Division of Surgical Oncology at Virginia Commonwealth University Massey Cancer Center in Richmond and served as the trial’s protocol chair, said the results were encouraging but unlikely to change treatment standards any time soon.
For one thing, the B-40 trial’s results seem to conflict with those of another large study, the German GeparQuinto study.7 B-40 found that patients with hormone receptor-positive tumors benefited most from the addition of bevacizumab. The German study found that bevacizumab benefited patients with triple-negative cancers.
The time needed to validate outcomes also is problematic. Demonstrating pathologic and clinical complete responses is not the same as demonstrating extended life. The B-40 trial will have to follow patients for at least another two years to see whether more initial cancer—fighting translates into better overall survival outcomes.
“We have been working on this trial for several years,” Bear said. “And we have several more years of work to do, and there is certainly no guarantee that we will find any benefits that justify changes in treatment protocols.”
The complexities of testing targeted treatments against early-stage cancers create opportunities for treating physicians everywhere to make contributions. As the molecular drivers of tumors become increasingly characterized, enrolling patients in appropriate trials is expected to become more problematic not only for rare conditions, but also in more common cancers such as NSCLC, where more than a dozen mutations have been identified (Figure).
Discoveries about the heterogeneity of lung tumors are creating a need for new clinical trial designs.
Hirsch FR. Recent advances in biomarker research in lung cancer with special reference to new targeted therapies. Presented at: 13th International Lung Cancer Congress; July 19-22, 2012; Huntington Beach, CA..
Researchers must leverage online resources to make it easier for geographically dispersed patients not only to learn about tumor abnormalities but also to participate in clinical trials, noted D. Ross Camidge, MD, PhD, director of the Thoracic Oncology Clinical Program at the University of Colorado Denver, in an interview with OncologyLive in July.
For doctors who are willing to do more than refer patients, many study leaders are looking for satellite test facilities. These trials generally require many sites, not only because of the patient numbers, but also because of duration. It’s one thing to ask a patient to cross the country for a three-month test. It’s quite another to ask patients to repeatedly cross the country over a several-year period.
Patients also need to pitch in, of course, and agree to participate in studies. Fortunately, researchers say patients are generally more eager to participate in trials that add something new to an existing treatment routine than they are to participate in studies that swap in something new for an existing treatment.Are patients—and some researchers—right to hypothesize that adding targeted medications to existing earlier- stage treatments really will produce better results? So far, outcomes have been mixed.
For example, researchers who studied the effects of adding cetuximab to the standard adjuvant chemotherapy regimen for patients with resected stage III colon cancer and wild-type KRAS found the combination did not deliver better outcomes, even though benefits had been demonstrated in metastatic disease.8
Bevacizumab fared little better in a study that added the angiogenesis inhibitor to a modified standard chemotherapy regimen for patients with stages II-III colon cancer.9 The NSABP Protocol C-08 study found that one year of the combination therapy had “a significant but transient effect” upon disease-free survival, but that it did not reach statistical significance when compared with the standard regimen.
Even when studies show that targeted therapies do produce significant results in earlier stages, as in the B-40 trial, the figures can show benefits in small percentages of the patients. With both the colon cancer and the breast cancer studies, researchers concluded that the problem lay with insufficient understanding of which cancers the medications targeted. Fortunately, the data from many of these tests may help shed light on the problem.
“We naturally have tumor tissue samples from everyone in the study, so we can go back now and do the genetic analysis and, we hope, figure out why some people responded,” Bear said. “More accurate targets obviously lead to more consistent results.”Indeed, in cases where drugs and targets are accurately matched, the results can be significant. In 2011, researchers at the University of California-Los Angeles reported the impact of adding one year of trastuzumab to chemotherapy in 3222 women with early-stage HER2-positive breast cancer.10 At five years’ follow-up, trastuzumab treatment resulted in a disease-free survival (DFS) rate of 84% when combined with doxorubicin/ cyclophosphamide/docetaxel, compared with 75% for that chemotherapy regimen alone, and 81% when added to docetaxel and carboplatin.
Kenneth C. Anderson, MD
Looking forward, many observers expect to see a wide range of results from the many studies that are currently under way. That said, everyone interviewed for this story did expect that, on the whole, targeted medications will prove significantly more effective when used against early-stage cancers, particularly when they complement other treatments.
“Using targeted therapies against cancer at earlier stages probably won’t be ‘the’ answer, said Kenneth C. Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, Boston, Massachusetts.
“But it is a genuinely exciting area of research right now and it will become more exciting as we develop more targeted agents that can be used together, in optimized combinations informed by preclinical trials, so we can hit these vulnerable young tumors in even more ways,” he said.