Bilal Piperdi, MD
Treatment of stage III non-small cell lung cancer (NSCLC) with chemotherapy, radiation, and surgery has hit a plateau, and the key to improved outcomes will hinge on the testing of targeted therapies in clinical trials with more novel designs and better patient selection, according to a leading researcher.
“While there’s been a lot of progress with targeted agents in stage IV non-small cell lung cancer, these agents have been tested in the stage III population without much evidence of activity,” said Bilal Piperdi, MD, during a presentation at the 8th Annual New York Lung Cancer Symposium ® that Physicians’ Education Resource,® LLC hosted November 9, 2013, in New York City.
“What have we done wrong in these patients?” said Piperdi, associate professor of Clinical Medicine and director of the Thoracic Medical Oncology Program at the Montefiore Einstein Center for Cancer Care in Bronx, NY. “In a lot of these trials, we had no prior patient selection by imaging or molecular markers. There’s also increased toxicity with some of these agents, so we have to look at preclinical data to see if drugs are synergistic with chemotherapy and radiation or are too toxic to add.”
Further, trials in this very heterogeneous population will become more effective when (1) they feature quality controls ensuring that radiation is given according to protocol, since deviations in these regimens lead to poorer outcomes; (2) when the most effective drugs, such as targeted agents, where warranted, are given upfront; (3) when radiation treatments are not increased in dose but rather directed more precisely toward the tumors they are targeting; and (4) when patients who have been cured after chemotherapy/radiation are omitted from trials of maintenance therapy agents, Piperdi said.
In his presentation, Piperdi focused on patients with either stage IIIA or IIIB, locally advanced, resectable or nonresectable disease, who had a median survival of 14 months to 22 months, 5-year survival rates of 5% to 24%, and the need for a combined-modality treatment approach.
Piperdi discussed the trials that have shaped current thought about the sequencing of standard therapies for phase III NSCLC—chemotherapy and/or radiation, typically concurrent, in some cases before or after surgery—and also summarized recent studies that explored the use of targeted agents in the disease.
Shaping the Standard of Care
Several trials found that, in most patients, there was no need to add surgery after chemotherapy/ radiation, Piperdi said.
The phase III INT 0139 trial demonstrated that performing surgery after concurrent chemotherapy/ radiation was not statistically significantly more effective than continuing the chemotherapy/ radiation regimen, and also that patients with earlier stages of disease had better outcomes, Piperdi noted. Five-year survival rates for any T classification with N0 were 41%, while patients with any T level with N1-3 were 24%, he said.
Another phase III trial, EORTC 08941, showed that patients with unresectable stage IIIA N2 NSCLC had similar results when treated with induction chemotherapy followed by either surgery or radiation, Piperdi pointed out.
And, a randomized, phase III multinational trial of carboplatin and paclitaxel followed by radiotherapy, or by surgery and then radiotherapy,1
found no statistically significant advantage to including surgery in the regimen, except in patients with adenocarcinoma or T1N2 disease, he said.
Surgery after chemotherapy is called for in a small group of patients with stage IIIA N2 NSCLC, Piperdi said, and for those patients, the phase III SAKK 16/00 trial found that adding neoadjuvant radiation after chemotherapy did not bring benefit.
Still, it’s difficult to determine which patients will do well with surgery, and ongoing clinical trials may help resolve that problem, Piperdi said.
For instance, the phase II ECOG E3512 study, or MINT, includes patients eligible for surgery, and will use early PET and CT scans to try to predict whether neoadjuvant treatments will downstage the disease, increasing the chances of good outcomes with surgery, Piperdi said.
Exploring Targeted Agents
So far, trials in the stage III population have demonstrated that targeted agents are less successful when given concurrently with standard therapies, or afterward, Piperdi said.
For instance, while the monoclonal antibody cetuximab has shown some promise when combined with radiation, it has not brought benefit when combined with both radiation and chemotherapy, Piperdi said.
In 2010, the phase II trial N0422 tested cetuximab and radiation in elderly and poor-performance status patients with stage III NSCLC and found an improved overall survival rate, Piperdi said. The next year, he said, even stronger evidence of the combination’s effectiveness was reported via the phase II RTOG 0324 study.