Clinical Trial Changes Needed to Improve Outcomes in Stage III NSCLC

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.

But in a phase III study, RTOG 0617, cetuximab did not add any benefit to concurrent chemotherapy/ radiation, Piperdi said. He added that the trial compared the standard radiation dosage of 60 Gy against a dosage of 74 Gy, indicating that patients had better outcomes with the lower dosage.

Results with cetuximab were slightly better in another trial that explored a combination regimen. The phase II study CALGB 30407 tested a novel chemotherapy regimen—pemetrexed and carboplatin—in combination with radiation at 70 Gy, with or without cetuximab, in patients with locally advanced, unresectable NSCLC. While the 18-month overall survival rate was slightly lower in the cetuximab arm, median overall survival and 18-month failure-free survival were slightly improved in that cohort, and the study’s authors encouraged further investigation of the regimen.

Gefitinib is another agent that showed early efficacy in patients with advanced NSCLC but did poorly in a recent trial, Piperdi said. In the phase III SWOG 0023 study, gefitinib given as maintenance therapy after chemotherapy/radiation followed by docetaxel, showed less effect on median overall survival than placebo, the doctor noted.

He suggested that those results were due to a lack of selection of trial participants who were most likely to respond to the drug.

The need to avoid toxic combinations, Piperdi added, was highlighted by a phase I/II study of bevacizumab with standard erlotinib and concurrent chemotherapy/radiation,² whose results were published last year. Adverse events included a high rate of pulmonary hemorrhage in patients with the squamous form of the disease, as well as tracheoesophageal fistula and other toxicities; as a result, bevacizumab’s use with chemotherapy/ radiation is “strongly discouraged outside the setting of a properly designed clinical trial,” some of which are in progress, Piperdi said.

Evolving Trial Design

Some recent trials in the stage III NSCLC population feature more novel, and more promising, designs, Piperdi said.

The idea of using potentially powerful targeted therapy upfront was tested in the phase III EURTAC trial with good results, he said.

Preselected patients with EGFR mutations who were given erlotinib upfront had a 65% objective response rate, a much better outcome than the 16% objective response rate experienced by those who received upfront chemotherapy, Piperdi said.

In a pending trial that will also feature molecularly targeted patient selection, the phase III RTOG 1308/A 31101 study, those with EGFRmutated tumors or EML4-ALK fusion-positive tumors will be given chemotherapy/radiation with or without upfront erlotinib or crizotinib, respectively, Piperdi said. In a similar trial in Korea, patients will be stratified by EGFR status and given either erlotinib or chemotherapy with concurrent radiation, the doctor said.

In the phase II EVENT trial, Piperdi said, EGFR-positive patients will be treated with neoadjuvant erlotinib and then restaged by PET scan before their eligibility for surgery is determined. The aim is to find out whether using the most effective treatment upfront can lead to mediastinal nodal clearance in about 30% of patients, Piperdi said. And in the PAINT (PET-Adjusted IMRT for stage III NSCLC patients) study, he said, PET scans are being used to determine IMRT dosage based on metabolic tumor volume.

Finally, a recent phase III immunotherapy trial, the START (EMR 63325-001) study, also highlighted the importance of patient selection, Piperdi said. In the trial, patients who received the immunotherapy vaccine Stimuvax (L-BLP25) as maintenance therapy after concurrent chemotherapy/ radiation experienced a 10-month survival benefit compared with placebo. Patients who took Stimuvax after sequential chemotherapy and radiation had worse outcomes than trial participants who took placebo. The phenomenon will be studied further, he said.

“Hopefully, some of these trials will put new treatment regimens on the map,” Piperdi said. “At least, in these subgroups, giving targeted therapies upfront will help.”

References

1. Sorensen JB, Ravn J, Pilegaard HK, et al. Surgery for NSCLC stages T1-3N2M0 having preoperative pathologically verified N2 involvement: a prospective randomized multinational phase III trial by the Nordic Thoracic Oncology Group. J Clin Oncol. 2013;31(suppl; abstr 7504).
2. Socinski MA, Stinchcombe TE, Moore DT, et al. Incorporating bevacizumab and erlotinib in the combinedmodality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial [published online October 8, 2012]. J Clin Oncol. 2012;30(32):3953-3959.