NEW YORK—The advent of molecular profiling is the future of thoracic oncology and incorporating novel therapies into combined modality treatment is the future for locally advanced non-small-cell lung cancer (NSCLC), according to a talk here at the Perspectives in Thoracic Oncology meeting.
“The new molecular targeted agents, such as are being tested in the RTOG 1306/Alliance 31101 trial, are going to define how we move forward in this field,” said Anne S. Tsao, MD, Associate Professor and Director of the Thoracic Chemo-Radiation Program at the University of Texas MD Anderson Cancer Center.
Until then the field is open, she said, as some novel agents that had seemed hopeful have not done well in clinical trials. “We know systemic therapy can give a clear survival benefit in stage III disease—particularly when you can downstage these patients—but distant relapse still remains a significant cause of death in stage III patients. If we could just improve our systemic treatment, I think we could see a vastly improved outcome.
Individualizing combined-modality therapy is the aim of the new stage III RTOG 1306/Alliance 31101 for unresectable stage III NSCLC trial, with treatment based on the EM4-ALK biomarker. Tsao called discovery of the EML4-ALK fusion gene one of the biggest developments in the treatment of advanced NSCLC.
That gene—echinoderm microtubule associated protein-like 4-anaplastic lymphoid kinase—is found primarily in adenocarcinoma patients who are never- or light-former smokers, who have tumors that overexpress EGFR and wild type KRAS wild type, and are younger.
Treatment includes erlotinib induction for patients with EGFR overexpression, and crizotinib induction for those with ALK translocation. Patients in each arm of the study are then treated with concurrent chemoradiotherapy.
Tsao said targeted therapy and chemoradiotherapy may prove to be most appropriate for patients determined by molecular profiling to have this negative prognostic factor. “This trial may change our standard of care for these patients. Given that we are molecularly targeting so many more of our patients and developing targeted agents for them, this may be our future.”
Other avenues, though, have not been as promising, she noted:
- Maintenance gefitinib, following the SWOG 9504 regimen, is not appropriate and may be harmful in unselected stage-III NSCLC patients;
- Pemetrexed-based therapy should not be given in squamous cell carcinoma;
- Bevacizumab plus chemoradiotherapy led to high rates of morbidity in SWOG 0533; and
- Results of RTOG 0617 are awaited to define a role for cetuximab.
Cetuximab Initially Promising
Cetuximab, the IgG1 chimerized antibody to EGFR that blocks binding of EGF/TGF-alpha to EGFR, potentiates apoptosis, inhibits cell cycle progression, decreases production of angiogenic factors, and inhibits invasion and metastasis. Cetuximab is currently approved by the Food and Drug Administration for head and neck cancer with radiation, and also colorectal cancer.
For lung cancer, she noted, the results with cetuximab were positive in the Phase II RTOG 0324 trial, which treated 84 patients with cetuximab before and after paclitaxel-carboplatin-cetuximab and radiotherapy, followed by paclitaxel-carboplatin-cetuximab.
With a median follow-up of 21.6 months, the objective response rate was 62 percent, with a 29 percent rate of complete response. Progressive disease occurred in 11 percent of patients (Blumenschein et al: JCO 2011; 29: 2312-2318). Median overall survival was approximately 23 months.
And based on RTOG 0324, the large Phase III RTOG 0617 study of 419 patients was planned, with 237 patients receiving cetuximab (Bradley et al: ASCO 2013, Abstract 7501 ). Tsao said this is the trial that it is hoped will be used as the basis for the drug receiving approval for stage III NSCLC.
“Unfortunately, though,” she said, “there was no difference in the rate of distant metastases with cetuximab and no significant benefit in overall or progression-free survival.” Furthermore, there was higher overall grade 3-5 toxicity among patients who received cetuximab vs. those who did not, as well as higher non-hematologic grade 3-5 toxicities.
However it may be that patients with EGFR immunohistochemistry H-scores of 200 or greater had more benefit with cetuximab, she said, and further investigation should be made.
Another trial of cetuximab added it to pemetrexed, Tsao continued. As reported at the 2009 ASCO Annual Meeting, the CALGB 30407 trial tested the combination of carboplatin-pemetrexed vs. carboplatin-pemetrexed-cetuximab in patients with squamous cell carcinoma or NSCLC (Govindan et al, Abstract 7505).
“Cetuximab didn't add much,” she said. The median failure-free survival was 13 months for patients receiving carboplatin-pemetrexed vs. 12 months for those in the carboplatin-pemetrexed-cetuximab group, and overall response rates were 28 and 34 percent, respectively. There was a statistically significant advantage in patients with NSCLC vs. squamous cell carcinoma. “We think squamous cell carcinoma has an intrinsic mechanism of resistance to pemetrexed,” she said.
Use of cetuximab in combination with chemotherapy and radiation for locoregionally advanced NSCLC remains investigational, but identification of a predictive biomarker would be beneficial, she added. Meanwhile, cetuximab is not likely to be widely used in stage III NSCLC.
Gefitinib was another agent with disappointing results in NSCLC. SWOG 0023, with patients with unresected IIIA or IIIB NSCLC, showed that gefitinib maintenance therapy after concurrent chemoradiation (cisplatin, etoposide, and 61 Gy radiotherapy) and docetaxel consolidation therapy improved neither progression-free or overall survival compared with placebo. “In fact, it is possible that gefitinib may have a detrimental effect,” Tsao said, adding, though, that this remains under investigation.
But, long-term survival results were shown to be impressive with maintenance gefitinib in the SWOG 9504 trial for patients with stage IIIB NSCLC—“Certain subsets of stage IIIB can have a survival range of 20 to 37 percent,” she said. “Confirmatory randomized trials are needed, but cisplatin/etoposide given concurrently with radiation followed by docetaxel for three cycles is an appropriate regimen to use in stage IIIB NSCLC.”
Finally, she said, AE-941, a standardized cartilage extract from dogfish shark, has not been shown to be beneficial in lung carcinoma, even though preclinical data had given support for its having antiangiogenic and antitumor activity.