Integrating EGFR Blockade Into Combined-Modality Therapy for Non-Small Cell Lung Cancer

Walter J. Curran, Jr., MD, FACR
Emory School of Medicine, Atlanta, Georgia

It is estimated that nearly 50,000 patients will be diagnosed each year in the United States with stage III non–small cell lung cancer (NSCLC). Of these, a minority will undergo a definitive surgical procedure as a component of their therapy. A larger number of patients will receive a combination of thoracic radiation therapy (RT) and systemic chemotherapy. For those patients with a good performance status (PS) and <5% disease-related weight loss, there is randomized trial evidence that the optimal therapy consists of systemic chemotherapy delivered concurrently with thoracic RT. In several randomized trials, such an approach for this patient subgroup has resulted in a 5-year survival rate of approximately 15%.¹⁶⁸

Several strategies have been tested to improve upon this outcome. One involves incorporating metabolic imaging, in particular positron emission tomography (PET), into both staging and thoracic RT planning. This more sensitive staging modality results in a better selection of patients likely to benefit from aggressive multimodality treatment, and its incorporation into radiation planning allows for improved definition of target versus non-target tissues. Other improvements in radiation oncology management include the integration of target movement into the treatment planning paradigm. Target movement can be accommodated for by "gating" the RT delivery to the respiratory cycle or by assisting the patient in controlling respiratory motion. There are also phase II data suggesting a benefit to delivering a higher total dose of radiation in the 74.0 Gy range in conjunction with concurrent chemotherapy.^169,170 This total radiation dose is now being compared to 60.0 Gy in an active Intergroup phase III Radiation Therapy Oncology Group trial (RTOG 0617).

Efforts have also been made to improve the therapeutic efficacy by adding additional chemotherapy either prior to or after con current chemoradiation. No clear advantage of these strategies has been observed in the setting of delivering full or near-full doses of two cycles of cisplatin-based chemotherapy during the radiation phase. Many patients in the United States receiving concurrent chemoradiation currently are treated with weekly doublet chemotherapy (paclitaxel and carboplatin) during radiation, followed by several cycles of higher-dose chemotherapy. This is the regimen in the RTOG/Intergroup trial that is testing the 74.0 Gy RT dose. Pemetrexed is under active investigation in conjunction with a platinating agent and thoracic RT for stage III NSCLC; it has the advantage of being deliverable in full doses during concurrent chemoradiation. A randomized phase II trial has been completed by the Cancer and Leukemia Group B (CALBG), with reasonable tolerance,¹⁷¹ and an inter national phase III trial comparing pemetrexed, cisplatin, and thoracic RT to cisplatin, etoposide, and thoracic RT was activated in mid-2008.

Another strategy to improve the survival of stage III NSCLC patients is to integrate targeted agents into their chemoradiation. Inhibitors targeting the epidermal growth factor receptor (EGFR) have been the most extensively studied. Clinical trials have tested the tyrosine kinase inhibitor (TKI) gefitinib in con junction with chemoradiation, both concurrently and sequentially. The largest was a randomized phase III trial conducted by the Southwest Oncology Group (SWOG 0023) comparing an established regimen of cisplatin, etoposide, and thoracic RT with adjuvant docetaxel followed by gefitinib or placebo. Accrual to this trial was terminated early by the SWOG Data Monitoring Committee because the trial had reached its futility analysis. In the most recent update of this study, survival on the placebo arm was superior to the gefitinib arm.¹⁷² The reason for this surprising result is not readily apparent, nor is it easily explainable by any differences in reported toxicity rates between the two arms. One possible explanation is that randomization in this trial occurred much later in the patients' treatment course than in most trials, and there was no prior experience in stratifying stage III patients at that point in therapy. This could have resulted in an imbalance in randomization, producing a spurious result favoring the placebo arm.

Another ongoing phase III trial is comparing an oral TKI to placebo following chemoradiation. This trial, known as D0410, is comparing erlotinib 150 mg/day versus placebo as adjuvant therapy following a chemoradiation regimen of low-dose weekly docetaxel and cisplatin plus 61 Gy thoracic radiation. A total of 400 patients are planned to be enrolled, with progression-free survival as the primary endpoint. As of the last interim report in 2008, 100 patients had been enrolled and the toxicity profile was deemed acceptable.¹⁷³

Neither of these trials capitalized on the well-described synergism of delivering an EGFR inhibitor concurrently with radiation or chemoradiation. There is strong preclinical evidence that concurrent EGFR blockade and ionizing radiation therapy results in significant enhancement of tumor kill, and that additional enhancement can occur with concurrent delivery of radiation, EGFR inhibitors, and chemotherapy.¹⁷⁴ This principle has been convincingly supported for patients with head and neck cancer by the mature results of a phase III trial comparing radiation alone with radiation plus the EGFR-inhibiting anti body cetuximab.¹⁷⁵ In this trial, 424 patients with stage III or IV squamous cell carcinoma of the head and neck were randomized to receive curative radiation with or without weekly doses of cetuximab during the radiation. With a median follow-up of 4.5 years, patients treated with cetuximab/RT enjoyed a statistically significant improvement in survival over those who received RT alone, with a median survival time of 49 months versus 29 months and a 3-year survival rate of 55% versus 45% (P=0.03). This was accomplished without enhancing the mucositis that typically occurs with concurrent delivery of chemotherapy and RT for head and neck cancer patients. Since this report, several phase I and II trials have tested cetuximab with chemoradiation for head and neck cancer patients, with promising results.^176-178 These trials have led to an ongoing phase III trial, conducted by the RTOG (0522), comparing cisplatin/RT with or without cetuximab for stage III or IV squamous cell carcinoma of the head and neck. The trial will complete accrual in 2009, with over 1100 patients planned for enrollment.

Several phase I and II trials testing the concurrent delivery of EGFR blockade with chemoradiation for stage III NSCLC have now completed. CALGB 30106 was a stratified phase II 2-cohort trial in which gefitinib was added to a regimen of induction chemotherapy followed by concurrent chemo radiation for good PS patients, and to induction chemotherapy followed by radiation alone for lower PS patients. Gefitinib was added during or following the radiation or chemoradiation portion of the regimens. Both cohorts tolerated the addition of gefitinib well, with a suggestion of enhanced survival in the lower PS cohort.¹⁷⁹

The addition of cetuximab to chemoradiation regimens for good PS stage III NSCLC patients has now been reported in preliminary form by two North American cooperative groups. CALGB 30407 is a randomized phase II trial testing concurrent pemetrexed and carboplatin with thoracic RT to 70 Gy in one arm, compared to the same regimen with the addition of weekly cetuximab.¹⁷¹ A total of 106 patients were enrolled on this trial. After a dose reduction of carboplatin from an AUC of 6 to 5, the acute toxicity was judged to be acceptable. The only toxicity seen at a higher level in the cetuximab arm was skin rash.

The RTOG reported at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO) results of a single-arm phase II trial of weekly carboplatin, paclitaxel, thoracic RT, and weekly cetuximab (RTOG 0324).¹⁸⁰ A total of 87 evaluable patients were enrolled. The acute and long-term toxicity profile was similar to that seen with concurrent chemoradiation alone. Median survival was 22.7 months, and the 2-year survival rate was 49.7%. These findings compare favorably to prior RTOG trials with similar eligibility criteria and regimens of weekly carboplatin and paclitaxel with thoracic RT. Results of RTOG 0324 lend support to a recent modification in which cetuximab was incorporated into an ongoing phase III study. RTOG 0617 is a phase III trial with a "2 x 2" design, intended to determine the value of a higher RT dose as well as addition of concurrent cetuximab to a chemo-RT regimen. This study has a targeted enrollment of 512 patients and a primary endpoint of overall survival.

Finally, there is also interest among investigators in substituting an EGFR blockade for chemotherapy during the concurrent phase of combined-modality therapy. Such a regimen could potentially provide a synergistic antitumor effect while resulting in less toxicity to normal tissue than chemoradiation. The North Central Cancer Treatment Group (NCCTG) has recently received approval to conduct a trial testing thoracic RT with concurrent cetuximab alone for lower PS patients. For better PS patients, it is anticipated that a concurrent EGFR inhibitor with an RT regimen would be either preceded or followed by several cycles of chemotherapy.

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