Radiation Oncology/NSCLC/Miscellaneous

Role of Amifostine

 * RTOG 98-01 (1998-2002)
 * PMID 15800308, 2005 &mdash; "Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01." Movsas B et al. J Clin Oncol. 2005 Apr 1;23(10):2145-54.
 * 120 pts. Stage II-III NSCLC. Induction chemo and hyperfractionated RT with concurrent chemotherapy, randomized to +/- Amifostine.
 * Grade 3 esophagitis 30% (Amifostine) vs 34%, N.S. However, improved swallowing diary area under the curve suggests a possible benefit.

Gefitinib (Iressa)
Is an inhibitor of the tyrosine kinase domain of EGFR. EGFR is overexpressed in 40-80% of NSCLC.


 * Harvard, 2004 - PMID 15118073 &mdash; "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib." Lynch TJ et al. N Engl J Med. 2004 May 20;350(21):2129-39.
 * Most patients with NSCLC have no response to gefitinib, however about 10% show a rapid and dramatic response.
 * A subgroup of patients with NSCLC have specific mutations in the EGFR gene which correlate with response to gefinitib. The mutations lead to increased growth factor signaling
 * Conclusion: screening for EGFR mutations may enable selection of patients who will respond to treatment with gefitinib.


 * IDEAL (Iressa Dose Evaluation in Advanced Lung Cancer) trials
 * Previously treated NSCLC who failed 1-2 prior chemotherapy regimens.
 * IDEAL-1: PMID 12748244 &mdash; "Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial)" Fukuoka M et al. J Clin Oncol. 2003 Jun 15;21(12):2237-46.
 * IDEAL-2: PMID 14570950 &mdash; "Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial." Kris MG et al. JAMA. 2003 Oct 22;290(16):2149-58.
 * Both trials tested 250 mg vs 500 mg daily doses and showed no difference in efficacy but fewer side effects in the low dose arm.

Erlotinib (Tarceva)
Is a tyrosine kinase inhibitor.


 * NCI Canada Clinical Trials Group trial BR.21
 * PMID 16014882 &mdash; "Erlotinib in previously treated non-small-cell lung cancer." Shepherd FA et al. N Engl J Med. 2005 Jul 14;353(2):123-32.
 * 731 pts. Stage IIIB-IV who received 1-2 prior chemotherapy regimens. Randomized to erlotinib vs placebo.
 * Response rate 8.9%. PFS 2.2 vs 1.8 months (placebo), S.S. OS 6.7 vs 4.7 m (HR = 0.7).


 * TRIBUTE trial
 * PMID 16043829 &mdash; "TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non-Small-Cell Lung Cancer." Herbst RS et al. J Clin Oncol. 2005 Sep 1;23(25):5892-9.p
 * 1059 pts. Stage IIIB/IV. Randomized. Received 6 cycles of carboplatin and paclitaxel, combined with erlotinib vs placebo.
 * No difference in OS or TTP. Pts who never smoked had improved OS with erlotinib, 22 vs 10 months.

Predictors of response:
 * PMID 16043828 &mdash; "Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With Non-Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib." Eberhard DA et al. J Clin Oncol. 2005 Sep 1;23(25):5900-9.
 * From TRIBUTE trial, treated with chemotherapy +/- erlotinib. EGFR mutations (in 13%) associated with improved survival in all arms. Among those receiving erlotinib, there is an improved response rate for those with EGFR mutations and a trend toward improved TTP but no difference in survival. K-RAS mutations (21%) associated with decreased TTP and survival.