ASCO 2014 Report — Lung Cancer

Meeting Report |
June 20, 2014

ASCO 2014 Report — Lung Cancer

  1. Anne Tsao, MD

Highlights of new findings in non–small-cell lung cancer

  1. Anne Tsao, MD

At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2014), held May 30 through June 3 in Chicago, specialists discussed the latest cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to cover key presentations at the conference. Here, Anne Tsao, MD, reviews key positive and negative lung cancer studies.

Adjuvant Erlotinib Therapy in Resected Non–Small-Cell Lung Cancer

Two studies — by Kelly and colleagues (abstract 7501) and Shepherd and colleagues (abstract 7513) — reported on the international phase III RADIANT trial. The trial evaluated the use of adjuvant erlotinib (an epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) versus placebo in 973 patients with stage IB-IIIA, EGFR-positive, non–small-cell lung cancer (NSCLC) after they underwent resection with or without chemotherapy. The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and DFS and OS in patients with EGFR-mutation (del19/L858R). The study had an unusual statistical design with a hierarchical testing system that made secondary endpoint testing nonsignificant.

After a median follow-up of 47 months, no significant difference in DFS was seen in the intent-to-treat population, and the OS median was not reached in either arm. In a subgroup analysis of 161 patients with EGFR mutation (55% with del exon 19, 45% with exon 21 L858R), 102 patients treated with erlotinib had improved median DFS compared with 59 patients who received placebo (46.4 vs. 28.5 months; hazard ratio, 0.61; P=0.039). No preliminary between-group difference in OS was observed. Among EGFR-mutation patients, erlotinib recipients were more likely than placebo recipients to experience recurrence in the brain (40% vs. 13%) and less likely to experience bone metastases (14% vs. 29%).

It is clear from the developing body of literature that the use of an adjuvant EGFR tyrosine kinase inhibitor has no clinical benefit in unselected NSCLC patients. Although other reports have shown that this approach provides a benefit in EGFR-mutation patients, data are insufficient to justify it as standard-of-care practice. The ALCHEMIST trial is underway to further evaluate this and other novel adjuvant agents in mutation-specific populations.

Ceritinib Active in ALK-Positive NSCLC

In the prior dose-escalation portion of the international ASCEND-1 trial of oral ceritinib (LDK378) in patients with ALK-positive NSCLC, the maximum tolerated dose was determined to be 750 mg daily. Now, Kim and colleagues report results from the trial's dose-expansion cohort of 246 patients who received treatment at the recommended dose (abstract 8003). Of these patients, 67% had received more than two prior therapies.

The overall response rate (ORR) was 60%, with a median duration of response of 9.7 months. The time to first response was 6.1 weeks, and median progression-free survival (PFS) was 7 months. The 59 ALK-inhibitor–naive patients had an ORR of 69.5% but had not yet reached the median duration of response or PFS. In the subgroup of patients who previously received ALK-inhibitor therapy, the ORR was 55.4%, duration of response was 7.4 months, and median PFS was 6.9 months. The most common toxicities were diarrhea, nausea, vomiting, fatigue, and elevated liver function tests. A total of 52% of patients required dose reductions due to toxicities, and 9.4% discontinued treatment.

Ceritinib at 750 mg daily has significant activity in ALK-positive NSCLC and provides an additional treatment option for crizotinib-refractory patients. The FDA approved ceritinib for this indication on April 29, 2014. It remains to be determined whether ceritinib or crizotinib should be used upfront in this population and how these inhibitors should be sequenced for optimal effect.

CO-1686 Promising for Patients with EGFR-Mutation NSCLC

Sequist and colleagues conducted a dose-finding study of CO-1686, a third-generation, oral, covalent, EGFR-mutation, tyrosine kinase inhibitor that spares wild-type EGFR (abstract 8010). The agent is thought to have activity against common activating EGFR mutations and the T790M-resistance mutation. Updated results were presented from the ongoing phase I/II trial (NCT01526928), which enrolled previously treated NSCLC patients with activating EGFR mutations. The phase II trial involved NSCLC patients with T790M-positive biopsy at the time of trial entry and patients who had disease progression while receiving EGFR-directed therapy.

The best response in pretreated T790M-positive patients in the phase I and early phase II cohort (40 patients) was ORR 58% and median PFS not reached. Responses were seen in the central nervous system with brain metastases. The main toxicities of any grade included nausea, hyperglycemia, mild diarrhea, vomiting, and anorexia. No patient experienced grade-4 toxicity, but grade-3 hyperglycemia was observed. Based on initial promising results, CO-1686 received FDA breakthrough designation on May 19, 2014, for EGFR-mutation NSCLC. The TIGER program intends to further develop this agent in EGFR-mutation patients with phase II and III trials of front-line to salvage therapy in a randomized comparison with chemotherapy.

Negative Results for Onartuzumab, Development Halted

Spigel and colleagues reported phase III results from the METLung (OAM4971g) global trial of onartuzumab plus erlotinib versus erlotinib alone in previously treated patients with stage IIIB or IV NSCLC (abstract 8000). A prior randomized phase II trial showed a PFS benefit in MET-positive NSCLC patients who received onartuzumab plus erlotinib versus erlotinib alone. The current multicenter, randomized, placebo-controlled, phase III trial enrolled 499 MET-positive patients; MET status was determined by immunohistochemistry assay with the CONFIRM anti-total MET SP44 monoclonal antibody.

Onartuzumab plus erlotinib was negative for response, PFS, and OS. The combination also had more toxicity with peripheral edema, dyspnea, hypoalbuminemia, nausea, rash/dermatitis, and back pain. Due to the completely negative results, Genentech is halting all further development of onartuzumab.

Editor Disclosures at Time of Publication

  • Disclosures for Anne Tsao, MD at time of publication Consultant / Advisory board Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Speaker’s bureau Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Grant / Research support Department of Defense; SWOG Leadership positions in professional societies American Medical Association (Member); American Association of Cancer Research (Member); American Society of Clinical Oncology (Member); AACR-Women in Cancer Research (Member); International Mesothelioma Interest Group (Member); SWOG (Member); International Association for the Study of Lung Cancer (Communications Committee Chair); American Radium Society (Chair); RTOG (Member)

Reader Comments (2)

Barry H Kaplan, MD, PhD Physician, Oncology, Queens Medical Associates

It is outrageous that you would comment at all on the RADIANT trial one of the worst and most useless study presented at ASCO in years. Most of the patients were selected based on overexpression of EGFR not mutational status and then a small unplanned subgroup analysis was done. That this useless study was presented is outrageous and that you are dumb enough to cite it is a poor reflection on you and ASCO. I do agree that there are no good adjuvant studies available yet but there are patients for whom I would use targeted therapies. Dr. Kris has been doing this for some time. Ask him for comments

J Kako

It's outrageous that one out of one trials (as opposed to one out of three trials commented here) you made a comment on happened to be the one you claimed to be outrageous.

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