It was thousands of years ago in China. An elderly man was unhappy with the mountain that embraced his seaside village. He would need to walk for hours before he could reach the nearest town. So, as the old fable goes, he set his mind to move the mountain. Every day, he dug up basketfuls of rocks and dirt and dumped them into the sea. His neighbor got curious and finally asked: “Ha! Old man, are you sure that you can move the mountain in your lifetime by chipping away rocks and dirt like this?” The old man paused from his hard labor and responded: “I doubt if I can. But if I can’t, my son will continue with the task. And if he can’t, his son will, and his son’s son will….” This fable did have a happy ending. God, being impressed by the man’s persistence, moved the mountain for him.
Lung cancer is our mountain, and it is unlikely that God will move this mountain on our behalf. The only way to move the mountain is to chip away the rocks and dirt one basket at a time. With the discoveries of EGFR mutations in 2004 and ALK rearrangements in 2007, we managed to take a chunk out of this huge mountain.1-5
More recently—as reviewed in this issue of The ASCO Post—Shaw et al6 have successfully removed another big rock by demonstrating the clinical efficacy of crizotinib (Xalkori) in 50 patients with ROS1 rearrangement. They reported a tumor response rate of 72% and a median progression-free survival of 19.2 months. These outstanding results will likely lead to approval of crizotinib as a standard therapy for patients with ROS1 rearrangement. This is truly remarkable, but a number of key questions remain.
Still Searching for Answers
Should all patients with newly diagnosed adenocarcinoma be routinely screened for ROS1 rearrangement and receive first-line crizotinib if they harbor the alteration? The efficacy of crizotinib in ROS1-rearranged lung cancer appears to be similar to, if not better than, the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in patients with EGFR mutations and that of crizotinib in ALK-positive lung cancer.
Multiple randomized phase III studies3-5 have confirmed the role of first-line tyrosine kinase inhibitor treatment for EGFR-mutant and ALK-positive lung cancer, but it will be extremely difficult to complete an adequately sized randomized phase III study to confirm the superior efficacy of crizotinib over chemotherapy in treatment-naive ROS1-positive patients. It may be reasonable to assume that crizotinib has similar first-line efficacy in this setting, as it does in patients with ALK rearrangement. Only 7 of 50 ROS1-positive patients in the Shaw et al study were treatment-naive, and their treatment outcomes were not specifically documented. It is debatable whether we should act on assumptions alone. Or, should crizotinib be reserved only as second-line therapy for ROS1-positive patients?
Another important question is how we should develop targeted therapy for patients with uncommon driver oncogenes, such as BRAF mutation or RET rearrangement. The Shaw et al study sets an important precedence. The prevalence of ALK rearrangement is 3% to 5%, whereas most of the other actionable driver oncogenes are much less common. The impressive high tumor response rate and long progression-free survival in this single-arm study are the first and most important data that will support the approval of crizotinib in ROS1-positive patients. However, we cannot assume treatment efficacy to be equally impressive in other patient cohorts. Results in a European cohort are pending, and an Asian cohort is still accruing. What if the response rate is lower or the progression-free survival is shorter in these cohorts? What should be the cutoff threshold in a single-arm study? How should we estimate sample size for this type of single-arm “registration” study?
The study by Shaw et al faced such issues. Their statistical plan was to test the null hypothesis of a response rate of less than 10% or the alternative hypothesis of a response rate of over 30%. However, this plan didn’t contribute directly to the final decision on sample size. The maximum of 50 patients was an arbitrary decision to allow accurate assessment of treatment outcome. Similar challenges will confront the development of drugs targeting other uncommon driver oncogenes.
Persistence and diligence are the teachings behind the ancient Chinese fable. Although targeted therapy for ROS1 rearrangement is another meaningful addition to personalized medicine for lung cancer, we still have far to go in moving the mountain. We can only keep on digging. ■
Disclosure: Dr. Mok is a consultant and speaker for Pfizer, AstraZeneca, Eli Lilly, Merck Serono, Roche, and Novartis.
References
1. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.
2. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007.
3. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.
4. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013.
5. Mok T, Kim D-W, Wu Y-L, et al: First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): Results of a phase III study (PROFILE 1014). 2014 ASCO Annual Meeting. Abstract 8002.
6. Shaw AT, Ou S-HI, Bang YJ, et al: Crizotinib in ROS-1 rearranged non-small-cell lung cancer. N Engl J Med 371:1963-1971, 2014.
Dr. Mok is Li Shu Fan Medical Foundation Professor of Clinical Oncology, Department of Clinical Oncology, at the Chinese University of Hong Kong.
