editorials

n engl j med 371;23 nejm.org december 4, 2014 2227

Cancer-Drug Discovery — Let’s Get Ready for the Next PeriodDan L. Longo, M.D.

The use of drugs to treat cancer began about 70 years ago. After World War II, Louis Goodman and Alfred Gilman and their colleagues at Yale University noted that people who had been ex-posed to mustard gas often had bone marrow suppression. They identified the active chemical moiety in the gas, gave it to patients, and saw responses in patients with hematologic cancers.1 Thus, alkylating agents were developed and be-came key components of treatments for many forms of cancer.

Not all useful drugs emerged as a product of accurate hypotheses. Sidney Farber mistakenly thought that leukemic cells looked megaloblas-tic, and so he gave folate to some children with acute leukemia. Their disease accelerated, and the children died. This led to the hypothesis that an antifolate agent might be effective, and aminop-terin and amethopterin (methotrexate) were born.2

The most remarkable progress in the past two decades has come from a shift in focus from screening compounds for growth inhibition of tumor cell lines in culture in a mechanism- agnostic fashion3 to identifying novel therapeutic targets through genetic and cell biology studies of cancers. The prototype of this class of agents is imatinib, an inhibitor of the BCR-ABL onco-gene product that is formed by the t(9;22) trans-location and that is central to the pathogenesis of chronic myeloid leukemia (CML).4 The efficacy of imatinib in patients with CML is high, but the agent is not curative (high-dose chemother-apy plus hematopoietic stem-cell transplantation is the only known curative therapy for CML). Pa-tients take imatinib for years, for as long as it continues to work. CML is an unusual cancer in that, for the most part, a single factor, the BCR-ABL chimeric gene product, drives the tumor. The success of imatinib in patients with CML has given rise to a new strategy in cancer treat-ment: find the driver and disable it.

In most solid tumors, multiple genes (10 to >100) are mutated,5 different cells in the tumor have distinct genetic lesions,6 and it is not al-ways clear that a particular mutation is a critical one. Molecular analysis has led to the notion that many tumors that look alike under the mi-

croscope are not alike. The new nosology of tu-mors has identified multiple genetic varieties of tumors that used to carry the same diagnosis. Treating patients whose tumors have activating mutations in the epidermal growth factor (EGF) receptor with EGF-receptor blockers and tumors with activating mutations in BRAF with BRAF blockers, and so on, has produced some dra-matic transient responses but no cures.7,8 After a few months, the tumor seems to adapt to the blockade and find a way around it by amplifying the key gene, activating an alternative pathway, mutating the target so that the drug no longer blocks its function, or pumping the drug out before it can do damage — or by other mecha-nisms that are being elucidated through a study of sequential biopsy specimens of tumors.

In this issue of the Journal, Solomon and col-leagues9 report the superiority of the ALK inhibi-tor crizotinib over chemotherapy as the primary treatment in the subgroup of patients with lung cancer whose tumors bear activating transloca-tions involving the ALK gene. Responses to crizo-tinib were observed in 74% of the patients, and the median duration of response was nearly 11 months (as compared with a 45% response rate and a 7-month median duration of response with chemotherapy). Patients who were treated with crizotinib had improvements in quality-of-life measures as well.

Unanswered questions include the following: Why did 26% of the patients who received crizo-tinib not have a response? Why did the drug stop working in those who had initially had a response? Are there combinations of agents that might convert good partial responses to durable complete responses? Would crizotinib be effec-tive against tumors originating in other organs that also had ALK activation?

Crizotinib joins the growing list of kinase in-hibitors that are active in particular (sometimes very small) subgroups of patients. Many of these agents are producing tumor regressions in can-cers for which no other therapy has shown even minimal activity. In the case of the ALK inhibi-tors, even more effective drugs are in the pipe-line that produce even longer responses (median,

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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18 months) and are effective against central nervous system metastases.10 Solomon et al. have proved the superiority of crizotinib over chemo-therapy in a rigorous way, but the phase 2 results anticipated the findings. It may not be possible to perform phase 3 studies in molecular disease entities that are even more rare, such as the ROS-activated lung cancers.

We are coming to the end of the first period of the game. We are just beginning to under-stand our opponent’s offensive and defensive strategies. The outcome of the game will depend on our making adjustments in our strategy as the game continues: combining therapies, mixing in immune approaches, and adding new players.

However, we need to remember that these drugs also have toxic effects, they are enor-mously and inappropriately expensive, and they haven’t cured anyone yet. It is premature to be opening the victory champagne bottles.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

1. Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-

chloroethyl) amine hydrochloride for Hodgkin’s disease, lym-phosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc 1946;132:126-32.2. Farber S, Diamond LK. Temporary remissions in acute leu-kemia in children produced by folic acid antagonist, 4-aminop-teroyl-glutamic acid. N Engl J Med 1948;238:787-93.3. Grever MR, Schepartz SA, Chabner BA. The National Cancer Institute: cancer drug discovery and development program. Semin Oncol 1992;19:622-38.4. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-7.5. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science 2013;339: 1546-58.6. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor hetero-geneity and branched evolution revealed by multiregion sequenc-ing. N Engl J Med 2012;366:883-92.7. 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 2004; 350:2129-39.8. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707-14.9. Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77.10. Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rear-ranged non–small-cell lung cancer. N Engl J Med 2014;370:1189-97.

DOI: 10.1056/NEJMe1412624Copyright © 2014 Massachusetts Medical Society.

Surgery for Ischemic Mitral RegurgitationThoralf M. Sundt, M.D.

Defining the appropriate management of mitral regurgitation secondary to ischemic heart dis-ease — as opposed to primary disease such as rheumatic or myxomatous degeneration — has proved elusive. Coronary artery disease is com-mon, and so is associated mitral regurgitation, at least to some degree. The latter has been rec-ognized as an unfavorable prognostic sign for more than 25 years1 and thus has been a target of surgical interest, with the goal of negating the adverse effects on late survival without pay-ing too much of an up-front cost in terms of perioperative mortality.2 When the regurgitation is severe, debate has centered on the role of mi-tral-valve repair versus replacement, as recently addressed in the Journal by Acker and colleagues.3 When the regurgitation is only moderate, how-ever, the question has been whether coronary revascularization alone will suffice or whether intervention on the valve is required. Smith and colleagues4 now report in the Journal the results

of a randomized trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve annuloplasty.

This study is a notable contribution. There are precious few prospective, randomized stud-ies addressing valvular heart disease of any kind and even fewer involving surgical therapies. The Cardiothoracic Surgical Trials Network was es-tablished to address this deficiency, and this study is proof that it is capable of doing just that. Admittedly, the negative result is disap-pointing to the surgeon hoping to “fix the prob-lem” directly and is counter to the popular sur-gical trend to encourage valvular intervention, but it cannot be said to be entirely unexpected. A number of observational studies over the years have shown much the same.5-7 But does this result showing no significant difference be-tween the two surgical approaches put the de-bate to rest? Unfortunately, I think not.

The trial as described suffers from the same

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