At the 14th International Lung Cancer Congress, held recently in Huntington Beach, California, Tony S.K. Mok, MD, Professor of Clinical Oncology at the Chinese University of Hong Kong, was the honored recipient of the Bonnie J. Addario Lung Cancer Foundation Award. The award was presented by Ms. Addario, a 9-year lung cancer survivor and nationally recognized business leader, and her husband, Tony. Dr. Mok delivered the Addario Lecture at the meeting.
“Pain, suffering, and mortality are obvious to those of us treating lung cancer,” Dr. Mok said. “The impact of this ‘war on lung cancer’ on us is great. How do we deal with it?”
Tobacco Timeline
The war began in 1492, when tobacco was discovered in the New World. It gained steam in 1902, when the cigarette rolling machine was popularized, and became entrenched in 1950, when the Marlboro Man became a household image.
Since then, smoking rates have decreased in Western countries, but this is counteracted globally by increasing rates in the East, especially Asia, where half of all tobacco consumption occurs. In China, one tobacco company alone contributes 10% of the country’s gross domestic product, and the country’s smoking rate is 1,711 cigarettes per person annually. For a population of 1.3 billion, this amounts to a “huge amount of tobacco consumed,” and accounts for billions in company profits, he noted.
“The global war on lung cancer was initiated by humans and is fueled by a desire for financial gain,” Dr. Mok observed.
‘How We Fight This War’
The Art of War is an ancient Chinese military treatise attributed to Sun Tzu, a military general, strategist, and tactician. Key principles espoused in the book can be instructional for the global war on lung cancer, according to Dr. Mok, who shared pivotal quotes.
“If you know the enemy and know yourself, you need not fear the result of a hundred battles.”
The question, he said, is whether we really know the enemy, lung cancer. “What we do know is how the cancer occurs, its appearance, where it is located, its clinical behavior, treatment outcomes, and now its genomic abnormalities,” he said. “But do we really know? Knowledge changes how we deal with it.”
With increasing understanding of the complex molecular profile of the tumor, “subgroups of subgroups” are becoming recognized. “Our general knowledge about lung cancer may or may not be applicable to all patients. It’s important to know what we don’t know. Then we can start looking for an answer.”
For example, it remains unclear why mutation patterns differ between Eastern and Western populations. In squamous cell carcinoma, the TP53 mutation is prominent, but a means of targeting it has eluded researchers. Primary resistance occurs irrespective of tyrosine kinase inhibition of the driver oncogene, but why? Why is there heterogeneity between the primary and nodal or distant lesions?
“We must have ways to tackle what we don’t know,” he said. But the “greatest fear,” he continued, “is that we don’t know what we don’t know. It will take a global effort to know our enemy better.”
“In war, the way is to avoid what is strong and to strike at what is weak.”
“This is common sense, but when, if ever, does lung cancer become weak?” Dr. Mok questioned. This is an area that needs dedicated research, to be able to exploit the tumor both in the early and later stages. Currently, the approach is to treat local disease and hope for a response, then wait until the disease progresses before re-treating, but it is possible that “hitting” the tumor while it is already under attack might be a good idea, he said.
“Supreme excellence consists of breaking the enemy’s resistance without fighting.”
If a tumor’s resistance to treatment could be overcome, the war would be won, he said. The problem is that only the tumor—not the clinician—understands this resistance. “This is how lung cancer fights us: by innate immune resistance,” he said. “Our immune system tries to fight it, but the cancer evades us.”
With the novel anti–programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies, treatment is getting “smarter”; however, PD-1/PD-L1 is only one means by which cancer deceives the complex immune system, Dr. Mok noted. “We need to learn a lot more in order to use the immune system to fight cancer.”
“Strategy without tactics is the slowest route to victory. Tactics without strategy is the noise before defeat.”
Most optimal treatment strategies prove to be short-lived, therefore, researchers must continually refine their moves, Dr. Mok emphasized.
“Our current tactic is to identify a molecular target and conduct randomized trials to prove a target agent is better than standard therapy. This has made a difference to our patients and changed our treatment paradigm. However, this tactic may not be sufficient for us to win the war on lung cancer. For such, we must reexamine our strategy,” he said. Identifying new mutations and pairing patients with relevant drugs is a good start, but even that tactic is flawed, he said.
Strategy on Research Funding
The current approach is to aim for novel discoveries, primarily through academic-based research. This leads to the development of a drug and a biomarker, which is evaluated in a clinical trial whose objective is registration of the drug. If successful, the drug becomes available and is further studied for different indications.
“This general strategy is reasonable, but there is a problem, and that is how we place our ‘soldier’ in this war. The soldier is the money,” Dr. Mok suggested.
The vast majority of research funding is directed toward clinical research, the goal being to fulfill the criteria set by the Food and Drug Administration and to achieve registration of the drug. “What if we put that amount of money into novel discovery efforts? Think of how much more we could learn about the enemy,” he maintained.
If the drug approval process eliminated the need for large phase III trials to evaluate drugs for uncommon targets, and if the process were carried out on a global scale, rather than country by country, that would also be more efficient and cost-saving, he pointed out.
‘Me Too’ Strategy
Finally, Dr. Mok called for streamlining the drug pipeline. For example, there are currently 12 MET inhibitors on the “short list” in development. “Do we need that many?” he asked. “Because of the ‘me too’ strategy, one company makes a nice discovery and everyone wants a piece of that market.”
“We are fighting this war on an individual scale and also among each other. Is it possible we can combine forces as a group? This would save money, effort, and patient resources,” he said.
Collaboration may be ideal, but it is not without its obstacles. “We have to be humble to do this, to eliminate products. Everyone looks at their baby as beautiful, and we all agree, ‘Yes, your baby is beautiful,’ as a matter of courtesy. But if we had an external tribunal that looks at the pipeline as a whole, maybe its advice would be, ‘Your baby doesn’t look that good, after all.’ This is difficult, but we need to change our ‘me too’ strategy and do this!” he insisted.
‘Me Better’ Strategy
The “me better” strategy should also be reconsidered, he continued. For example, studies of maintenance therapy with both pemetrexed (Alimta) and bevacizumab (Avastin) found median survival to be around 12 months. To determine which of these might actually be superior, the PRONOUNCE trial was conducted. “No surprise, they were exactly the same,” he noted. “Millions of dollars were spent in order to know that the benefit of these drugs is the same.”
“Small differences won’t help cancer patients, only big differences. When we invest in finding small differences, we lose out on our soldier and our money,” he said. “Unfortunately, I have done many of these studies, spending too much money to learn too little and provide limited benefit to the patient.” He said he would welcome a philosophical shift in which companies aim to maximize patient benefit, rather than profits.
In closing, Dr. Mok remembered Martin Luther King. “He had a dream, and today Barack Obama is President.… I hope to wake up from my own dream some day and say, ‘Take that, lung cancer! We won!’” ■
Disclosure: Dr. Mok receives honoraria from AstraZeneca, Eli Lilly, Eisai, F. Hoffman-LaRoche, Merck Serono, Bristol-Myers Squibb, BeiGene, Pfizer, Boehringer Ingelheim, AVEO, Taiho, and GlaxoSmithKline Biologicals; he is a speaker for AstraZeneca, Eli Lilly, Boehringer Ingelheim, F. Hoffmann-La Roche, and Merck Serono; and he receives research funding from AstraZeneca.
