March 2011

Few books have attracted as much interest and impassioned debate around the Frankel Group offices recently as Siddhartha Mukherjee’s The Emperor of All Maladies.

Styled as a “biography of cancer,” Mukherjee’s journey of the scientific, intellectual, cultural and, yes, personal, impacts of cancer through the centuries is a masterful achievement. Mukherjee – a medical oncologist trained at the Dana Farber and Harvard Medical School and now at Columbia Presbytarian – has crafted an astonishingly page turning narrative. His achievement has been widely praised. Mukherjee writes with an expert command of the science. But it is his vivid emotional life as an oncologist which separates his work from other popular science. He even shamefully admits that he thought a patients’ death would conclude his book (She does not oblige).

From this real, messy account of patients, fellow residents, and brilliant but flawed scientists, we see cancer’s arch through history. Treatment evolves from hospice, to surgery, to the blunt murder of all dividing cells (malignant or not), past the promise of the atomic age, towards today’s exquisitely targeted treatments. Each age brings its own grand theory, a unifying and tempting vision of a singular way to fight cancer. Perhaps we are simply not removing enough tissue around the tumor. Or our chemotherapies are not dosed highly enough. Or we are not interrupting the correct pathway.

These approaches are straightforward, obvious – and wrong; or, more accurately, incomplete. Each new approach brings promise, and progress, but the tumors evade any single approach. Mukherjee’s vision of cancer is heavily informed by our experience with HIV – something we might learn to live with, not die from – and he encourages us to play small ball. He wants to hit singles and doubles, inning after inning, until we find cancer to be just another chronic illness, instead of continuing to swing for the fences and striking out.

For us at The Frankel Group, trying to draw lessons from Mukherjee’s masterful history, two things jump out:

1. The Importance of Intellectual Infrastructure: Advances in the basic science of disease progression and translating that work into medicines is often seen as the essential element of creating cures. But developing new ways of thinking, not just new compounds, is just as important. A core intangible intellectual infrastructure must serve as scaffold for those tangible discoveries.

Two examples: Mukherjee tells us that those opposed to the horrible disfigurement of radical mastectomy had difficultly ending the practice because they lacked the statistical tools needed to prove non-inferiority in a clinical trial. Today, those tools are an essential part of improving the safety profile of oncology treatment regimens.

Similarly, Sidney Farber failed to translate his experiences with the first anti-folates into a widespread anticancer strategy until he and others developed a common language of protocols. This common language then made possible multi-site trials run by fledgling cooperative oncology groups. Today, multi-site trials are standard procedure in virtually all drug development.

Companies at the forefront of new anti-cancer modalities today, such as immune therapies and cancer vaccines, are finding that an intellectual infrastructure built for evaluating chemotherapies is ill-equipped to assess their new approaches. Beyond drug development and patient recruitment, they too are arguing that novel intellectual infrastructure – such as new measures of tumor response – are needed.

2. All Drugs Fail – even the ones which work: Almost without exception, the anti-cancer medicines which broke new ground in modality and approach (Herceptin, Gleevac, Avastin, and so on) failed, and sometimes spectacularly.

To pick just one of many examples: Avastin failed to meet its primary endpoint of progression free survival in a phase III breast cancer trial in 2002. Yet Genentech kept at it, and it was ultimately launched in 2004 for metastatic colorectal cancer. Avastin is not a wonder drug, and not without controversy, but sales are well north of $2 billion and it just recently showed compelling positive data in ovarian cancer.

After each setback or clinical failure, Mukherjee finds the zealots – both committed scientists and very brave patients – who pushed through. Often this entailed substantial pressure on corporate managers and regulators, without any assurance of success.

Today, investors and strategists are told to expect failure for the vast majority of biotech’s portfolio. (One respected analyst just called for a “Chief Dead Drug Officer” in the C-Suite of large pharma). Indeed, failure is the norm. But unless the most novel new approaches are given second, or third, chances, there is real risk of premature abandonment. As financing for early stage compounds tightens, this problem may be accelerating.

Mukherjee here has little to say – he barely touches on the astronomical cost of drug development or novel medicines. But he does warn us that the next great hope for a singular attack on cancer (cancer vaccines again come to mind) is more likely to be a double than a home run.










About the author: Dan Rosan is a consultant at the Frankel Group. To contact him regarding this post, email blog@frankelgroup.com.