The Pill That Could · The Patients Who Waited

The Patients Who Waited, part 4

Jürg Zimmermann, the chemist who had actually made the molecule — who had synthesized, optimized, and refined the 2-phenylaminopyrimidine series until it produced the compound that became imatinib — retired from Novartis a few years ago and lives, the last I knew, in the Basel area. He has not been a frequent presence in the public-facing accounts of the imatinib story; the chemist who made the drug is, in a pattern that recurs across pharmaceutical history, often less visible than the clinician who tested it. Zimmermann's work was extraordinary. The drug exists because of it.

* * *

What does the whole story add up to, looking back?

It adds up, first, to a single drug for a single disease. CML, a disease that killed two-thirds of patients within ten years in 1990, kills a small fraction of patients within ten years in 2026, and the patients who die of CML in 2026 are mostly the ones whose disease presented in advanced phase, or who could not tolerate the drug, or whose disease developed mutations that the available drugs could not address. The bulk of CML patients now live normal lives. This is, by the standards of any other oncology indication, an unusual outcome. It is also the central thing the story this book has told actually delivered.

It adds up, second, to a paradigm. The targeted-therapy approach — identify the molecular driver, design a drug to inhibit it, give the drug to patients identified by a molecular test — has, since imatinib, been the dominant frame of cancer drug development. Some of the drugs that have come out of this paradigm have produced benefits comparable to imatinib's; many have produced smaller benefits; some have produced none. Cumulatively, across cancers, the paradigm has saved or extended the lives of an enormous number of people. It has not delivered the universal solution that the 2001 coverage sometimes implied it would. It has delivered an enormous number of partial solutions, in particular cancers, for particular patients, that did not exist before.

It adds up, third, to a way of thinking. Cancer, in 1990, was understood by most physicians as a category of disease defined by the organ of origin — breast cancer, lung cancer, colon cancer, leukemia. Cancer, in 2026, is increasingly understood by most physicians as a category of disease defined by molecular features — EGFR-mutant lung cancer, HER2-positive breast cancer, BRAF-mutant melanoma, KRAS-G12C cancer, BCR-ABL-positive leukemia. The unit of clinical thinking has, slowly and incompletely, shifted. Some breast cancers are more like some leukemias, molecularly, than they are like other breast cancers. Some lung cancers respond to drugs that work in melanomas. The map of cancer has been redrawn, partially, around the molecular drivers rather than the tissues of origin. This redrawing is unfinished. The continuing redrawing is, in some measure, a continuing legacy of imatinib.

It adds up, fourth, to the patients. The thousands of CML patients who, in 1993, were facing a fatal disease and who, in 2026, are not. The hundreds of thousands of HER2-positive breast cancer patients whose recurrence rate has been cut in half by adjuvant trastuzumab. The smaller numbers of patients with rarer cancers — GIST, ALK-rearranged lung cancer, BRAF-mutant melanoma, BRCA-mutant ovarian cancer, IDH-mutant cancers, KRAS-G12C cancers — whose lives have been extended by drugs that did not exist a generation ago. The story this book has told is, in some ways, an institutional and scientific story, but at every step the institutional and scientific story has been about whether a particular person somewhere would have a few more years with their family. Some of those people are around to be asked. The arithmetic of how many of them is, by 2026, well into six figures and rising.

* * *

There is a kind of book this book is not.

It is not a book about how everything will be fine. Cancer is not solved. Pancreatic cancer is still pancreatic cancer. Glioblastoma is still glioblastoma. Triple-negative breast cancer is still mostly treated with the cytotoxic drugs from the 1980s. Many cancers, in 2026, are still essentially the same disease they were thirty years ago. The 1993 patient with pancreatic cancer would have been told they probably had a year. The 2026 patient with pancreatic cancer is told they probably have a year and a half. The improvement is real, but small, and it has come more from incremental refinements in chemotherapy and surgery than from the targeted-therapy revolution this book has been about. There are, for the patients in those clinics, no equivalents of imatinib. There may someday be. There are not yet.

It is not a book about how heroes did this single-handedly. The drug was developed by hundreds of people, most of whom this book has not been able to name — the chemists who tried earlier compounds in the 2-phenylaminopyrimidine series before Zimmermann landed on the right one; the technicians who ran the cell culture work in Druker's lab and Sawyers's lab and Witte's lab and many others; the pharmacologists who did the dog studies and the clinical pharmacology; the regulatory affairs specialists at Novartis and at the FDA who actually wrote and read the documents that allowed the drug to advance; the doctors at sites we have not had room to mention who enrolled patients into trials; the patients themselves, in their thousands, without whose willingness to take an experimental drug there would be no drug. The book has focused on a small number of people because narrative requires this; the actual story involves vastly more people than any narrative can reasonably name.

It is not a book about a single decisive moment. There are, in the history this book has told, many candidate moments — Hungerford at the Zeiss in 1959 or 1960; Rowley at her dining room table in 1973; de Klein at the lightbox in 1982; Druker counting colonies in 1995; the first phase 1 dose in June 1998; the FDA's approval in May 2001 — each of which is, in some accounts, presented as the moment everything changed. None of them is the moment everything changed. The moment everything changed was, accurately, the cumulation of all of them, plus many smaller moments, plus the slow shift in what the field considered possible. The story is the story of a long argument over many decades. The story does not have a single fulcrum.

It is, finally, not a book about heroes and villains. Novartis was not the villain of chapter five; Druker was not heroic in any sense his own description of himself would accept; the FDA was not benevolent or malevolent in chapter seven, just a regulator doing its job in a particular framework. The story is, in its actual texture, a story about ordinary professionals trying to do work they thought was right, in institutional contexts that pushed back on them in some cases and supported them in others, with occasional individual acts of conviction and stubbornness and luck that, in retrospect, made specific differences. There is no single moment in the story that requires a moralizing frame. There are many moments that require a careful one.

* * *

The patient is back in Druker's exam room — a different patient now, the third of the morning, a woman in her late fifties who was diagnosed with CML six months ago and is starting to get used to her daily pill.

She is asking about side effects. She has been having some muscle cramps, particularly at night, and some mild fluid retention around her eyes when she wakes up. Druker explains that these are common and usually manageable, that they often improve over the first six months, that there are simple measures she can try — magnesium for the cramps, hydration, sometimes a slight dose adjustment — if they don't. He asks her how she is doing emotionally. She says she is doing all right, mostly; the diagnosis was hard, and the first weeks on the drug were harder, but she is starting to feel less like a sick person and more like a person who takes a medication. He says that's good. He says that's typical. He says that, if her response continues to track the way it has been tracking on her early monitoring, she should expect, in a year or two, to feel essentially like herself, with the difference being that she takes a pill in the morning that she did not used to take.

She nods. She asks, with some hesitation, whether this is going to shorten her life. Druker, in the way he has answered this question for several thousand patients over the past quarter-century, says that the honest answer is probably not, that the data on chronic-phase CML on imatinib are now mature enough to support a lifespan close to normal, and that there are good reasons to expect the same will be true for her. He says it might not be true — every individual patient is an individual — but that on the available evidence she has good reason to plan for a long life.

She thanks him. She gathers her things. She walks out into the waiting room, where her husband is reading something on his phone.

Druker writes a few notes in the chart. He glances at the next name on his list. He goes to the door of his exam room, opens it, and calls the next patient back.

Outside, on the hill above the Willamette River, it is raining lightly. It is mid-morning. There are several more patients to see before lunch.

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