Chapter 1 – How It All Began
In 2007, Japanese researchers made a discovery that fundamentally changed the treatment of a small subgroup of patients with non-small cell lung cancer (NSCLC).
They identified rearrangements involving the anaplastic lymphoma kinase (ALK) gene—today commonly referred to as ALK rearrangements, ALK translocations, or simply ALK fusions.
For the first time, lung cancer could be defined not only by its appearance under the microscope, but also by its molecular driver.
This discovery marked the beginning of a completely new chapter in thoracic oncology.
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Crizotinib (PF-02341066) became the first tyrosine kinase inhibitor (TKI) developed specifically for patients with ALK-positive NSCLC.
Beginning in 2008, patients carrying an ALK rearrangement were enrolled into the first-in-human clinical trial, PROFILE 1001, followed by several additional studies.
Toward the end of 2009, the study was expanded to include patients whose tumours carried a ROS1 rearrangement, revealing that crizotinib was active against both molecular targets.
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[Fig. 1 – Crizotinib molecule structure]
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arrator’s note:
The PROFILE 1001 study was led by Dr. Alice Shaw, who at that time was working at Massachusetts General Hospital in Boston.
She also served as the principal investigator of PROFILE 1007, the pivotal trial that ultimately formed the basis for the first regulatory approval of crizotinib.
For this reason, PROFILE 1007 is still often referred to simply as “the Shaw study.”
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Crizotinib represented a major breakthrough.
For the first time, patients with ALK-positive lung cancer experienced response rates that had previously been unimaginable with conventional chemotherapy.
Yet it soon became clear that the drug also had important limitations.
One of its greatest weaknesses was its limited penetration of the blood-brain barrier.
As a consequence, many patients developed brain metastases, even while their disease outside the central nervous system remained well controlled.
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Another challenge soon emerged.
Within only a few years, tumour cells learned how to escape ALK inhibition by acquiring resistance mutations.
Among ALK-positive patients, one of the earliest and most important mutations was L1196M.
In ROS1-positive disease, the corresponding challenge became G2032R.
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While early ROS1 inhibitors initially showed only limited activity against the G2032R resistance mutation, the situation for ALK-positive patients developed much more rapidly.
Several second-generation ALK inhibitors entered clinical development, each designed to overcome crizotinib resistance while providing substantially better penetration into the central nervous system.
Among them were:
• Ceritinib (LDK378)
• Alectinib (CH5424802)
• Brigatinib (AP26113)
Interestingly, these drugs often proved to be even more effective when used as first-line therapy, before patients had ever received crizotinib.
This observation would fundamentally reshape the treatment strategy for ALK-positive lung cancer.
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Unfortunately, the story did not end there.
Just as resistance had eventually developed during crizotinib therapy, new resistance mechanisms also emerged under the second-generation ALK inhibitors—regardless of whether they were administered after crizotinib or as the initial treatment.
Among the most important resistance mutations were G1202R, I1171T/N/S, and V1180L.
It became increasingly obvious that every new generation of ALK inhibitors solved one problem while simultaneously creating the next.
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Pfizer therefore embarked on its second major journey.
The company set out to develop an entirely new tyrosine kinase inhibitor for patients with ALK- and ROS1-positive lung cancer, once again working in close collaboration with Alice Shaw and her laboratory at Massachusetts General Hospital.
The objectives were ambitious. Very ambitious.
The new drug should:
• inhibit virtually all clinically relevant resistance mutations observed in both
ALK- and ROS1-positive disease
• cross the blood-brain barrier far more effectively than existing therapies,
prevent the development of new brain metastases,
and successfully treat brain metastases that were already present
– or had developed despite treatment with second-generation ALK inhibitors.
Whether all of these goals could be achieved simultaneously
…nobody knew.
References:
[1] Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013
[2] Shaw AT et al. Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer. N Engl J Med. 2014
[3] Shaw AT et al. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013
[4] Shaw AT, Chen J et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017