Box 1. Squamous smorgasbord.
Although Ret proto-oncogene fusions offer the
most promising example for how recent genomic analyses of lung cancer have
identified newly actionable oncogenic alterations, additional clinical trials
are seeking to validate other new targets, particularly in squamous cell lung
cancers. Thus far, none of the ongoing trials have reported results as effective
as Ret proto-oncogene inhibition.
One area of particular focus is mutations or amplifications of fibroblast growth factor receptors (FGFRs). In 2011, researchers published work
suggesting that about 20% of squamous cell lung cancers (SCCs), a subtype of
non-small cell lung cancer (NSCLC) associated with smoking, carry
amplifications of FGFR1 (CD331).13 More recently,
activating mutations in FGFR family members have been reported in lung cancer,
and last week FGFR oncogenic fusions were reported in a variety of cancers
Peter Hammerman, instructor in
medicine at Harvard Medical School and a thoracic oncologist
at the Dana-Farber Cancer Institute, is leading a
trial of Iclusig ponatinib in patients
with lung or head and neck cancer with FGFR alterations.
At the American Association for Cancer Research
(AACR) meeting this week, Ariad Pharmaceuticals Inc. had a poster
that showed Iclusig inhibits FGFR1-4 at low nanomolar concentrations and also
potently inhibits the growth of cell lines bearing FGFR alterations, including
"Ponatinib was selected because it is an FDA-approved agent, and
the other high-potency FGFR inhibitors like BGJ398 and AZD4547 are still in
Phase I," Hammerman said.
BGJ398 is a pan-FGFR inhibitor being developed by Novartis AG. The pharma presented data at
the AACR meeting last year showing that one SCC patient with amplified FGFR1
had a partial response to the molecule.
AZD4547 is a pan-FGFR inhibitor being developed by AstraZeneca. This
week at the AACR meeting, the company presented data showing that one SCC
patient with FGFR1 amplification treated with the compound had a partial response
that lasted 12 weeks. The patient was 1 of 21 with FGFR1 or FGFR2 (KGFR; CD332) alterations in various cancers that
were treated with the compound, and the trial is ongoing.
Thomas, chair of the Department of Translational Genomics at the University of Cologne, cautioned that FGFR
amplifications in SCC may not be as straightforward to target as gene fusions. "We
have data that shows that the biology of FGFR1 amplification is more
complicated than originally thought, and we should also keep in mind that [ALK
and RET] are more precise genomic alterations compared to amplifications.
Unfortunately, though, we do not have response rate data from the AZD4547 or BGJ398
trials yet, so at this point we cannot really draw any conclusions yet."
Alice Shaw, assistant professor of medicine at Harvard Medical School
and a thoracic oncologist at Massachusetts General Hospital, agreed that
advances in SCC have not been translated as fast as she had hoped. "Squamous
has been hard for a number of different reasons. In adenocarcinomas with ALK and ROS1 and RET, it seems like the
pace has been quicker."
In addition to FGFR-targeted therapies, patients with SCC who have
activating mutations in discoidin domain
receptor tyrosine kinase 2 (DDR2) have been
enrolled in targeted clinical trials. Hammerman led a 2011 team that found DDR2 mutations drive 3%-4% of SCC cases and showed that Sprycel dasatinib can inhibit
the kinase and block cell proliferation.
Bristol-Myers Squibb Co.'s Sprycel is a tyrosine kinase
inhibitor marketed to treat acute lymphoblastic leukemia (ALL) and chronic
myelogenous leukemia (CML).
Based on these results, a Dana-Farber investigator started a trial of
Sprycel in patients with SCC who have DDR2 activating mutations.
The study was terminated in January for undisclosed safety concerns.
Bruce Johnson, director of the Lowe Center for Thoracic Oncology at
Dana-Farber and leader of the aforementioned trial, declined to comment on its
termination. Because of its relative lack of activity against DDR2,3,16
Sprycel was being tested at 140 mg daily orally, which is its highest approved
Bristol-Myers is running its own trial of Sprycel at that dose in
patients with lung cancer who have activating DDR2 mutations.
That trial also is enrolling patients with inactivating mutations in BRAF. Last
year, a retrospective analysis of patients with lung cancer who received
Sprycel identified one patient with an inactivating mutation in BRAF who had a
complete response to the compound.17
Bristol-Myers declined to comment.