2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

50%
50%
100%
Change in Tumor Size
mutations later confirmed in vivo. This discovery resulted in
the development of a novel generation of TKIs that are
highly effective in suppressing the mutated CML clones
and have demonstrated clinical efficacy in patients with
imatinib-resistant CML. Second-generation TKIs resulted
in complete cytogenetic response rates of 50% or more in
such patients; these responses were durable and reduced
the post-imatinib resistance mortality rate from 10% to 15%
annually to 5% or less. 24,25 These results encouraged the
front-line use of these agents, which when compared with
imatinib, produced higher rates of complete cytogenetic
response, major molecular response, and complete molecular
response. 14,15 More importantly, they were associated with
lower rates of transformation to the accelerated and blastic
phases of CML. 14,15 Together, these data suggest that the
earlier use of more potent TKIs could further suppress the
inherent mechanisms of resistance of CML clones at diagnosis
in at least some patients. Furthermore, the successful
development of potent T315I inhibitors demonstrated their
high efficacy among patients with T315I-mutated CML.
Such experiences should also be considered in the context of
research and solid tumors.
Why Are We Not Achieving Similar Results in
Solid Tumors?
The development of imatinib for the treatment of CML is
considered a paradigm for targeted therapy. Despite numerous
promising drugs and herculean efforts by expert oncologists,
to date the CML/imatinib success remains
unmatched. At least two possibly valid conclusions can be
reached: 1) the CML/imatinib experience is singular (i.e.,
CML is so genetically simple and homogeneous that it is not
a relevant comparison to solid tumors) or 2) the use of
targeted therapy in solid tumors has not yet followed the
highly successful strategy used by CML investigators.
Although targeted therapies in solid tumors have not yet
transformed disease outcomes to match a normal life span,
they certainly cannot be described as ineffective. Therapies
targeting the driving molecular abnormalities in solid tu-
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Survival Outcome
Fig 1. Left panel shows typical waterfall plot for successful targeted agent in metastatic solid tumors. Many patients show tumor regression
but few achieve complete remission.
Upper right hand panel shows typical survival curve for patients with metastatic solid tumors treated with an active targeted agent. Even with
improved survival, most patients die of their disease, with survival gains generally measured in weeks to months. Survival curves for patients
with CML blast phase remain similar, even in the imatinib era.
Lower right hand panel shows typical survival curve for patients with newly-diagnosed CML chronic phase treated with imatinib or other
Bcr-ABl TKIs. High rates of long-term survival are achieved.
182
% Surviving
Time
mors, such as vemurafenib for V600E BRAF mutations in
melanoma and crizotinib in ALK-rearranged lung cancer,
have resulted in substantial tumor response rates in preliminary
trials. In a landmark phase I trial, Flaherty and
colleagues 26 demonstrated an overall response rate of 81%
(26 of 32; two complete responses and 24 partial responses)
with the BRAF inhibitor vemurafenib given at a dose of 960
mg twice daily in the dose-expansion cohort of heavily
pretreated patients with mutated V600E BRAF metastatic
melanoma. Perhaps even more impressive, the doseescalation
phase demonstrated a 69% response rate (11 of
16; one complete response and 10 partial responses) with
vemurafenib at doses of 240 mg or more twice daily. Unfortunately,
disease control was transient in six of the 11
patients with response, and disease progressed within 9
months after the initiation of therapy. In the expansion
phase of the phase I trial of the ALK inhibitor crizotinib, the
response rate for patients with advanced, pretreated ALKrearranged
lung cancer was 57% (47 of 82; one complete
response and 46 partial responses). 27 These therapies were
largely well tolerated, especially when compared with standard
cytotoxic chemotherapy. Although exciting, the data
indicate that these targeted therapies do not commonly
result in complete responses, that “cures” are rare, and that
patients who have response will likely have relapse. At first
glance, these results may be perceived as disappointing
compared with the CML experience. However, on closer
observation, they have striking parallels. A portion of patients
with advanced disease, either CML or solid tumors,
benefit from targeted therapy, but resistance inevitably
develops (Fig. 1).
Importance of Early Therapy
WESTIN, KANTARJIAN, AND KURZROCK
In CML, the timing of targeted therapy is critical: patients
with newly-diagnosed CML do much better than those
with advanced or transformed disease (Table 1). As in CML,
it is generally accepted that newly-diagnosed solid tumors
are more responsive to therapy than previously treated or
relapsed cancers. Because of genomic instability, faulty