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First-line ceritinib
vs platinum-based
chemotherapy in
advanced ALK-
rearranged non-small
cell lung cancer
The Lancet
Take-home message
•
In a prospective, multicentre phase III study, patients with untreated
ALK-rearranged non-small cell lung cancer (NSCLC) were
randomised to receive platinum-based chemotherapy (n = 187) or
ceritinib (n = 189) to evaluate the safety and efficacy of ceritinib.
The primary endpoint was progression-free survival. The ceritinib
group had longer median progression-free survival (16.6 months vs 8.1
months; HR, 0.55; P < 00001). Adverse events with ceritinib included
diarrhea (85%), nausea (69%), vomiting (66%), and elevated ALT
(60%); with chemotherapy, adverse events included nausea (55%),
vomiting (36%), and anaemia (35%).
•
Ceritinib was associated with a significant improvement compared
with chemotherapy as a first-line treatment in patients with ALK-
rearranged NSCLC.
Abstract
BACKGROUND
The efficacy of ceritinib in patients with untreated anaplastic lym-
phoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not
known. We assessed the efficacy and safety of ceritinib versus platinum-based
chemotherapy in these patients.
METHODS
This randomised, open-label, phase 3 study in untreated patients with
stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres
across 28 countries. Eligible patients were assigned via interactive response
technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cis-
platin 75 mg/m
2
or carboplatin AUC 5–6 plus pemetrexed 500 mg/m
2
] every
3 weeks for four cycles followed by maintenance pemetrexed); randomisation
was stratified by World Health Organization performance status (0 vs 1–2), previ-
ous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases
as per investigator’s assessment at screening. Investigators and patients were
not masked to treatment assignment. The primary endpoint was blinded inde-
pendent review committee assessed progression-free survival, based on all
randomly assigned patients (the full analysis set). Efficacy analyses were done
based on the full analysis set. All safety analyses were done based on the safety
set, which included all patients who received at least one dose of study drug.
FINDINGS
Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly
assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free
survival (as assessed by blinded independent review committee) was 16.6
months (95% CI 12.6–27.2) in the ceritinib group and 8.1 months (5.8–11.1) in the
chemotherapy group (hazard ratio 0.55 [95% CI 0.42–0.73]; p<0.00001). The
most common adverse events were diarrhoea (in 160 [85%] of 189 patients),
nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotrans-
ferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients),
vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group.
INTERPRETATION
First-line ceritinib showed a statistically significant and clinically
meaningful improvement in progression-free survival versus chemotherapy in
patients with advanced ALK-rearranged NSCLC.
First-line ceritinib versus platinum-based chemotherapy in advanced ALK-re-
arranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label,
phase 3 study.
Lancet
2017 Jan 23;[EPub Ahead of Print], JC Soria, DS Tan, R
Chiari, et al.
evolving sort of concept.
In the meantime, many patients are getting the drugs. So, what
I would suggest is as we give the patients the drugs, we col-
lect samples and we’re seeing that. There are more and more,
the MoonShot programs, the Parker Foundation, the National
Cancer Institute now has multiple supplements that they’re
issuing to cancer centres to study this very process. So, we all
realise what we need now is take what we know about immune
biomarkers from retrospective studies and incorporate them
prospectively into studies with clinical annotated follow-up to
figure this out.
Dr Haffizulla:
Absolutely, and maybe having an adaptive trial
design as well, too.
Dr Herbst:
Oh, that would be wonderful. We just need to have
enough prior probability to do that. But if we had some sense of
what you need, let’s say you have a tumour, and the tumour has
no inflammation. You might need to use an agent that’s going
to bring T-cells in, or let’s say a tumour has very few mutations.
Pick the mutation that you think might be the most likely to
cause a response and develop a vaccine. This is what we really
need, personalised immunotherapy.
Dr Haffizulla:
Absolutely. Now how, again, in the spectrum of
epitopes that are expressed in that tumour, do you decide which
ones are going to initiate the greatest immune response, or
which ones matter? I know we’re still in that space of thinking.
Dr Herbst:
That’s very hard, and I will tell you that in my opinion,
just sequencing is not going to be enough. Then you need to do
functional studies. You’ve got to actually go back to the lab, and
you’ve got to make T-cells that go after that mutant protein. So,
you have to engineer the receptor to go after it, and actually see
if, in fact, that’s happening in any given patient, so that’s going
to be a bit more complicated.
Farzanna Haffizulla, MD, FACP, FAMWA practices
general internal medicine in Florida, within her own
internal medicine concierge practice. She was
previously the National President of the American
Medical Women’s Association (AMWA) 2014–2015.
LUNG
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VOL. 2 • NO. 2 • 2017