The coverage that followed the Aug. 5 news of the
failed trial of the much-heralded Opdivo (nivolumab) immuno-therapy drug from Bristol-Myers
Squibb has focused on everything but the actual strategy that Big Pharma
is employing to develop these novel drugs.
We’ve read about the “shock” that greeted this announcement as
BMS stock plunged like an airplane in free fall. (After all, a trial failure is so rare
in pharma and Opdivo was going to be such a sure shot in non-small cell
lung cancer, given its near miraculous effects in treating advanced melanoma,
that it was so surprising it failed, right?)
And then there were stories that looked at how Merck’s competing
Keytruda drug that corners only a small share of the lung cancer market
compared to Opdivo
would surely benefit from its rival’s flailing fortunes. (Both Keytruda and Opdivo are
cleared for second-line treatments in non-small cell lung cancer but doctors
need to administer a companion diagnostic test for the former while Opdivo
can be prescribed to any patient; hence the latter’s commanding
Still others concluded that BMS’ trial design was at fault —
the study was too broad in the way patients were selected leading to a
negative result, wrote Chris Scott, an analyst with JP Morgan in his research
note to clients. Scott was forced to adjust his revenue model for BMS.
But in all the fast and furious coverage of the fallout, there appears
to be no questions raised about whether standard drug development strategies
should be used when immunotherapy — both novel and exciting —
is concerned. One person who was bewildered at the response to the news
of the trial failure believes there should be.
“What happened (last) week is very informative about the cost of
hype,” declared Michael Kolodziej, an oncologist and former head
of Aetna’s oncology program, at the Precision Medicine Leaders Summit
in San Diego, Aug. 11.
Kolodziej is now national medical director, Managed Care Strategy at Flatiron
Health, which backed by Google Ventures, Roche and others, has developed
an oncology software platform.
In a phone interview after the conference, he expanded upon why current
drug development strategies are not suitable to the development of immunotherapy drugs.
“What they’ve done is applied this very encouraging, very exciting,
very novel therapeutic approach to a huge heterogeneous population of
patients where only a small percentage really benefit, but there’s
all this discussion about how this is a multibillion-dollar product for
manufacturer XYZ,”Kolodziej said. “That’s hype, if you
Currently only about 20% patients or thereabouts really respond to immunotherapy,
even though oncologists are toying with the unheard term of “cure”
to describe the response in some melanoma patients with advanced disease.
This means that more effort needs to be expended in selecting the patients
who can respond to immunotherapy drugs. But properly identifying which
patient is best suited requires pharma companies to invest time and money
in researching predictive biomarkers and developing companion diagnostic tests.
“I really do believe we will be able to identify the subset and that
will result in a way to make sure that the right people get the treatment
but if you look at the development strategy from the pharmaceutical companies
with immuno-oncologic agents, they look just like the strategies for conventional
chemotherapy drugs — basically every disease, every line of therapy,”
In fact even though having a biomarker as part of the drug development
process provides a three-fold increase in the probability of ultimate
FDA approval, only 20 of 159 cancer drugs today come with a predictive
biomarker or companion diagnostic. That’s according to Nicholas
Dracopoli, vice president and head of Oncology Biomarkers at Janssen Research
& Development, part of Johnson & Johnson, who also spoke at the
San Diego conference.
Recalling this meager datapoint, Kolodziej characterized the lack of predictive
biomarkers in drug development as a problem. The fault, he believes, lies
largely with Big Pharma’s reluctance to spend time, effort and money
in identifying which patients are most suited for immunotherapy drugs.
“My personal opinion is that the most important thing is getting
to market,” he charged of drugmakers. “Nothing else matters.
Coming up with a biomarker limits their market size – why would
they do that?”
A BMS spokeswoman didn’t address the speed-to-market or patient-selection
issue but provided a statement. Here’s the relevant portion from
BMS recognized the unique mechanism of action of immuno-oncology drugs
early, and that the efficacy and side effect profiles of these agents
would differ from traditional drugs such as chemotherapy. In order to
demonstrate the clinical value of immuno-oncology, we took a different
approach to how we discover these medicines, how the efficacy of these
agents is assessed, how the clinical trials are designed, how adverse
events are managed and, ultimately, how we treat cancer patients.
It’s a historical time in cancer research, and we believe we have
an unprecedented opportunity to transform cancer treatment across many
tumors for patients waiting for new medicines, and will continue to take
bold steps to help even more patients defeat cancer.
An ononcologist — Timothy Byun with the Center for Cancer Prevention
and Treatment at St. Joseph Hospital in Orange, California — described
Big Pharma’s race to develop meaningful immuno-oncology drugs as
a “gold rush.” While agreeing with Kolodziej that the advances
made in this therapy is truly exciting for patients and physicians alike,
he said there is still not enough known about which patients respond best
Take for instance the biomarker probes that Merck’s Keytruda uses
and BMS’ Opdivo trial used. Those probes are used to select patients
based on how much their tumor cells express PD-L1.
“There’s three or four PD-l1 immunohistocheimcal probes and
they are not all the same. Merck has one probe and BMS used their own
probe that was different than the Merck probe,” Byun said. “And
it’s not comparing apples to apples. You don’t know if the
50% staining on the tumor cells correlates to a 50% staining using another
probe. And to further complicate the matter, you don’t know whether
you should be testing and looking for the PD-L1 staining in the cancer
cell or the immune cells or both.”
In other words, there’s a lot we don’t know and perhaps it’s
time to slow down. And yet Kolodziej is only too aware that it is not
what patients battling cancer want to hear.
“You as the patient and you as the physician want to get access to
that drug as quickly as possible. I get that,” he said.
So what gives?
A reset of the current regulatory and reimbursement where approval and
payment of novel drugs can be conditional until evidence clearly shows
benefit for a certain group of patients seems to be in order.
“We’ve developed accelerated approval, breakthrough designation
all this stuff to get drugs to market faster but it’s relative uncommon
for approval to be conditional and more uncommon for approval to be reversed
based on evidence,” Kol0dziej said. “Could we see a universe
in which conditional approval and payment based on encouraging clinical
results but the requirement that there be some sort of date by which further
evidence or better evidence regarding the population that would most likely
benefit be mandated?”
He amplified on this theme arguing for a lower level of reimbursement for
a provisionally approved drug but affording drugmakers the ability to
increase prices once the evidence threshold is met. This is not unlike
what happens in some European markets, Kolodziej pointed out.
“We need to find a way to solve for getting access to therapies as
quickly as possible without granting basically carte blanche to a pharmaceutical
manufacturer based on a registration trial where there is no biomarker,” he said.
Perhaps this approach may prove to be a win-win for patients, who have
been disappointed by achieving no response to a therapy that seems to
be marketed as a silver bullet in the battle against cancer — and
it well may be when we identify the patient population. Not to mention
for those folks whose wealth got wiped out after BMS’s stock plunge.