Will These Trials Make Cancer History? : I Doubt It, But They Could

Will These Trials Make
Cancer History? : I Doubt It, But They Could

By

Leonard Zwelling

         It is late May and early June so it must be time for the
Indianapolis 500, the Belmont Stakes and the Oscars of Oncology, the media
darlings of ASCO.

         My sources at ASCO have told me that the excitement at the
meeting was higher than ever what with the breakthroughs in immunotherapy and
molecularly-based targeted pharmaceuticals changing the landscape of oncology as
never before. But is this truly a unique moment in cancer history?

         In one case we are going to find out.

         The Wall Street
Journal announced with great fanfare two very large trials under the
auspices of the NCI in one case and ASCO in another, using many drugs, in many
types of malignancies and co-sponsored by many different drug companies. This
can only be a good thing.

         The WSJ describes
this as “Rivals to Join Cancer-Drug Trials.” One trial is NCI-MATCH that
proposes to test the tumors of 1000 advanced cancer patients for specific
molecular abnormalities and match the detected mutations with drugs that target
them specifically regardless of the anatomic site of the tumor. The idea is
that molecular determinants of tumor aggressiveness and pharmacologic susceptibility
may be more important than characteristics of cancers as grouped by organ of
origin, i.e., breast vs. colon cancer. Supposedly 10 companies will be
supplying 20 drugs for this trial. It will be done at 2400 sites.

The
other trial is called TAPUR and is sponsored by ASCO according to the WSJ and is using 13 drugs.

         The idea is to reduce impediments to therapeutic progress caused
by the drug approval system that tends to analyze new agents in specific
cancers with identical anatomic sites of origin. The new idea is to supplant this
classification system with one based on categorizing the cancers and their
therapies at the molecular level. This is being done because it is believed
that these molecular abnormalities are the true drivers of carcinogenesis and
of the cancer’s clinical behavior. Two tumors from different anatomic sites
with similar gene profiles might respond to the same targeted agent.

         My opinion is consistent with that of my former MD Anderson
colleague now from the FDA, Rick Pazdur, who is quoted in the WSJ article saying: “it’s a much more
complicated issue than most people would like to hear.”

         Absolutely correct. Or, said another way, complicated
problems have simple answers. And they are usually wrong.

         When a cancer becomes clinically detectable, it consists of
at least 1 billion cells. These are rarely clonally identical, but have
undergone many, sometimes imperfect, cell divisions prior to the initial diagnostic biopsy.
Perhaps more cell divisions took place before clinical detection than between
diagnosis and death. Mutations, post-translational modification, genetic
rearrangements and translocations of all sorts could have arisen, even if just
by chance rather than purpose, and resulted in a heterogeneous mass of lethal
cells with highly developed and highly variable tools to invade blood and
lymph, spread to other organs and kill the host. That these things are true
were proven by Fidler and Kripke over 30 years ago in what is still to me the
most clinically relevant and seminal cancer biology finding of the past 50
years. How likely is it that a singular genetic fingerprint of any patient’s
cancer is likely to be found and be significantly heuristic therapeutically for
the patient’s doctors to augment the patient’s survival over conventional
therapeutic approaches (i.e., a good guess)? I don’t know, but I do know it’s
worth trying to find out, so my friend Jim Doroshow and the others leading the
charge are doing the right thing after 15 years of speculation (since the
culmination of the initial human genome sequencing project) and very little
proof that molecularly-based targeting will actually lengthen lifespans of
cancer victims. These trials may go a long way to tell us whether or not this
approach holds any promise as its advocates assure us it does.

         My guess, is that it will work sometimes, perhaps 20% of the
time. And whether work means smaller tumor or actual increased survival will be
crucial to determine. If it does work, it is likely to run the country’s
medical bill even higher than the 17.6% of GDP it is now and extend the average
life span of Americans a few months. Whether that is of significant value is
for others to determine. Additionally, the opportunity cost of sequencing
cancers vs. vaccinating kids in the underserved communities of America must
also be considered, for there is not unlimited money.

         I am far more hopeful about the newest advances in cancer
immunology in which the body’s intrinsic system to eradicate cancer may be
malfunctioning in cancer patients but be amenable to reprogramming. This seems
like a truly great idea to me and far more likely than the targeting of
molecular aberrancies in explanted malignancies is to contribute to the wellbeing
and survival of cancer patients.

         But I am always wrong so let’s do the trials.

         Just, please for goodness sake, let’s do them right without
misconduct and with as few ego problems as is possible in academics.

         Yeh, right! The blame will be hard to come by if it fails,
but the credit will be a war zone if it works. Either way, we need to know.