A Novel Antibody-Drug Conjugate and Chemotherapy’s Future in Lung Cancer

D. Ross Camidge, MD, PhD

Following the conclusion of the 16th World Conference on Lung Cancer (WCLC), held September 6–9 in Denver, Colorado, we spoke with Dr. David Ross Camidge, director of the thoracic oncology clinical and research programs at the University of Colorado, about the results of an early-phase antibody-drug conjugate lung cancer trial that he presented at the meeting, and the evolving role of chemotherapy in the treatment of advanced lung cancer.

Cancer Network: First, can you tell us about this antibody-drug conjugate trial. What is the target of this antibody and what is the toxin it’s linked to?

Dr. Camidge: This was a relatively early-phase study with a drug that has possibly one of the longest names out there-sacituzumab govitecan-but in order to be practical it’s called IMMU-132, and it’s an antibody-drug conjugate. Now, what that means is that you have an antibody that is acting as a delivery system to FedEx a toxic molecule, often the same kind of toxic molecule that might be used in chemotherapy, and the goal is to try to get it concentrated into the tumor by using the antibody to direct it into the tumor cells.

There are many antibody-drug conjugates. IMMU-132 uses an antibody directed against TROP-2, a surface marker present on many different solid tumors, including esophageal, gastric, colorectal, prostate, and both small-cell and non–small-cell lung cancers. We are using that antibody to direct SN-38, a toxic drug that is the active ingredient of the well-known chemotherapy called irinotecan. The idea of delivering it here is to get a better efficacy/toxicity ratio (ie, to make it more effective because we are delivering it to the tumor and make it safer because we are not delivering to most normal tissues).

Cancer Network: What were the results of this study so far, and what is next for this agent in lung cancer?

Dr. Camidge: So, we presented data on about just over 50 patients with both small-cell and non–small-cell lung cancers at what we thought were the active doses of this drug. And if we take the non–small-cell group together-and the striking thing is that this was a heavily pretreated group of patients, on average they had had at least three prior lines of therapy and some of them had even received up to eight lines of therapy-we got about 30% to 32% of patients with fairly dramatic shrinkage. So we achieved an objective response-this included patients with squamous lung cancer and adenocarcinoma of the lung-and the median progression-free survival was 5.4 months at the dose [the company] plans on taking forward (10 mg/kg). So it seems to be active in a heavily treated population, and the duration of benefit is quite reasonable.

We showed images of one particular patient who happens to be one of my patients. He had four previous chemotherapies, and I have to say that apart from going bald, which is a side effect of the drug-possibly because that marker is also contained in the skin or hair follicles-he is actually tolerating the drug very well, is still working full time, and in every single scan we have done his tumor looks a little bit smaller. He is coming up to a year on therapy now. This is a guy with a KRAS mutation and he is a heavy ex-smoker, so he doesn’t meet any of the usual criteria for people who are responding to some of the targeted therapies.

The small-cell data was a bit more modest. They were getting about a 30% response rate overall. At the recommended dose, they were getting about a 60% response rate, but that is only three out of five patients treated at that dose, so I don’t know if we can place a lot of confidence that that number is going to stay the same. The median progression-free survival in the small-cell cohort at the recommended dose was 4.6 months-so again, OK, but not perhaps as exciting as the non–small-cell data. But this was also a heavily pretreated population (usually 2.5 prior lines of therapy and ranging from 1 to 7).

Cancer Network: In the context of current chemotherapy lung cancer therapies, which have been the mainstay for lung cancer, and the new anti-PD-1 antibodies that are now available for advanced lung cancer patients, what do you see as the current role of chemotherapy?

Dr. Camidge: So, if you like, an antibody-drug conjugate is sort of in the halfway house of an immunotherapy (where you are really using antibodies to try to turn on the patient’s own immune system to reject the cancer) and chemotherapy (where you are just hoping the treatment is more poisonous to the cancer than to the body). These directed antibodies sit in that middle ground.

I think chemotherapy will continue to have a role, and it will continue to have a role for two things. One is we have not yet cured cancer and so you will need many lines of defense, and maybe we move the ordering of the lines of defense but we are still going to need them. And the other thing, which is interesting, is whether some of these-either chemotherapies or antibody-drug conjugates-may kill cells in a manner that makes them more stimulatory for the immune system. So maybe we are going to need these things in concert.

At the WCLC this year we also saw data on a combination of the Roche/Genentech anti-PD-L1 antagonist with some standard first-line chemotherapy, a relatively small study, but they were getting some astonishingly high response rates, in the 60% to 70% range-of course we haven’t seen how long those responses will last yet. It is an area of interest to see if these things are not mutually exclusive, but have a combinatorial role in the future.

Cancer Network: Thank you so much for joining us today, Dr. Camidge.

Dr. Camidge: It’s my pleasure.