Immunotherapy Perspective From a PD-1 Pioneer

Suzanne L. Topalian, MD

It was 4 years ago that Suzanne L. Topalian, MD, stepped into the spotlight at the ASCO Annual Meeting to report early efficacy for a novel antibody aimed at what was then the little known PD-1 immune checkpoint.

Since then, therapies aimed at the PD-1/PD-L1 pathway have mushroomed, with three approved agents indicated in a total of five tumor types and continuing development suggesting that more new drugs are on the way.

Although the rapid expansion of these therapies sounds like an overnight success, Topalain has been studying ways to harness the human system to fight cancer for more than 30 years. In 140 peer-reviewed articles, she has explored cancer vaccines, tumor-infiltrating lymphocytes, and the immune checkpoint CTLA-4 in addition to the PD-1/PD-L1 pathway.

A graduate of Tufts University School of Medicine, Topalian spent 21 years in the Surgery Branch of the National Cancer Institute. In 2006, she was named to lead the Melanoma Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore.

In June, Topalian was recognized for her groundbreaking work in immunotherapy along with Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center. The two clinician-scientists were named as the joint winners of the 2016 Taubman Prize for Excellence in Translational Medicine. They will share the $100,000 prize, which is awarded by the University of Michigan’s A. Alfred Taubman Medical Research Institute and will be presented in October.

OncLive: When you presented the first research into PD-1 inhibitors at ASCO 4 years ago, you indicated that this approach could potentially be applied in multiple tumor types. Are you surprised that anti-PD-1/PD-L1 inhibitors have become such a big focus and success, or is this what you had envisioned?

OncLive sat down with Topalian during the 2016 ASCO Annual Meeting to discuss progress in PD-1/PD-L1 immunotherapies and the prospects for developing biomarkers to better identify patients who would benefit from the new agents.Topalian: Four years ago, of course, we were just giving the first report that one of the anti-PD-1 drugs was active in three different cancer types. So that was very early but very promising evidence. At that time, I think the most surprising aspect of it was the responsiveness of non—small cell lung cancer, which had not been responsive to other kinds of immunotherapy before that report. But the responsiveness of lung cancer suggested that maybe additional types of cancer could be responsive as well.

Some observers have suggested that immunotherapy, particularly the PD-1/PD-L1 pathway agents, are the new chemotherapy in the sense that they will become a backbone of cancer treatment, even replacing chemotherapy in some settings. Would you agree with those observations?

I think what we’re seeing here at the meeting in 2016 are reports on many different kinds of cancers now that are responsive to several different anti-PD-1 or anti-PD-L1 drugs. Although we hoped that this might be the scenario, I think this has really exceeded our expectations.I hope that they will in some cases replace chemotherapy. If the meaning is that it will become as commonly used as chemotherapy, we hope that will happen.

Do you see PD-1/PD-L1 inhibitors moving into first-line therapy even when patients have a mutation that can be targeted?

But they’re not the new chemotherapy in the sense that in many cases they are not as toxic as chemotherapy. The quality of life for patients who are getting PD-1 inhibitors is actually better and this has been shown in some of the randomized trials that have been published comparing these agents with chemotherapy. One notable example is in lung cancer comparing second-line chemotherapy to an anti-PD-1 inhibitor.1 Hopefully, this is a better way to use the patient’s own immune system to treat cancer, which will not have all the toxicities that we have experienced with standard chemotherapy.Yes, I think we’re already there, at least in melanoma where two different drugs have been approved now in the first-line setting, two anti-PD-1 drugs.

Do you think that this will be the case in other tumor types?

And in melanoma, the BRAF mutation is very common. That’s found in 50% or more of patients with melanoma. There are several different BRAF inhibitors that are already FDA approved. But quite frankly in practice now, melanoma oncologists are tending to use anti-PD-1 drugs first, even in patients who have the BRAF mutation.I think it’s really going to depend on the response rates of these drugs in each particular cancer. In melanoma in the first line, the response rate is 40% or higher and we know that the responses are very durable. In fact, just this past April we reported on the longest follow-up of patients with melanoma receiving anti-PD-1, where one-third of them were still alive 5 years later.2

You spoke at this year’s ASCO meeting about immunotherapy biomarkers. What is the current landscape for developing immunotherapy biomarkers?

These are the kinds of results—this durability— that distinguishes anti-PD-1 from chemotherapy and kinase inhibitors that is leading people to look at them as preferred first-line agents.In 2012, we reported the first evidence that the expression of the partner molecule for PD-1, which is the ligand PD-L1, in pretreatment tumor biopsies could identify a group of patients who were more likely to respond to anti-PD-1 therapy. This was our first attempt to find a biomarker. Since then, three different biomarkers for PD-L1 testing in tumor biopsies have been approved by the FDA to guide treatment-making decisions in patients with advanced melanoma, lung cancer and, most recently, bladder cancer. And yet this is a very, very difficult biomarker to use in every circumstance.

We may find that it’s useful for certain kinds of cancers and maybe not so useful for others. This is still a story in evolution. But in the meantime we have additional biomarkers such as genetic biomarkers.

With the microsatellite instability [MSI] testing that we’ve heard about in colon cancer and some other kinds of cancers, patients who have the so-called MSI-high result have tumors that harbor many mutations and they’re more likely to respond to anti-PD-1 therapy.

There’s also an emerging area of virus-associated cancers. About 20% or more of all cancers worldwide are associated with viruses, and these viruses are very strongly seen by the immune system because they’re completely foreign to the immune system.

Are there any other immunotherapy biomarkers that look particularly promising?

What research presented at 2016 ASCO is noteworthy concerning immunotherapy biomarkers?

So now one major question is whether viruses in tumors can provide a biomarker of tumors that are more likely to respond to anti-PD-1 therapy. These are things that are on the horizon.There are additional biomarkers which are in much earlier research and development stages, such as the microbiome. Bacteria that live in the gut and the airways have different compositions in different people, and the question is whether the composition of an individual’s microbiome correlates with responsiveness to immune checkpoint blockade.One thing that was noteworthy from the genitourinary oncology session were four different talks about using various anti-PD-1 or anti-PD-L1 drugs in bladder cancer. All of these studies also included a PD-L1 immunohistochemistry test, but they used different tests according to which drug and which company.

What do you think is important for practicing oncologists to know about immunotherapy biomarkers at this point?

One of the four reports showed a very strong correlation of the outcome of the patients with PD-L1 positivity.3 Patients whose tumors were PD-L1—positive were much more likely to respond to the drug, whereas the other three reports did not seem to show much of a difference between the PD-L1 positive and negative tumors. So, again, we’ll need more evidence to put all of this information together, but it may be that certain markers are more predictive. It may be that markers are better used in some cancers and not others.I think it’s important to know that they’re very different than the biomarkers that we use for kinase inhibitors. Those biomarkers are really fixed in the tumor; the tumor either has a particular mutation or translocation or it does not.

Whereas with the immunotherapy biomarkers, these are biomarkers that may or may not be expressed at different points in time. Expression can vary by different sites in the body, whether it’s a lymph node metastasis, a liver metastasis, or the primary tumor in the same patient. And so it’s much more difficult to learn how to use the immunotherapy biomarkers. For the time being, the FDA has created a new category of diagnostics that they call complementary diagnostics as opposed to the companion diagnostics for the tyrosine kinase inhibitors. The FDA views the companion diagnostic as a marker that’s required for the safe and effective use of a particular drug. The complementary diagnostic terminology was invented by the FDA particularly for PD-1 inhibitors, and that’s meant to guide treatment but it’s not required for treatment decision making.

References

1. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non—small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639.
2. Hodi SF, Kluger HM, Sznol M, et al. Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial. Presented at the 2016 AACR Annual Meeting; April 16-20, New Orleans, Louisiana. Abstract CT001.
3. Rosenberg JE, Petrylak DP, Van Der Heijden MS, et al. PD-L1 expression, Cancer Genome Atlas (TCGA) subtype, and mutational load as independent predictors of response to atezolizumab (atezo) in metastatic urothelial carcinoma (mUC; IMvigor210). J Clin Oncol. 2016;34(suppl; abstr 104).