April 2017 Edition Vol.11, Issue 4

AACR 2017 Roundup: Bugs, Drugs, and an Electric Hat

By Neil Canavan

This year’s meeting of the American Association for Cancer Research (AACR) was nothing if not varied—it seems that any possible wrench worth chucking into the machinery of tumor cells is under enthusiastic investigation.

Of the novel examples highlighted herein we have:

  • A drug that was just approved for a type of cancer that until now had no approved treatments
  • A 5-year follow-up of patients with advanced lung cancer (who typically do not survive the 5 years to be followed)
  • A study suggesting that cancer therapies work better if the patient has the right bugs in their gut
  • A combination regimen using a virus; and an electronic device for treating brain tumors

A Drug to Call One’s Own

Few words in the English language elicit such an immediate emotional response as the word, “orphan” which is why the phrase “orphan disease” conjures images that are more distressing still.

Merkel cell carcinoma (MCC) is an orphan disease, defined as such because, one—it is so rare, with less than 2,500 new cases diagnosed in the U.S. annually, and two—because until just two weeks prior to the AACR 2017 meeting there were no approved drugs to treat it. That is no longer true as there is a newly approved drug for MCC, called, avelumab.
“I’m really happy to show this slide,” said Howard Kaufman, MD, surgical oncologist at Rutgers Cancer Institute of New Jersey in New Brunswick, New Jersey, speaking of the disclaimer slide fronting the AACR presentation of his study treating MCC patients; the disclaimer described in detail avelumab’s approved indication.

“I’m happy because about ten days ago we were pleasantly surprised that the FDA has approved avelumab for the treatment of metastatic Merkel cell carcinoma.” (The approval being contingent on the data set Kaufman was presenting.)

It was very good news indeed. MCC is a very aggressive form of skin cancer with a poor rate of survival (when metastatic, survival is typically less than a year), and no chemotherapy agent with any activity in this disease has made any difference in overall survival.

Enter avelumab, a new drug in a new drug class, the so-called checkpoint inhibitors. Avelumab is an anti-PD-L1 drug—PD-L1 being the ligand for the PD-1 receptor, itself the subject of several recent drug approvals.

As reported by Dr. Kaufman, the JAVELIN Merkel 200 trial enrolled 88 patients with advanced MCC disease for second-line treatment with avelumab. An open-label study, JAVELIN patients were treated until they experienced disease progression, or unacceptable toxicity.

Results of the study showed that after a median follow-up of 16.4 months, treatment with avelumab achieved an overall response rate of 33%, and an overall survival rate of 52% at one year. “Which is quite remarkable for this disease,” said Kaufmann.

The reported rates for adverse events were low, with low-grade fatigue being most common (50%). So, all in all, a homerun.

Question: With such improvements in survival outcomes as compared to historical rates for this disease, should avelumab be used frontline?

“I think so,” said Dr. Kaufman, “Even before this approval we were trying to get one of these (checkpoint) drugs for these patients because this is the first time we’ve actually seen a real benefit in this disease setting,” adding that, “I think it’s really important that patients get access to these drugs as soon as possible.”

Breathing Life Back into NSCLC

The prognosis for anyone with late-stage, non-small cell lung cancer (NSCLC) is somewhere between bad, and devastating. The 5-year survival rate in this setting is less than 4%.

There has been some progress in the last few years with subsets of NSCLC patients with specific mutations (e.g. ALK, or EGFR), but even in patients with targetable mutations, eventual resistance to treatment is a common, if not universal outcome, and the majority of NSCLC patients do not even qualify via mutational status for those meager improvements in disease management.

Immunotherapy, particularly with anti-PD1 agents has dramatically changed that, greatly enhancing the patient pool who can benefit from curative treatment.

For proof, look no farther than the data from a 5-year follow-up of NSCLC patients treated with the anti-PD1 drug, nivolumab, reported at AACR by Julie Brahmer, MD, program leader at the Johns Hopkins Bloomberg/Kimmel Institute for Cancer Immunotherapy.

“Prior to the introduction of immunotherapies, treatment options were limited for patients with NSCLC who progressed after first-line platinum doublet chemotherapy,” said Brahmer, noting that the majority of such patients die within one year of diagnosis.

In the present analysis—the 5-year update from the previously reported CA209-003 study—Brahmer reported on the survival rate at 5 years, as well as a bit about the survivors themselves.

(Briefly, CA209-003, a phase II study, enrolled 129 treatment-experienced, late-stage NSCLC patients in one of 3 dose-ranging cohorts of nivolumab. Patients were on active treatment for up to 2 years.)

Results of the analysis showed that the estimated 5-year survival for all dose cohorts was 16% (1-year OS was 42%; 3-year, 18%). “After three years the survival curves plateau,” said Brahmer, “Which is similar to what has been seen in the past in other disease treated with immunotherapy.” The plateau illustrates the long duration of response, a hallmark of checkpoint immunotherapy.

As for the characteristics of the 16 patients who made it to the 5-year mark, a high rate of PD-1 expression played a major roll (43%, high, vs. 20% low PD-1 expression) and, as has been suggested before, smokers do much better than non-smokers. In fact, there is one former smoker enrolled on the CA209-003 study who is 6 years out post-treatment initiation and, “remains alive and well and in response without evidence of disease.”

To drill down just a bit, this patient’s tumors were sequenced and found to have 314 somatic mutations—a very high rate—just the right setting for immunotherapy. The more mutations, the better one responds.

Commenting on the study, Suzanne Topalian, MD, director of the Melanoma Program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: “It should be noted that the 5-year follow up reported here is nearly quadruple the survival that we would otherwise expect if these same patients had received chemotherapy.”

Germ Theory­

If you are a clinician/scientist involved in immunotherapy (IO) investigations and you notice your data being inexplicably buggy, there is a good a chance that actual bugs are the problem. As demonstrated in a study by Gopalakrishnan, et al, response to anti-PD-1 therapy is strongly associated with the diversity, and overall composition of the bugs in a patient’s gut, the so-called microbiome.

This striking observation is not exactly the first of its kind in oncology; Laurence Zitvogel, el al, of Institut Gustave Roussy were the first to publish on the relationship between the gut microbiome and the relative efficacy of the chemotherapy agent, cyclophosphamide (Science, 2013).

To investigate the possible relationship between the gut microbiome and the class of IO agents known as checkpoint inhibitors, Gopalakrishnan’s group established bacterial “signatures” by performing genomic assays on buccal, and stool samples from 110 metastatic melanoma patients previously treated with anti-PD-1 agents; the signatures of those who responded to anti-PD-1 treatment were compared with those who did not.

Results showed that there was no association between the buccal microbiome and anti-PD-1 response, but the diversity of the gut microbiome proved a significant aspect in the response to anti-PD-1 treatment. Specifically, responders to anti-PD-1 blockade had a greater diversity in their microbiome in general, and an enrichment of Clostridiales, and, Ruminococcaceae species in particular, as compared with non-responders (p=0.017).

“These findings have several implications,” says Jenn Wargo, MD, Associate Professor, Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, who was the PI on the study. “One: perhaps we should be profiling the microbiome of our patients—at least in patients going on immuno-oncology agents.” Two: it begs the question of whether tweaking a patients’ microbiome could enhance a therapeutic response.

“I think the answer there is a resounding, yes,” says Wargo. Of course, the question then becomes, how do you do it? “You could possibly do it with a fecal transplant, for example, or perhaps you could do it with a tailored pre/probiotic, but we still don’t know the right microbial composition. Alternatively, you could also potentially do it through diet… but all options should be studied within the context of a (multidisciplinary) clinical trial, at least at the outset. It’s going to take a collaborative effort to do it right.”

Going Viral

Checkpoint inhibitors have been the bomb since their inception in 2011, scoring unprecedented efficacy in disease settings that were once invariably fatal. Yet, for the majority of patients the results seen with checkpoints are more fizzle than bang, with less than 30% of patients experiencing any response.

One way to address this shortcoming is to combine checkpoint therapy with the administration of a virus—the so-called, “oncolytics” approach—which is hoped to relight the immunotherapeutic fuse. (This prospect is not baseless conjecture, indeed, a herpes-based therapy, called talimogene laherparepvec [TVEC] was approved in 2015 for use in advanced melanoma.)

The study reported herein used a different virus, a Coxsackievirus, called CVA21 that investigators think will have broader utility than TVEC when combined with a checkpoint inhibitor.

(Note: In brief, oncolytics work because certain virus will replicate in tumors, but not healthy tissues; the reasons for this are complex and due to space limitations are not discussed here.)

In a report of 22 evaluable patients with advanced melanoma who had progressed despite previous treatment (some with checkpoint inhibitors), CVA21 was combined with the checkpoint inhibitor, ipilimumab in a phase I study.

Ipilimumab was infused systemically, whereas CVA21 was injected directly into tumors.

Results showed an overall response rate of 50%, with a response rate of 36% in patients who were previously treated with ipilimumab (the response rate for ipilimumab monotherapy is typically less than 15%).

“I would mention that there’s another study of ipilimumab, given to patients after failing pembrolizumab (anti-PD-1) where the objective response was 13%,” said study lead investigator, Brendan Curti, MD, director of the Clinical Biotherapy Program at the Providence Cancer Center in Portland, Oregon. “So we believe this is a finding of interest.”

Importantly, 4 patients who had a complete response with the combination had previously failed ipilimumab. More important still, 67% of lesions not injected with CVA21 regressed at least 50%; this response is indicative of the “abscopal effect” a Holy Grail of anti-tumor treatments.

Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center, thought the results were provocative. “The take home point for me is that one can potentially prime the immune response with this combination approach and basically make a tumor cell population that has been resistant to checkpoint therapy become sensitive again. I think this has relevance for patients not only who have refractory disease to checkpoint antibodies, but also those folks who have earlier stage disease.”

Head Case

Finally, when it comes to treating the nearly invariably lethal cancer of glioblastoma, clinicians are willing to try most anything. A case in point: there’s a new device that creates an electrical field in your head that has, when combined with the standard of care drug, temozolomide, demonstrated equivalent efficacy to radiotherapy combined with temozolomide—and with fewer side effects.

“Glioblastoma is the most aggressive and deadly form of brain tumor,” says Roger Stupp, MD, professor of Neurological Surgery at Northwestern University Feinberg School of Medicine. “One of the challenges of treating this disease is many drugs simply cannot penetrate the blood brain barrier, so for years the standard treatment is surgery, radiotherapy, and chemotherapy (with temozolomide).” Thus, this is an outside the box approach.

The device—essentially a skullcap with wires powered by an external battery—works by using electrical energy to disrupt the cellular scaffolding of dividing tumor cells formed by polymers of the molecule, tubulin. With tubulin disrupted, the cells collapse.

In a phase III study of newly diagnosed glioblastoma patients the device (Optune; manufactured by Novocure) was combined with temozolomide (O/TEM: N=466) and compared to temozolomide alone (TEM: N=229).

Results showed that the O/TEM combination offered superior survival rates over a 5-year period as compared to treatment with TEM alone, translating into a 37% reduction is risk of death in this difficult to treat patient population.

“In the beginning the patients thought it was kind of weird,” reports Dr. Stupp, “But they quickly get used to it. It gives them greater independence—I don’t have to see them in the clinic nearly as often, also, it gives them a feeling of empowerment that they are doing something themselves. Patients like it.”

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