May 2015 Edition Vol.11, Issue 5

AACR 2015: Immunotherapy Marches On

AACR 2015: Immunotherapy Marches On

By Neil Canavan


Immunotherapy in oncology (IO) is rapidly becoming the new standard of care in a number of difficult to treat tumor types. At the recently held conference of the American Association of Cancer Research (AACR), key IO clinical studies were presented that indicate this new treatment modality is here to stay.   

“For years we were shouting in the wilderness,” said James Allison, PhD, executive director of immunotherapy clinical research at M.D. Anderson Cancer Center. “Nobody took immunotherapy seriously. For the longest time cancer therapy was all about small molecules, and targeting the causative lesions and trying to deal with the resistance mechanisms that the cancer cells came up with to avoid it.”

“I remember going to a major cancer meeting in 2004 – I was the only immunologist there – and I don’t mean just speaking, I mean there, in attendance. My talk was pretty well received but there was a lot of skepticism.”

But that’s all changed. Immunotherapy-themed sessions at AACR have, in just a few short years, grown from a handful of presentations to being the dominant theme of the conference. “Five years ago there were maybe two or three sessions,” said Dr. Allison. “Maybe with luck there would be a major symposium, but now…  I can’t even count. This year there were at least half a dozen major sessions – all immunotherapy focused, and held in the very biggest rooms, and they’re packed.”

All this IO instigated excitement is, thankfully, not the product of hyped-up predictions prompted by a handful of miraculously cured rodents. IO is in the clinic, or in late-stage clinical trials, and some patients are in such long-term remissions that the word “cured” is now increasingly used to describe their prognosis.

Indeed, the march of clinical outcomes – successes that have no precedent – continued apace as reported at AACR 2015.

Checkpoint Fever

At the head of the IO column are the so-called checkpoint inhibitors. Their mechanisms of action are described here in brief: The immune system is held in check by signals, checks, if you will, that are performed by the cells of the immune system as they interact with the various other cell types of the body. The checkpoint is a stop/go decision junction, a place where an immune response is allowed to proceed in, say, clearing an infection, or is terminated, in order to prevent the phenomenon of autoimmune disease.

Tumor cells are able to commandeer this fail-safe mechanism and turn the attacking immune cells – cytotoxic T-cells – off. Checkpoint inhibitors turn them back on.

There are currently two flavors of checkpoint inhibitors that target two different interactions of the immune response. Generically, these agents are known as anti-CTLA-4 and anti-PD-1.

Both targets now have approved drugs on the shelf. Yervoy, an anti-CTLA-4 drug was approved in 2011; Keytruda, and Opdivo, both PD-1 inhibitors, were approved in 2014. The initial indication for all three monoclonal antibody agents is advanced melanoma. 

Others checkpoints are in the pipeline and clinical trials to investigate the efficacy of these compounds can’t be recruited fast enough; the IO questions now being studied include:

  1. Can two effective checkpoint inhibitors be used in combination?
  2. Is one checkpoint drug better than the other for use as monotherapy?
  3. Is the drug class effective in other tumor types?

Some answers from AACR 2015:

Study CA209-069: Checkpoint Combinations

In this study, presented by Stephen Hodi, MD, Dana-Farber Cancer Institute, Yervoy was combined with Opdivo in a cohort of patients with advanced melanoma, with or without the BRAF mutation (N=150).

Results showed that the overall response rate for the checkpoint combination was 61% versus 11% for Yervoy alone in BRAF wild-type patients, and 52% versus 10%, respectively, in BRAF mutants. For both patient cohorts the complete response rate for the combination was 22% versus 0% for Yervoy alone.

Rates of treatment-related adverse events (AEs) were higher for the combination arm – 86% for any grade AE versus 43% for Yervoy – but these events were largely considered to be manageable. That said, there were three rather sudden onset treatment-related deaths while on study, providing further emphasis for the need to educate both the patient and the attending healthcare team about side effects specific to immunotherapy drugs (ie, pneumonitis).

Regarding overall survival (OS) the study is still ongoing, however, a phase I trial with the same combination demonstrated an OS rate of 79% at two years.

Commenting on the data, Louis Weiner, MD, director of the Lombardi Comprehensive Cancer Center said, “When I was finishing my training, one of my mentors – when we were talking about melanoma –said, ‘yeah, that’s one of the diseases that gives cancer a bad name.’ And he was right. Yet, here we are now, not too many years later and we’re talking about treatments that are yielding durable responses. This is really revolutionary,” he said, “not only for the treatment of patients with this disease, but the implications for people who have other tumor types, which is profound.”

KEYNOTE-006 Study: Is one checkpoint better than the other?

This study was a head-to-head comparison of Keytruda with Yervoy, in patients with advanced melanoma (N=834). Results showed that patients in the Keytruda arm had a 2.8 times greater overall response rate to treatment than patients in the Yervoy arm. Furthermore, 74.1% of the patients treated with Keytruda were alive at one year vs 51.2% of patients treated with Yervoy (P<0.0001).

“Not that long ago we would be in front of patients and we would be talking about treatment options that would help maybe one in ten patients,” said study investigator, Antoni Ribas, MD, PhD, associate director of the tumor immunology program at the Daved Geffen School of Medicine, “and most of those responses were temporary.” There are Yervoy patients now that received the drug during clinical trials that are still in remission 7 years later, essentially, they are cured of what would have been a fatal disease.

If the data hold up, survival results for Keytruda look even better.

KEYNOTE-001 Study: Will checkpoint inhibitors work in other tumor types?

In the KEYNOTE-001 investigation, Keytruda was used to treat a cohort of patients with non-small cell lung cancer (NSCLC; N=495). The utility of PD-1 as a biomarker for response to PD-1 agents was also investigated.

Results showed an overall response rate for the entire patient cohort of 19.4% for Keytruda – not bad, as compared to historical data for chemotherapy in the setting of NSCLC. However, a response rate of 45.2% was observed for those patients with the highest degree of staining for PD-1, thereby validating the biomarker approach.

“People often ask me what was the most exciting moment for me personally in the development of anti-PD-1 drugs,” said Suzanne Topalian, MD, Johns Hopkins University School of Medicine. “And I would say it was the realization that lung cancer could respond to this form of immunotherapy. Then we knew that we should branch out to other kinds of cancers to ones that would be susceptible.”

TNBC Study: A simple acronym for a notoriously deadly tumor subtype — Triple Negative Breast Cancer. There are currently no approved agents in TNBC that have any impact on survival.

“Triple negative is a particularly interesting target for cancer immunotherapy, especially anti-PD-L1 therapies,” said study investigator, Leisha Emens, MD, Johns Hopkins. “There’s a higher mutation rate than other breast cancer subtypes, and this lends to its ability to produce neo-antigens that can be recognized as foreign by the immune system.” (Note: PD-L1 is the ligand for the PD-1 receptor.)

In this small phase I study of 54 patients with metastatic TNBC (N=54), the investigational anti-PD-L1 agent, MPDL3280A produced an overall response rate of 19% (21 patients were evaluable for response) and the 24-week progression-free response rate was 27% — highly favorable in this disease setting.

Safety data for the entire cohort showed that the treatment was well tolerated.

Commenting once again on IO clinical outcomes, Dr. Weiner emphasized just how extraordinary even the early results for IO treatment have been. “Generally, people who do phase I clinical trials are pleased if they see even a hint of activity that would justify moving forward with a phase II. But in this case – a case where the activity signal is unequivocal – the implications for the future for patients with triple negative breast cancer are very exciting.”

Other pilot studies looking at checkpoint inhibition activity in bladder cancer, kidney cancer, head and neck cancer, and Hodgkin’s lymphoma all show promising early results, and without doubt we will hear much more about it at AACR 2016.

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