There was lots of buzz about immunotherapy going into the San Antonio Breast Cancer Symposium (SABCS) this year. Immunotherapy includes treatment to boost a patient’s immune system to fight diseases such as cancer as well as therapy to train the immune system to attack cancer cells specifically. We know that the immune system is important in cancer and recently there have been some advances using immunotherapy in other cancers (melanoma, lung, pancreatic, etc.).
A large body of evidence going back many decades shows immunotherapy may be important for breast cancer. Multiple epidemiological studies found a proportion of breast cancers will go away without treatment, indicating that the natural immune system is able to handle some cancers and prevent them from becoming life-threatening. It’s this very fact that makes population-based screening for breast cancer so problematic, as imaging tools like mammograms may be finding early-stage cancers that would never become clinically apparent, or life-threatening, and do not need treatment.
Research trends come in waves and the interest in immunotherapy and breast cancer has been slowly re-gaining strength since the last wave that offered mostly hope and hype. While expectations for advances in immunotherapy were high going into the 2014 SABCS conference, after the data was presented, frankly, I felt that the mood was split. On the one hand, the quiet consensus among researchers not working in immunotherapy was research findings this year were rather lackluster and not nearly as striking as they had been led to believe. On the other hand, researchers in the field of immunology expressed enormous excitement that “game-changing” advances were “around the corner” and asserted that research in the last three to four years has firmly put breast cancer at the forefront of immunology.
In the educational sessions before the conference officially kicks off, one panel, moderated by Dr. Douglas Yee from the University of Minnesota, called “Introduction to Immunotherapy” presented a variety of research to educate the broader breast cancer research and treatment community about advances and trends in immunotherapy.
One of the challenges of immunotherapy is that cancer cells have many of the same characteristics as healthy cells and are often very effective at evading the immune system. Dr. Nora Disis noted that because tumors can become immune unrecognizable, she believes immunotherapy could be probably more effective with early stage disease that has not spread. The trick then is to activate the immune system against cancer while leaving healthy tissue unaffected. Dr. Jeff Weber noted the substantial toxicities of some immunotherapies and warned about “letting the genie out of the bottle.” Dr. Disis, in introducing the immunotherapy session, noted that when talking about ‘unleashing the immune response,’ it’s important to make sure it’s the right kind of immune response—as opposed to the wrong kind, when the body attacks itself.
Immunology is complex. Researchers are excited by indications that a strong immune response may be more than additive but may actually be synergistic with chemotherapy, where the sum is greater than the parts. Yet, despite findings that patients with two aggressive sub-types of breast who exhibited a higher immune response did better (HER2+ in Abstract 6 & triple negative in Abstract 8), other evidence shows that more response is not always better. For patients with an already high immune response, giving more stimulation can counter-intuitively actually be a bad thing, as it can cause T cell exhaustion. [Note research that finds that patients with a lot of T cells don’t do well with Herceptin.]
With this focus on understanding immune response to breast cancer, several researchers noted that it appears that the primary mechanism of Herceptin is to stimulate the immune system, specifically adaptive immunity – the ability of the body to recognize an abnormality and react to it. Dr. Soon Paik suggested that Herceptin may work as anti-stem cell therapy in HER2+ breast cancers. The Mayo Clinic’s Dr. Edith Perez presented her research on stromal tumor-infiltrating lymphocytes (S-TILs) in the alliance N9831 trial which entailed a retrospective analysis of tumor blocks to find patients who benefited from chemo but not Herceptin. Her research suggests that patients with a strong immune response did not benefit from the addition of Herceptin (trastuzumab). This finding that around 1 in 10 patients with HER2+ tumors may not benefit from Herceptin, which is the standard of care for this sub-type of breast cancer, may prove beneficial in reducing the harms of treatment if it enables doctors to use tumor-infiltrating lymphocytes as a biomarker to identify patients who can be spared the adverse effects and expense of Herceptin and still do well/have good outcomes.
Breast cancer researchers are trying to benefit from the learnings in immunotherapy with other cancers, most notably melanoma and lung cancer. Two studies presented looked at PD-L1 and PD-L inhibitors. Some researchers believe these immunotherapies are most effective in tumors that have high levels of infiltrating immune cells including T cells. Approximately 55-65% of breast cancers find PD-L1 activation in stroma or on tumor itself. The PD-1 inhibitor pembrolizumab (Keytruda) was approved in September 2013 by the U.S. Food and Drug Administration (FDA) for second line use in melanoma (and fast-tracked for lung cancer) and researchers looked into the safety for breast cancer patients.
Dr. Rita Nanda at the University of Chicago presented data from KEYNOTE-012, which is a phase 1B study (focused on safety) looking at whether pembrolizumab (MK-3475), an immunotherapy drug recently approved by the FDA for the treatment of metastatic melanoma, is safe and tolerable for patients with triple-negative breast cancer. The study enrolled 32 patients with metastatic or recurrent triple negative breast cancer; data was presented on 27 patients with sufficient data for analysis. One-fifth of women were African American. Patients were treated with pembro antibody given via IV every two weeks. Treatment-related adverse events occurred in 56% of patients in the clinical trial, most commonly low grade fatigue, nausea, arthralgia, and myalgia. However, of the 32 patients enrolled in the trial, four experienced grade 3 toxicity and one patient died. Nearly one-fifth of patients (18%) had overall response, one of which with complete response, and nearly one-third (30%) experienced a reduction in maximum tumor burden. Median follow-up is just under 10 months and three patients (one with a complete response and two with a partial response) remain in treatment.
As a patient advocate, it’s hard to celebrate as “game-changing” a safety study in which only 10% of patients continue treatment, and toxicity is identified as notable and includes one death. Interestingly, many of the researchers and press coverage noted the “promising activity” of pembrolizumab in PD-L1 expressing triple negative breast cancers. I suspect that this disconnect is a reflection of the very modest progress researchers have become accustomed to celebrating after decades of incremental progress.
A second multicenter phase 1 trial tested MPDL3280A for safety in triple negative breast cancer patients. There was sufficient data for safety analysis for 12 patients who received the drug. MPDL3280A was administered by IV every three weeks for up to a year in patients with the PD-L1 protein, most of whom had received at least two prior therapies. Of the nine patients evaluated for efficacy, response was seen within six weeks of receiving the first dose of the drug, with one patient experiencing a complete response, two with a partial response, and one with stable disease.
There are currently no targeted therapies for triple negative breast cancer and survival for women with metastatic triple negative breast cancer averages about one year, demonstrating the urgent unmet need for this cancer subtype. While some researchers are encouraged by the data presented at SABCS 2014, privately many doctors and patients are discouraged by the modest data.
“Introduction to Immunotherapy” moderated by Dr. Douglas Yee from the University of Minnesota called with Dr. Mary (Nora) Disis from the University of Washington, Dr. Jeffrey Weber from the Moffitt Center in Tampa, and Dr. Sherene Loi at the Peter MacCallum Cancer Center in Melbourne, Australia.