Notes on ESMO17: Cancer immunotherapy
Clinical Brief — September 27th
ESMO, or the European Society of Medical Oncology Congress, is an annual gathering of cancer experts and patient advocates. Here are some studies from this year’s ESMO that may be of use.
Final results of a Phase III trial confirm survival benefits of adjuvant chemo + cell-based immunotherapy for non-small-cell lung cancer.
Between 2007 and 2012, researchers from the Chiba Cancer Center, Japan, led an independent study with about 100 patients with non-small-cell lung cancer. Try as I might, it doesn’t seem like this was an industry-funded trial.
Patients with cancers ranging from stage Ib — IV were recruited. Everyone first had surgery for their cancer, and were then randomized 50/50 to adjuvant chemo-immunotherapy or platinum-doublet chemotherapy.
Now here’s where it gets interesting: The “immunotherapy” they used here weren’t the often-encountered checkpoint inhibitors, nor was it the fabled CAR-T therapy. They did an auto-transplant of the patients own immune cells.
Basically, researchers took the patient’s own lymph nodes to extract T-cells and dendritic cells and grew them in culture with a cytokine called IL-2 before injecting it back into the patient. IL-2 has been used to treat metastatic melanoma and kidney cancers. It works by stimulating the immune system and is known to be quite toxic. But by activating these immune cells outside of the body, the patients were spared nearly all of its side effects.
The result? They first published promising data back in 2015 where an estimated 93% of patients who had adjuvant chemo-immunotherapy survived past 2 years vs 66% on adjuvant chemo. Median survival at the time was not reached for patients on chemo-immunotherapy vs 48 months for chemo.
Fast forward to ESMO 2017. With longer follow-up, the results of their trial remain largely consistent with their previous findings.
An estimated 96% of patients who had adjuvant chemo-immunotherapy survived past 2 years vs 65% on adjuvant chemo. Estimated 5-year survival was 69% for chemo-immunotherapy vs 45% for chemo.
Their abstract doesn’t mention the safety profile of chemo-immunotherapy, but their previous publication reported that 7% of patients receiving adjuvant chemo-immunotherapy had chills and shivering; 6% had a fever.
Does checkpoint inhibitor immunotherapy make any subsequent treatment with chemo more toxic?
Researchers at the Royal Marsden Hospital in London, UK, found that prior exposure to a checkpoint inhibitor immunotherapy was tied to greater toxicity with future chemotherapies.
They looked through the records of about 100 patients receiving chemotherapy for cancer: 14 patients were previously treated with an immunotherapy vs 85 patients who had no prior exposure to immunotherapy.
In terms of chemo toxicities, the odds of severe (Grade 4) neutropenia were 7-times higher for patients who were previously treated with immunotherapy vs those with no prior exposure; the odds of moderate or severe thrombocytopenia was 14-times higher vs those with no prior exposure.
They also made a statistical model that accounted for prior chemo exposure, the type of chemo patients were currently on, as well as prior immunotherapy exposure.
In this model, the odds of moderate or severe myelotoxicity was 4-times higher for patients who were previously treated with immunotherapy vs those with no prior exposure.
These results highlight a potential new risk for patients when it comes to checkpoint inhibitors: If we take it before chemo, does it make future chemo treatments more toxic?
A larger trial is needed to validate these observations.
For reference, checkpoint inhibitors include atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda).
Trials with checkpoint inhibitor immunotherapies often use progression-free survival and tumor response as endpoints, which may not predict survival benefit.
Two abstracts looked at progression-free survival and tumor response separately.
In the first, researchers from Nagoya University, Japan, reviewed about 50 trials and identified nine Phase III randomized trials fit for their analysis. Six trials were with nivolumab (Opdivo) and three were with pembrolizumab (Keytruda).
They found no correlation between progression-free survival and overall survival in these trials. In five trials where the progression-free survival data disagreed with the overall survival data, overall survival was significant but progression-free survival was not.
In the second, researchers from Australia reviewed nearly 90 Phase II trials with checkpoint inhibitor immunotherapies. Tumor response was the primary endpoint in every 3 out of 5 trials.
They found that tumor response data couldn’t be used to predict 6-month progression-free survival, nor 12-month overall survival.
In a meta-analysis of about 60 trials, researchers summarized the safety profile of anti-PD-1/PD-L1 immunotherapies.
Researchers from China and the US reviewed trials involving atezolizumab (Tecentriq), avelumab (Bavencio), nivolumab (Opdivo), pembrolizumab (Keytruda), and BMS-936559. An impressive 10k-patient population was reflected in this analysis.
About 7 in 10 patients experienced a side effect of any grade, and a little over 1 in 7 patients experienced a moderate or severe side effect.
Fatigue was the most common side effect, affecting more than 1 in 5 patients.
Side effects affecting between 1 in 5 and 1 in 10 patients were itchiness, rash, diarrhea, and nausea. Side effects affecting between 1 in 10 and 1 in 20 patients were decreased appetite, joint pain, vitiligo, fever, hypothyroidism, and asthenia.
The most common moderate or severe side effects were low blood sodium levels, lymphopenia, and fatigue.
Being on corticosteroids before starting treatment, having a high LDH level, or being physically dependent may predict diminished benefit to anti-PD-1 immunotherapies.
Researchers from Japan reviewed the records of about 200 patients treated with nivolumab (Opdivo) for non-small cell lung cancer.
They found that patients who were on any corticosteroids before treatment with an immunotherapy had more than double the risk of shorter progression-free survival vs those who weren’t on a steroid.
The risk of limited progression-free survival was also 63% higher for patients who had an LDH level >240 IU/L at baseline vs those with LDH below 240 IU/L; 57% higher for patients who were physically dependent as measured by an ECOG performance status of >2 vs those who were more independent.
For more presentations from #ESMO17, take a look at my hand-curated Twitter moment :).
