IMpower010 was designed to look at adjuvant atezolizumab in early stage resected non-small cell lung cancer. We’ve seen tremendous advances in treatment options for advanced stage lung cancer, especially with the immune checkpoint inhibitors and with targeted therapies but in early stage lung cancer, other than the use of osimertinib for EGFR mutated non-small cell lung cancer, we really haven’t seen advances in the past 15 years, ever since we discovered the use of chemotherapy could improve cure. So it made sense to take the immune checkpoint inhibitor, bring it into early stage. So IMpower010 enrolled patients who had resected disease, they received chemo and then randomised to get atezolizumab or not. That was a design really hoping that we would see the same sort of benefits in early stage disease that we see in metastatic disease with the immune checkpoint inhibitors.
What was the methodology used in this study?
IMpower010 was a randomised phase III trial that enrolled over 1,000 patients with resected stage 1b to 3a non-small cell lung cancer. The time of enrolment was before chemotherapy, so all patients received chemotherapy and it was cisplatin based, there were four partner drugs that could be chosen. The patients who wanted to continue on study, and we did have some drop-off as patients were going through chemotherapy where they decided they didn’t want to continue, but for those who did we had 1,005 patients who were randomised to either receive atezolizumab at the standard dosing every three weeks for up to a year or to just be followed with best supportive care.
The study was designed with a hierarchical testing strategy such that the first population to be looked at for disease free survival were patients with stage 2 to 3a disease who had any level of PD-L1 expression. Then to look at those who had any stage 2 to 3, regardless of PD-L1 and then all comers regardless of PD-L1 and then the final formal testing is for overall survival which requires positivity of those others and then to have had enough events.
What were your findings?
The key findings from IMpower010 were the disease free survival outcomes in the first two populations. I’m going to give a little bit more background: we enrolled just over 1,000 patients and randomised 1,005. When we look at who those patients were, two-thirds had non-squamous histology and for that group we actually mandated testing for EGFR translocations and ALK. The other third had squamous histology, they were not tested for the driver mutations necessarily, they could be. The patient population, about 12% had stage 1b, 40% stage 3a and everybody else had stage 2 disease. When we talk about the outcomes it’s important to keep that in mind. The other key thing was when we did the PD-L1 testing 55% of patients had at least 1% expression of PD-L1 using the SP263 assay.
The first population, at least 1% expression of PD-L1, again that’s 55% of the patient population, stage 2-3a disease, again that’s about 90% of the patient population, disease free survival hazard ratio of 0.66 – 34% reduction in disease recurrence or death. This was statistically significant and it’s important to note that the treatment only continued for a year. We have a median follow-up going out to 32 months and when we look at the disease free survival curves they don’t come together, they stay separated at about the same distance, even after that one year mark, and continuing out during the follow-up. So 0.66 hazard ratio for disease free survival with the PD-L1 expression; we then looked into all comers with stage 2-3a and there again the disease free survival hazard ratio was statistically significant, it is 0.79. In that group we got to look at PD-L1 expression levels and we found that for those that had the PD-L1 of 1% a hazard ratio of 0.66, we already knew that. For those with the PD-L1 expression greater than 50% the disease free survival hazard ratio was 0.43 which is pretty striking. But for those who did not have PD-L1 expression on their tumours there did not seem to be any benefit, the disease free survival hazard ratio was 0.97. So this does seem to be driven by the PD-L1 expressing tumours, patients with those.
Patients with EGFR and ALK did not seem to benefit but we were statistically significant for that all comers, 0.79 so the next step is to look at the intention to treat population which brings in the 12% of patients with stage 1b, again, regardless of PD-L1 expression. We have not yet had enough events for the significance boundary to be crossed. The trend is looking very similar to what we saw for the all comers with stage 2-3a but we don’t have a final analysis on that. We also don’t have overall survival data yet. Very, very preliminarily it does look like the curves are starting to separate a little bit but again it’s too early to say.
How can these results impact the future treatment of NSCLC?
When we talk about non-small cell lung cancer our ultimate goal is to try to cure. So the best way to do that is to prevent the disease and then to find the disease early when it is more curative. So it’s really important that we keep focussing on screening efforts so we can find lung cancer early. When we do find lung cancer early we still have surgery as the primary modality, radiation for some. We still have chemotherapy playing an important role for cure but now we have two other strategies that can also improve outcomes, at least disease free survival as we know it at this time. That would be for patients with EGFR driver mutations in their tumours, osimertinib, and now for patients with PD-L1 expression it seems that adjuvant atezolizumab can also lead to disease free survival outcomes.
So we don’t have approval yet for that but this reinforces the idea that we need to be doing biomarker testing when we do find early stage lung cancer so that we can identify the driver mutation tumours, the PD-L1 expressing tumours and treat appropriately. We also want to get to a time where we aren’t treating the people who don’t need it, so a way to identify those patients who have been cured by the surgery and chemotherapy alone so that they can be done. And then to identify those who are at high risk of recurrence and how do we do that? Probably with ctDNA and other liquid biomarkers that help us look and scan the body to see if there is still evidence of residual cancer.
Is there anything else important that you would like to mention?
In the IMpower010 study the adjuvant atezolizumab did have toxicity, as we would expect. We unfortunately don’t have any cancer therapeutics that come without toxicity. The toxicities that we’ve seen were those that we know about from patients treated in the metastatic setting and also across diseases so it’s autoimmune toxicities. We did see some evidence of liver function abnormalities but very, very low rates of true hepatitis, very, very low rates of any particular toxicity but we add them all up together. Serious adverse events that were felt to be treatment related were in about 7% of patients and so that is something we need to be mindful of as we move forward with any sort of therapy, especially in an adjuvant setting.