It’s been a long, long time that patients who have operable non-small cell lung cancer have not really had much more than conventional chemotherapy to support better long-term outcomes. We know that recurrence originally from micrometastatic disease at the time of surgery is an all too common occurrence for this population so there was a huge unmet need. CheckMate 816 is actually the first study to report the addition of immunotherapy in the pre-operative window to support the systemic effort to reduce distant disease so a very important study for a growing population of patients.
What was the methodology used in the study?
CheckMate 816 is a phase III randomised controlled trial, open label, comparing conventional cisplatin doublet chemotherapy to chemotherapy plus nivolumab for three cycles prior to surgery for patients with operable stage 1b-3a, by the old HACC7 staging classification. Surgery had to be lobectomy, bilobectomy, extended lobectomy or pneumonectomy and there was no adjuvant immunotherapy although patients could receive either additional chemotherapy or adjuvant radiation based on physician/tumour board/patient consensus. We now have the results of the independent primary endpoint of pathological complete response which was reported by Dr Patrick Forde back in the spring at AACR. Here we’re reporting the exploratory surgical feasibility and safety outcomes accompanying those results.
What were the key findings?
As I said, the pathological complete response rate was dramatically higher in patients who received chemoimmunotherapy before surgery, indicating a far more efficacious treatment regimen from a biological standpoint. It was a little more than twelvefold increase in the rate of pathological complete response, meaning no residual tumour cells in the tumour bed or lymph nodes by blinded independent review. This was on an intent to treat basis so on its own an extraordinarily important finding showing that we have a highly active regimen in this space. Of course if that was accompanied with a higher surgical risk or worse perioperative outcomes this would have been a serious problem so that speaks to the importance of the results we’re presenting now where we see that patients who received chemoimmunotherapy prior to surgery actually had a lower rate of requiring pneumonectomy, higher rate of complete resection with no adverse event signal, in fact quite the contrary – it seems that the operations may have been easier with a shorter operative time in the patients who had received chemoimmunotherapy prior to surgery. As I said, no adverse event signal in the post-operative period so very compelling results that we have a highly biologically active regimen that doesn’t confer any additional risk if not, perhaps, some benefits.
How can these results impact the future treatment of lung cancer?
Although the FDA hasn’t yet approved pathological complete response as a surrogate endpoint for survival in lung cancer, it’s an improved metric for breast cancer, that’s going to come. Checkmate 816 is also powered for event free survival so as those data mature I’m confident that this will be positive. As I mentioned, patients in the treatment arm of chemotherapy plus nivolumab had fewer pneumonectomies, quite a bit fewer pneumonectomies. We know that the 90 day mortality from pneumonectomy is 2-3 times higher than patients who have lobectomy so on its own early event free survival promises to be positive but we’ll see. But even without an OS signal the fact that you have a highly active regimen that allows for safer, less impactful, less lung resection being required, less high risk lung resection being required, is an extraordinarily important endpoint, one that is not yet recognised by regulatory agencies but we’re talking about the lung which is a vital organ and contributes significantly to people’s quality of life and morbidity profiles. So the combination of the pathological complete response rates with this very encouraging surgical safety set of findings promises to change the way we think about approvals of new regimens for lung cancer patients.
Is there anything else important to mention?
It’s important to recognise that this is just the first wave of immunotherapy based regimens in the preoperative window. Although you could say we only saw 25% pathological complete response rate, there’s an enormous opportunity to improve upon that with various combinations, be it by changing dosing schedule, regimens, frequency and bringing in other novel agents. So the next few years will see higher and higher levels of pathological complete response rate so it will be necessary for us to be able to predict that in a non-invasive fashion so that we can tailor future trials to decide whether local therapy is even necessary in some patients or not.
So very exciting times for lung cancer patients, a lot of opportunities to improve their care, not just on overall survival but on their entire experience of the treatment trajectory which I think is extremely important.