An Interview with Dr. Federico Cappuzzo: Checkpoint Inhibitors Have Replaced Old Strategies

Posted: March 1, 2019

Federico Cappuzzo, MD, PhD, has been the director of Medical Oncology at AUSL della Romagna, Ravenna, Italy, since April 2016; in January 2017 he became the director of the Hematology and Oncology Department. The author of more than 200 papers, Dr. Cappuzzo is an extremely active member of the IASLC, having served in various leadership and faculty roles for numerous planning committees and meetings. The IASLC Lung Cancer News spoke with Dr. Cappuzzo about checkpoint inhibitors (CPI) in the first- and second-line settings, as well as about the future therapeutic horizon.

Q: As CPIs move to front line, which regimen or regimens are now “standard” in the second-line setting in advanced NSCLC?
A: Of course this is an important question for clinical practice because CPIs are now mainly used in front-line settings in combination with chemotherapy, particularly with platinum-based chemotherapy. When this is ineffective, the standard second-line option is, unfortunately, docetaxel unless a CPI is used as a single agent in the front line, in which case the standard second-line regimen is platinum-based chemotherapy.

Q: Does this reinvigorate the role of combination docetaxel and ramucirumab in this setting?
A: Yes, we know that docetaxel alone is not an optimal treatment in the second-line setting for patients who have already received platinum-based chemotherapy. We also know that the combination of docetaxel with an antiangiogenic agent, such as ramucirumab or even nintedanib, could be a reasonable option that we can offer patients to ensure a more effective regimen.

Q: With respect to patients who have been on chemotherapy/CPI combinations front line, do you think there is a role for platinum re-challenge in patients whose disease has stabilized or responded to prior platinum regimen(s) and who experience disease progression on CPI alone or on pembrolizumab/pemetrexed?
A: Re-challenge of platinum-based chemotherapy is generally considered an option when we have a patient whose disease responds to the therapy and the duration of response is relevant—for example, lasting at least 1 year. I think that this concept remains applicable even in the era of immunotherapy, meaning that if we have a patient treated with a platinum-based chemotherapy and CPI combination whose disease responds to the therapy and maintains the response for a long time after chemotherapy is stopped, re-challenge with the platinum-based agent at the time of disease progression could be preferable to docetaxel. Of course, it’s only reasonable to consider a platinum-based chemotherapy re-challenge as long as the patient tolerated the therapy well in the first-line setting and there is no residual toxicity.

Q: In a patient with nonsquamous NSCLC in such a scenario, would you consider resuming carboplatin, substituting a taxane for pemetrexed, and switching the CPI for an angiogenesis inhibitor? Why or why not?
A: We can certainly change the drugs that we’re using from the front-line setting, with the idea being that, regardless of what is used front-line, we will re-challenge with chemotherapy. If we have a patient who was already on an immunotherapy in the front-line setting, using a platinum-based chemotherapy regimen, replacing one of the agents and adding an antiangiogenic therapy (for example, bevacizumab) could be reasonable.

Q: What role is there for adding new immunotherapeutic agents (e.g., vaccines and CTLA4 inhibitors) to frontline CPIs in those with “smoldering progression”?
A: Combinations of different immunotherapy agents in the first-line setting is very attractive considering that generally patients are reluctant to consider chemotherapy and frequently ask for a chemofree combination. Recent data show that combination nivolumab and ipilimumab could be more effective than chemotherapy or chemotherapy/CPI combinations, particularly for patients with high tumor mutational burden (TMB). Additional data are needed, but this approach allows for avoidance of chemotherapy in the first-line, whereas an effective therapy—platinum-based chemotherapy—can be reserved for those whose disease progresses on CPIs.

Q: How long are you treating patients with CPI in the second line?
A: The duration of treatment in the second line with CPIs generally continues up to disease progression, toxicity, or patient refusal. Many studies have continued treatment for up to 2 years. Optimal duration is not defined, but we know from clinical studies that, in patients who benefit from the treatment, stopping therapy at 1 year is not recommended. So in my practice, we use CPIs up until progression in both the first- and second-line settings.

Q: Do some biomarkers (TMB, for example) influence your choices to (re) use CPIs in patients based on PD-L1 expression status?
A: In the future I think TMB will be used in clinical practice, but at the present time the only biomarker that we are using is PD-L1. In the first-line setting CPIs can be considered in combination with chemotherapy irrespective of PD-L1 expression. In the second-line setting, the efficacy of a CPI, even as a single agent, has been demonstrated in clinical trials irrespective of PD-1 expression. This is not an optimal situation because we know that PD-L1 is not the optimal biomarker: a consistent proportion of patients with high levels of PD-L1 expression do not respond to immunotherapy, and some patients with no or low PD-L1 expression have shown positive effects of CPIs. We need additional biomarkers to refine patient selection, not only to identify those patients who will demonstrate a strong response to therapy but also to save patients who are not likely to respond from unnecessary treatment. However, at the present, based on the current data for TMB, PD-L1 remains the most standard biomarker.

Q: What do you see on the horizon in the next few years for CPI?
A: I think we will have additional combinations of existing and new immunotherapeutic agents. Of course, what we urgently need are agents for patients who have disease progression on the current CPIs because the fallback for these patients remains chemotherapy. We need new strategies and new drugs that we can employ as second-generation immunotherapeutic agents. ✦