Embracing an opportunity
While the data for this combination are not yet mature, there is already enough reason to embrace it.
Rationale for chemotherapy-immunotherapy combinations
The relationship between chemotherapy and the immune system is complex and despite many preconceptions, not necessarily antagonistic. Chemotherapy has the potential to overcome some of the barriers to an antitumor immune response . Resistance to immunotherapy may be mediated by myeloid-derived suppressor cells and T-regulatory cells, which can be depleted by cytotoxic chemotherapy. The lack of effector lymphocytes within the tumor may also limit responses to immunotherapy. Chemotherapy can reverse this T-cell depletion and promote tumor infiltration of cytotoxic T-cells. Antigen presentation can also be enhanced by chemotherapy, which upregulates the machinery necessary for tumor recognition .
Limitations of combination therapy
There are concerns about a combinatorial approach. While chemotherapy can be immunomodulatory, not all chemotherapy has the same effect . Optimization of the agents and schedule in these combinations is needed. There is also a cost to combination approaches. Certainly, the financial cost will have systemic consequences, but the other cost is toxicity. While early data have shown tolerability, little is known about late effects. If there is no difference in long term benefit, these costs may not be justified. Some concern regarding the combination is simply the lack of long-term results – for both safety and efficacy.
A practical consideration
While the concerns are valid, a compelling argument can be made to support the combination. There is scientific rationale supporting it and the safety data have been reassuring in multiple iterations. Perhaps most importantly, this approach will offer more patients the opportunity to achieve the durable benefit possible with immunotherapy. For patients whose tumors do not highly express PD-L1, which is the majority of patients, chemotherapy-immunotherapy combinations are particularly appealing. If checkpoint inhibitors are reserved for second-line use, a significant number of patients will simply never receive them and forfeit the opportunity to benefit.
Our “success” at giving second-line chemotherapy is poor. In a study published a decade ago, over 300 patients treated with platinum-doublet chemotherapy were randomized to receive immediate docetaxel or to be observed and receive docetaxel at progression . Among patients in the delayed docetaxel group, only 63% of patients received treatment. The most common reason that docetaxel was not given at progression was progression itself.
Given the safety profile of immunotherapy and the enthusiasm towards it, we expected the rate of second-line use to be higher with checkpoint inhibitors; it was the same. In KEYNOTE-024, there was a crossover to pembrolizumab for patients who received first-line chemotherapy. Even when including patients who received immunotherapy off study, only 64% of patients effectively crossed over .
Despite our best efforts, nearly 40% of our patients with NSCLC do not receive intended second-line therapy. The stark reality is that lung cancer is an unforgiving disease. Even under the closest observation, progression can be a devastating and fatal event. If we administer chemotherapy and promise to give immunotherapy at progression, we must understand that for many patients, we simply cannot keep that promise.
The field is still developing. There is no doubt that we need more data – longer follow-up, mature survival comparisons, larger safety datasets, and reliable predictive markers for combination therapy – but we will always need more. And we must always be willing to change our practice based on emerging data. New combinations are under investigation; the addition of atezolizumab to carboplatin, paclitaxel, and bevacizumab reportedly improved outcomes. KEYNOTE-189, the phase III confirmatory study of carboplatin and pemetrexed with or without pembrolizumab, will be very informative to the use of this combination and may ultimately change our view of this combination. But in our clinics, we cannot defer decisions – we must make recommendations based on what is available now.
Chemotherapy-immunotherapy combinations may not be the perfect strategy, but for many of our patients, the approach is far better than the current alternative. Immunotherapy is a potentially transformative treatment, but to receive that benefit, you must receive the drug. Combination therapy is a means for more of our patients to do just that.
- Destefano CB and Liu SV, Combinatorial Immunotherapy and Chemotherapy. In: Early Phase Cancer Immunotherapy. Edited by SP Patel and R Kurzrock. Switzerland: Springer, Cham 2017; 199-218.
- Fidias PM, Dakhil SR, Lyss AP et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2009; 27: 591-598.
- Brahmer JR, Rodriguez-Abreu D, Robinson AG et al. Progression after the next line of therapy (PFS2) and updated OS among patients (pts) with advanced NSCLC and PD-L1 tumor proportion score (TPS) ≥50% enrolled in KEYNOTE-024. J Clin Oncol 2017; 35(Suppl 15): 9000-9000.