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Pembrolizumab-chemotherapy combination in non-small cell lung cancer

23-01-2018 | Non-small cell lung cancer | Article


Sally C Lau MD, Natasha B Leighl MD MMSc FRCPC, Stephen V Liu MD

Immunotherapy has forever changed the management of non-small cell lung cancer (NSCLC). Its impact extends far beyond the introduction of new treatment options and improving our standard of care; immunotherapy has changed our perception of what our treatments can achieve. In particular, checkpoint inhibitors, and specifically programmed cell death protein 1 (PD-1) axis inhibitors, have provided promising results and offer the opportunity for durable, more meaningful benefit. While an improvement in median survival is certainly welcome, what captures the imaginations of patient and physician alike is a chance, albeit a modest one, of long-term survival; a goal historically beyond our reach in metastatic NSCLC.

Immunotherapy in NSCLC: monotherapy 

There are three checkpoint inhibitors approved for the treatment of advanced NSCLC: PD-1 inhibitors nivolumab and pembrolizumab, and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab. In phase III trials, all three improved survival compared to second-line docetaxel [1-3], leading to their approval in NSCLC as monotherapies after platinum-doublet chemotherapy. Pembrolizumab was then approved as a first-line therapy based on KEYNOTE-024, a randomized trial comparing pembrolizumab to platinum-doublet chemotherapy [4]. The population was enriched using high expression of PD-L1 (at least 50% using the Dako 22C3 IHC assay) as an entry criterion. In this population, pembrolizumab was associated with a higher response rate, superior progression free survival, and longer survival. Pembrolizumab was then approved as first-line monotherapy in patients with high PD-L1 expression. Unfortunately, PD-L1 testing is not always done. In the KEYNOTE-024 trial, 15% of patients screened did not have samples evaluable for PD-L1 expression [4]. 

Chemotherapy-immunotherapy combinations

When PD-L1 testing is performed, high PD-L1 expression is seen in only 30% of patients with NSCLC. For the remaining 70%, chemotherapy has been the standard, with immunotherapy relegated to the salvage setting. However, recently, those with non-squamous NSCLC have been given another option: a combination of chemotherapy and immunotherapy. In May 2017, the United States Food and Drug Administration (FDA) granted accelerated approval to the combination of pembrolizumab, carboplatin and pemetrexed for first line treatment of non-squamous NSCLC, irrespective of PD-L1 expression, based on the phase II KEYNOTE-021G cohort.

KEYNOTE-021G (Click for more detail)

The accelerated approval of this treatment regimen based on limited data has prompted debate over whether this should be adopted as a standard of care. Below we outline our own personal perspectives on this new treatment strategy.


04-01-2018 | Non-small cell lung cancer | Article

Embracing an opportunity

Stephen V Liu MD

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 [1]. 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 [1].

Limitations of combination therapy

There are concerns about a combinatorial approach. While chemotherapy can be immunomodulatory, not all chemotherapy has the same effect [1]. 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 [2]. 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 [3]. 

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.


23-01-2018 | Non-small cell lung cancer | Article

Too soon to be a new standard?

Sally C Lau MD, Natasha B Leighl MD MMSc FRCPC

Though the United States Food and Drug Administration (FDA) has approved the combination, should the rest of the world have followed suit without an appropriately powered phase III comparison measuring the primary outcome of survival?

Study design

One of the challenges of KEYNOTE-021 was that it was designed prior to the establishment of first-line single agent pembrolizumab in patients with PD-L1 tumor proportion score (TPS) ≥ 50% based on the KEYNOTE-024 randomized phase III trial. This demonstrated improved survival and symptom control, as well as superior response rate, PFS and a more favourable toxicity profile compared to first-line platinum doublet chemotherapy. Thus, KEYNOTE-021G does not reflect our current challenge, namely how should we incorporate immunotherapy for those with PD-L1 TPS ≤ 50%, and for those with TPS ≥ 50%. Indeed, the small sample size has led to conflicting results within subgroups. The addition of pembrolizumab to chemotherapy markedly improved response rates in 21 patients without PD-L1-negative tumours compared to chemotherapy alone in 23 patients (62% versus 17%). Similarly, in those with PD-L1 TPS ≥ 50% tumours, the combination improved response rates compared to chemotherapy alone (80% or 16/20 patients versus 41% or 7/17 patients). However, counter to our expectations, those with intermediate PD-L1 tumour staining (TPS 1-49%) appeared to benefit from chemotherapy rather than the combination (39% or 9/23 patients versus 26% or 5/19 patients receiving the combination). Can we truly rely on these results, based on a few dozen patients, to define a new standard of care for all our patients?

Choosing an endpoint

Is response rate the best endpoint for practice-changing trials in lung cancer? It is an efficient measure to screen for treatment activity, and avoids potential confounding from such variables as post-progression therapy or treatment cross-over. But our patients need to live longer and feel better, and deserve more than temporary relief from “scan-xiety”. One could argue that a better endpoint is the time to starting docetaxel when comparing upfront combination therapy versus the standard sequential approach of chemotherapy followed by a checkpoint inhibitor or vice-versa. Response rate alone may underestimate the impact of immune checkpoint inhibitors on long-term survival, and may not be an appropriate endpoint to screen for activity of this class of agents.  As a surrogate endpoint, neither response rate nor progression-free survival in advanced non-small cell lung cancer has not been shown to have strong correlation with survival [1,2]. For example, what if the FDA had approved selumetinib in patients with advanced KRAS mutant lung adenocarcinoma based on its highly positive phase II randomized trial results? This study demonstrated markedly better response rates (37% versus 0), and a doubling of median progression-free and overall survival when selumetinib was added to second-line docetaxel [3]. However, the larger phase III study of this combination did not confirm these results [4].

Translating promise into practice change

Randomized phase II trials allow us to explore treatment activity using time-dependent endpoints such as overall and progression-free survival, and even quality of life (when blinded). We often use these trials to provide a “go-no go” signal for phase III development, as they can decrease the risk of proceeding to a phase III study if the new treatment is not truly effective. But it is important to recall that randomized phase II studies do not necessarily predict the outcome of phase III trials. It has been suggested that the probability of a positive randomized phase II trial result predicting a positive phase III result is approximately 1 in 20, similar to a chance finding using a p value of 0.05 [5]. While these trials increase the level of comfort investing in phase III development, they are not designed to define practice change.

To establish the superiority of immunotherapy plus chemotherapy over chemotherapy alone, an estimated 570 patients are needed in the ongoing phase III KEYNOTE-189 study [6,7]. An initial press release reports that the combination improved both PFS and overall survival significantly [8]. While final data have not been released, it is our hope that these results will significantly improve patient outcomes, and change the standard of care so that more may benefit from immune checkpoint inhibitors.

Unanswered questions remain

As neither study restricted enrolment by PD-L1 tumour staining, we hope that we can interpret the impact of adding immunotherapy to chemotherapy in those with PD-L1 TPS ≤ 50%. If benefit is statistically significant but clinically marginal, we will need to know the impact on patient quality of life and symptoms, in order to balance the increased toxicity of the combination. For patients with PD-L1 TPS ≥ 50%, the appropriate first-line comparator is no longer chemotherapy but pembrolizumab. Survival, quality of life and toxicity will be key endpoints when comparing pembrolizumab plus or minus platinum doublet chemotherapy in this group. And can we translate these findings to our patients with squamous carcinoma, who were not eligible for KEYNOTE-189? Other phase III trials, such as KEYNOTE-489, have been designed to answer that question and will hopefully be reported soon. Finally, will there still be a role for biomarkers such as PD-L1 and tumour mutation burden to help us select our patients mostly likely to benefit from immunotherapy?

Immunotherapy has had a profound impact on the treatment and outcome of patients with advanced lung cancer. We look forward to expanding the population that benefit from this exciting class of agents – high level benefit based on high level data, which we can use to change practice and improve outcomes worldwide.