By Mirjana Rajer, MD, PhD
Posted: April 1, 2019

For many years, the treatment of patients with stage III lung cancer has been a topic of intense debate among surgeons, radiation oncologists, and medical oncologists. Each discipline has eagerly expected new trials and results to make these discussions clearer and more optimistic. One of the most important trials in this arena was the PACIFIC trial, which was published in 2017.¹ Prior to the PACIFIC trial, there were no breakthroughs for many years; we treated patients with stage III inoperable NSCLC in the same way. Patients received a high dose of radiation (60 Gy-66 Gy) and usually one or two cycles of concurrent chemotherapy, with or without induction chemotherapy. Such treatment was called radical, even if we managed to cure only up to 20% of patients. We can no longer be satisfied with these results.

In the PACIFIC trial, patients were randomly assigned to two groups: one group received the so-called “standard treatment” (chemotherapy, irradiation, and placebo afterwards), while the other group’s standard treatment was followed by immunotherapy with durvalumab for up to 1 year. The results of the trial were excellent. The median progression-free survival (PFS) from the completion of standard treatment was 16.8 months in the immunotherapy group, compared to 5.6 months in patients receiving placebo. A similar PFS was reported in a recently published article with updated results, with a PFS of 17.2 versus 5.6 months, respectively. PFS is an important endpoint, but patients are more eager to know if they will live longer with the new treatment, and PACIFIC recently gave us an answer to this question: overall survival (OS) in the durvalumab group was superior (median not reached vs. 28.7 months in the placebo group, HR 0.68).^1,2 These results, together with the lack of major toxicity differences between the two groups, have caused a flood of optimism for oncologists and their patients.

Implications for Standard of Care in Europe
Is there something keeping us from considering this treatment strategy the absolute new standard of treatment? Of course. As with every trial, we are looking at PACIFIC with critical judgment. For example, one reservation is the possibility of long-term toxicity, with pneumonitis and lung fibrosis our main concerns. In the PACIFIC trial, the incidence of pneumonitis was not significantly higher in people treated with immunotherapy, but we will have to wait and see whether this holds true in the long run.

Unexpectedly, skepticism has emerged from another perspective. Post-hoc analysis showed that baseline PD-L1 status might play a role in outcome. Data showed a benefit in PFS but not OS in patients with less than 1% PD-L1 expression. This observation has “informed” the drug approval process. While the U.S. Food and Drug Administration (FDA) approved durvalumab for all patients, the European Medicines Agency (EMA) restricted its approval to patients with PD-L1 expression of greater than 1%. Of course, I cannot unilaterally oppose the decisions of any health care authorities, but as a treating oncologist in Europe, I must express at least a bit of doubt about this process. If we look at the data, we soon realize that a lot is missing and that the obvious answer may not be the right answer. In the PACIFIC trial, PD-L1 testing was not mandatory; 37% of patients were not tested, analysis according to PD-L1 expression was not pre-planned, and a benefit was observed in PFS in patients with less than 1% expression. Therefore, to get the definitive answer, we would need another trial that would prospectively assess results based on PD-L1 expression. Personally, I think that will never happen.

Another issue that deserves consideration is the PD-L1 status per se. Evidence suggests that PD-L1 can be induced with radiotherapy. The problem is how to monitor it because repeating a biopsy after chemoradiotherapy is impractical and potentially even dangerous for patients. One potential option to address this issue came from a trial conducted by Adams et al. They monitored PD-L1 in blood samples and showed that in 31% of patients whose tumors did not have PD-L1 expression before radiotherapy, PD-L1 was detected in their blood samples after the completion of radiotherapy, suggesting that radiotherapy could induce the expression of PD-L1.³

Currently, durvalumab is available to many European patients with PD-L1 expression of 1% or greater. In some countries the drug was made available immediately, after EMA approval (e.g., Germany), whereas in other countries, patients can get it only through so-called “early-access” programs. The exception is Switzerland, where patients get access to new drugs immediately upon European Medicines Agency approval. How many patients in other European countries will actually have access to the drug through current reimbursement paradigms is still difficult to estimate. In most European countries, negotiations with insurance companies are conducted either on a national or regional level or even with individual insurance companies; consequently, it can take many months or years, if ever, to get such agents reimbursed. This is a particularly important issue for lower-income, East European countries.

Limiting approval to patients with PD-L1 expression greater than 1% can have a positive effect regarding immunotherapy in stage III disease. It could facilitate access because there will be less financial toxicity, which often prevents payers from authorizing reimbursement. On the other hand, this is the first treatment in decades that has actually shown a benefit in stage III NSCLC. The results of the PACIFIC trial are clear and convincing; however, exclusion based on PD-L1 expression of greater than 1% is not as scientifically sound.

In summary, most patients with stage III disease will receive immunotherapy, either as primary treatment or after progression, where immunotherapy is not limited by PD-L1 status. Our biggest concern is that under current standards, some patients who could be cured by adding immunotherapy will not be able to receive this treatment. ✦

About the Author: Asst. Prof. Rajer is radiation oncologist and resident in medical oncology at the University Clinic Golnik, Slovenia.

References:
1. Antonia SJ, Villegas A, Daniel D, et.al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919-1929.

2. Antonia SJ, Villegas A, Daniel D, et.al. Overall Survival with Durvalumab after Chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342-2350.

3. Adams DL, Adams DK, He J, et.al. Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy. Clin Cancer Res. 2017;23:5948-5958.

Patient Advocate Comment

“If a treatment is significantly beneficial for a group of patients, they should have access to this treatment; approvals should follow proven benefit. With the developments in cancer care, the current healthcare systems in Europe must adjust. On national and international levels, all stakeholders will have to work together, with goals based on provision of best-possible patient care, not based on research cost or financial profit.”

–Merel Hennick, ROS1 patient advocate in the Netherlands