After the success of the original PACIFIC trial, which demonstrated sustained overall survival (OS) and durable progression-free survival (PFS) benefits with immunotherapy (IO) after chemoradiotherapy for patients with stage III non-small cell lung cancer (NSCLC), there was some surprise earlier this year when the primary results from PACIFIC-2 were not positive. PACIFIC-2 was the first phase III study designed to assess the efficacy of concurrent IO plus chemoradiation followed by consolidation IO in unresectable stage III NSCLC.
ILCN recently spoke with radiation oncologist and PACIFIC-2 principal investigator Jeffrey D. Bradley, MD, to hear his insights and thoughts on why the results were not as expected. Dr. Bradley is Vice Chair of Proton Therapy & Technology Development at Penn Medicine, Philadelphia.
ILCN: Why do you think PACIFIC-2 was negative despite the positive results seen in the original PACIFIC trial?
Dr. Bradley: Why was it negative? This was the first of several trials that are testing concurrent IO with chemoradiation in locally advanced non-small cell lung cancer. Before we knew the results, people had already criticized the design because the control arm was not the PACIFIC regimen.
The reason the control arm was not PACIFIC is that in several countries, that regimen was not approved until the overall survival results were released. So, in the countries where this ran, which included Asia, Eastern Europe and South and Central America, those patients didn’t have access to durvalumab because their regulatory bodies had not approved its use.
We thought adding IO concurrently must help, but it didn’t. We didn’t see any uplift of the curve in the first 6 months. After that, it looked like there was a PACIFIC effect with the patients having IO after they completed chemoradiation. However, we saw several patients discontinued therapy on the investigational arm. When patients are on trial and you start to have side effects, often the easiest thing to do is drop the investigational drug, in this case the concurrent IO.
A lot of these patients had bulky central tumors; more than half the patients had T4 tumors. And these are the patients we know have toxicity, including high rates of esophagitis. This higher percentage of T4 tumors and the large tumor volumes on this trial suggest that this appears to be a different population compared to PACIFIC.
My personal impression is that concurrent IO with chemoradiation therapy is not beneficial in lung cancer. We recently saw similar results from CheckMate-73L, which evaluated nivolumab in combination with concurrent chemoradiotherapy, followed by nivolumab plus ipilimumab or nivolumab monotherapy.
Delivery of daily doses of 2 Gy can damage lymphocytes, which are very sensitive to radiation therapy. With bulky central disease, you end up irradiating the blood volume daily and killing off lymphocytes, which means that you’re negating the effects of the immunotherapy. So, it may not be the specifics of the patient population or central tumors, but instead, it may be irradiation to structures with large blood volumes during the delivery of immunotherapy.
I can’t prove that based on the data from PACIFIC-2, however, I think with all the trials together, we will get a clearer picture about whether that is the problem or not.
ILCN: Would we fare better if we tested IO alone in combination with radiotherapy rather than concurrent chemoradiotherapy?
Dr. Bradley: I think that’s a wonderful question to ask. We are asking it in a trial called NRG-LU004. We are enrolling patients with a PDL1 status of greater than 50% and giving 60 Gy of radiation in 2 Gy fractions with immunotherapy without chemo in the high PDL1 population.
ILCN: Part two of that question was would you restrict it to patients with PDL1 expression above 50%.
Dr. Bradley: Yes. But I think you would only do that in a trial. That question is being asked in different clinical trial settings. If one is a patient in this situation, they might ask, “do I really need chemotherapy?” This is an appropriate question, and it needs an answer!
ILCN: That leads us to our next question, which is about the toxicity of the concurrent regimen. Did that influence the outcome? Could toxicity have contributed to the negative outcome? Could eliminating the chemotherapy reduce the toxicity?
Dr. Bradley: There were several patients that discontinued treatment. If you looked at the toxicity scores, yes, there was more toxicity in the IO group. They were not severe toxicities necessarily, though they were enough to have them discontinue the IO. There is more toxicity with chemotherapy, specifically esophagitis and pneumonitis. If you were to design a trial today, you might ask whether you need chemo, specifically in the high PDL1 group.
Maybe sequencing is an option. People are starting to ask, should we give chemo-IO followed by chemoradiation? Should we sequence it in that fashion? These are sort of crystal ball questions. Between PACIFIC 2 and CheckMate-73L, we now have two negative trials testing concurrent chemoradiation. The ECOG/NCTN E5181 trial was designed similarly to PACIFIC 2, although the control arm included consolidative durvalumab. As these results are still pending, we don’t know what that’s going to show. However, I suspect administering chemo and IO upfront as a neoadjuvant strategy might work.
ILCN: Is there any data on subsequent therapies? Were there any imbalances in that regard? Especially considering that much of the population was in the second and third world?
Dr. Bradley: About half the patients did not receive subsequent therapy. It’s hard to imagine in the United States, but in many places if chemoradiation fails, patients don’t get a second-line strategy. It’s hard to imagine that. You wonder about the health status of these folks if they were not eligible for a second-line treatment. Maybe they were a sicker patient population than the PACIFIC population.
And most people would agree that 50% is a high number. I can’t remember the last time I had a treatment fail and the patient didn’t get some kind of second- or third-line treatment. So that’s a little disturbing. It may speak to the health status of the patients that participated in the study. Or to what treatments were available.
ILCN: Is there anything else you think is important to put this into context?
Dr. Bradley: A lot of people have questioned the radiation quality in PACIFIC and now in PACIFIC-2.
We do not have that data from PACIFIC, but in PACIFIC-2, as a radiation oncologist and as a PI, I wanted to make sure we had that data. For PACIFIC-2, we reviewed the radiation plans within the first week of the patient starting and provided suggestions for improvements. Several investigators updated their plans to fit protocol constraints. I found it very encouraging that not only could we get back to investigators within a week, but also that they made the changes that we suggested could improve the plan. So I found that successful.
I don’t think you could point a finger and say radiation quality was an issue.
From the Editor
By Associate Editor Suresh Senan, MRCP, FRCR, PhD
The results of the PACIFIC-2 trial were a surprise to some, and the insights provided by Dr. Bradley are welcome. These results were followed by a press release on the CheckMate 73L study, where concurrent thoracic chemo-radiotherapy with nivolumab followed by ipilimumab plus nivolumab failed to meet its primary endpoint of improving PFS compared to a PACIFIC-like arm of only adjuvant durvalumab. Earlier concerns about combining immunotherapy with loco-regional chemoradiation had emerged after two phase III trials in locally advanced squamous cell carcinoma of the head and neck failed to show an event-free survival benefit compared to standard of care chemo-radiation.1,2
Exploratory studies in head-and-neck tumors, and in the tumor-draining lymph nodes of murine models, revealed that T cell priming occurs within tumor-draining lymphatics. The upregulation of conventional type I dendritic cells and type I interferon signaling are required for response to immune checkpoint inhibitors, and this response is lost with lymph node ablation.3 Lymphoid tissues may be highly radiosensitive, and low radiation doses may impair any synergy between radiation the immunotherapy.
In addition, the tumor microenvironment may also play a role as was shown by the improved event-free survival observed in another head-and-neck tumor, namely locoregionally advanced nasopharyngeal carcinoma in the phase III CONTINUUM trial. This study investigated the addition of sintilimab (anti-PD1) to standard gemcitabine-cisplatin induction chemotherapy plus concurrent chemoradiotherapy.4 Unlike squamous cell carcinoma, nasopharyngeal carcinoma is characterized by an elevated expression of PD-L1 in tumor cells and tumor-associated immune cells.
If the negative findings of the PACIFIC-2 and CheckMate 73L studies are confirmed by readouts from other trials, including ECOG/NCTN E5181 and KEYLYNK-012, strategies evaluating lymphatic-preserving sequential treatments should be explored further in patients with inoperable NSCLC.
References
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- 4. Liu X, Zhang Y, Yang KY, Zhang N, Jin F, Zou GR, Zhu XD, Xie FY, Liang XY, Li WF, He ZY, Chen NY, Hu WH, Wu HJ, Shi M, Zhou GQ, Mao YP, Guo R, Sun R, Huang J, Liang SQ, Wu WL, Su Z, Li L, Ai P, He YX, Zang J, Chen L, Lin L, Huang SH, Xu C, Lv JW, Li YQ, Hong SB, Jie YS, Li H, Huang SW, Liang YL, Wang YQ, Peng YL, Zhu JH, Zang SB, Liu SR, Lin QG, Li HJ, Tian L, Liu LZ, Zhao HY, Lin AH, Li JB, Liu N, Tang LL, Chen YP, Sun Y, Ma J. Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicenter, open-label, parallel-group, randomized, controlled, phase 3 trial. Lancet. 2024 Jun 22;403(10445):2720-2731. doi: 10.1016/S0140-6736(24)00594-4. Epub 2024 May 30. PMID: 38824941.