PD-1/CTLA-4 Combos, Broader Patient Population Are Next Steps With Immunotherapy in Locally Advanced NSCLC

David Gerber, MD, highlights the impact of the PACIFIC trial and other next steps with immunotherapy in patients with stage III NSCLC.

On the heels of impressive long-term data from the PACIFIC trial, researchers are now intrigued to see if combination immunotherapy with concurrent chemoradiation, among other approaches, in patients with stage III locally advanced non–small cell lung cancer (NSCLC) could take survival outcomes to the next level, according to David Gerber, MD.

For example, the ongoing phase 3 CheckMate-73L trial (NCT04026412) is enrolling patients with treatment-naïve locally advanced NSCLC. In the open-label study, patients will be randomized to 1 of 3 arms: nivolumab (Opdivo) plus concurrent chemoradiation followed by nivolumab and ipilimumab (Yervoy), nivolumab plus chemoradiation followed by nivolumab, or chemoradiation followed by durvalumab (Imfinzi).

This type of research effort builds upon data from the international, phase 3 PACIFIC trial, in which patients with unresectable stage III NSCLC who did not progress after chemoradiation were enrolled and randomized to either durvalumab or placebo. In 4-year follow-up findings that were presented during the ESMO Virtual Congress 2020, results showed that the median overall survival (OS) in patients who received durvalumab was 47.5 months compared with 29.1 months for placebo (HR, 0.71; 95% CI, 0.57-0.88).

Initial results of the trial led to the February 2018 approval of durvalumab as a treatment for patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemoradiation.

“Both [progression-free survival and OS] end points look to be better to clinically meaningful extent,” said Gerber. “For this reason, this regimen really has become a standard of care for patients with locally advanced NSCLC.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Gerber, a professor of internal medicine, Hematology/Oncology Division, and co-director, Experimental Therapeutics Program, UT Southwestern Medical Center, further highlighted the impact of the PACIFIC trial and other next steps with immunotherapy in patients with stage III NSCLC.

OncLive®: What are the most exciting changes in treatment for patients with locally advanced or stage III NSCLC?

Gerber: When it comes to the treatment of [patients with] locally advanced or stage III NSCLC, one can argue that it's 1 of the most debated areas in all of lung cancer therapy. What has become clear is that a single treatment modality is probably never enough, and patients need at least 1 local treatment. In the United States, for some time, the most common treatment was chemoradiation.

Recent studies have looked [to change up] our traditional approach by increasing the dose of radiation, by adding more chemotherapy after radiation is finished, and/or by adding targeted therapies, such as oral kinase inhibitors or intravenous monoclonal antibodies, during or after chemoradiation. None of those have improved outcomes. In fact, a number of them were associated with worse outcomes when compared with traditional concurrent chemoradiation.

There has always been a real interest in combining [immunotherapy] with radiation. It's [thought] that radiation depends on aspects of the immune system for its own efficacy. Giving patients immunotherapy with radiation may make the radiation more effective and, in turn, radiation itself may improve the efficacy of immunotherapy by making the cancer release more of its antigens. Therefore, [it makes the cancer] more apparent or obvious to the immune system.

A number of clinical trials comprised vaccine-based treatments, primarily after the end of chemoradiation. While some looked promising, ultimately none of them really improved outcomes compared with chemoradiation alone. We have seen PD-L1 inhibitors, when administered after chemoradiation for up to 1 year, improve [disease control and overall survival in patients with] stage III locally advanced lung cancer.

A pleasant surprise [from the PACIFIC trial] was that the addition of immunotherapy after chemoradiation does not appear to substantially increase toxicity. We always have to be careful when we're giving an immune checkpoint inhibitor to our patients, because very diverse toxicities can happen fully throughout treatment. When you're giving chemotherapy and then radiation to the chest, followed by an immune checkpoint inhibitor, we're particularly concerned about pulmonary adverse effects from the [immunotherapy]. Thus far, it appears that rates of pneumonitis or inflammation of the lung appear more or less comparable with what we might expect from chemoradiation alone. Nevertheless, it's something that requires ongoing attention when we're treating our patients.

Could you expand on the long-term data from the PACIFIC trial?

The PACIFIC trial enrolled patients with stage III, locally advanced NSCLC that was not considered amenable to surgical resection at any point during treatment, who had already completed their chemoradiation and tolerated it relatively well, and did not appear to have the cancer progressing during or immediately after chemoradiation.

[The trial] had a 2:1 randomization, where two-thirds of patients received intravenous durvalumab, an anti–PD-L1 monoclonal antibody, for up to 12 months and one-third of patients received placebo. The [dosing] schedule was every 2 weeks. [As a side note,] durvalumab has been studied at an every-4-week schedule in trials in lung cancer and other malignancies. That's an important question to keep in mind with a regimen like this going forward to optimize patient convenience.

In this clinical trial, patients did not need a certain degree of PD-L1 expression in the tumor for enrollment eligibility. Importantly, when we look at the subset analysis of patients, [regardless of the level of PD-L1 expression], it appeared that all patient subsets benefited from the addition of [durvalumab].

Is this because it is a small subset analysis? Is it because PD-L1 expression doesn't actually matter in this setting? Or, does the administration of radiation somehow change tumor biology to make it more antigenic, regardless of the baseline PD-L1 expression? We don’t know for sure, and that's more information that we'll be getting subsequently.

Was a 1-year duration of immunotherapy administration chosen arbitrarily, or was there a rationale for its use?

This is a debated area. In the stage IV setting, the active question is: is 2 years [of therapy] sufficient or should it be longer? Some earlier clinical trials in the stage IV metastatic setting looked at 1 year versus longer treatment. The general sense, in stage IV disease, is that stopping at 1 year for patients who have disease control at that point may not be sufficient. It’s going to be a while before we really know the optimal duration.

When we look at stage III disease, there is an inflection point. When you think about the fact that most recurrences, or most cases of progression, tend to occur within 12 to 18 months after completion of chemoradiation, that might be a principal rationale for why in the PACIFIC trial, and [other similar trials in this lung cancer setting], have used a 1-year duration of immunotherapy.

What emerging approaches are you excited about in this setting?

There are some clinical trials looking at some other questions in stage III disease. For example, is there a role for giving an immune checkpoint inhibitor simultaneously or concurrently with thoracic radiation? Five years ago, we would have considered that an extraordinarily high-risk question to ask. However, once you've got the experience from a very large phase 3 trial like PACIFIC, giving immunotherapy immediately after thoracic radiation is completed seems fine. This is a question that is now being asked in some clinical trials.

Some [other] clinical trials in stage III disease are looking at whether other forms of checkpoint inhibitor therapy may improve outcomes even beyond [what was reported in PACIFIC], such as combining a PD-1 and CTLA-4 inhibitor together in this setting of concurrent chemoradiation. This obviously leaves some major questions.

At this point, we don't have a clear sense of how [an] immune checkpoint inhibitor would fit with chemoradiation and surgery for stage III disease. I don't know if a large clinical trial will ever be done answering that question because multimodality clinical trials in stage III lung cancer are very, very difficult to coordinate, evaluate, and conduct.

Another question is that, in a clinical trial like PACIFIC, patients with a history of autoimmune disease were excluded. That's a general approach to immunotherapy trials; however, it turns out that this is a substantial part of the population. [Ongoing and planned] clinical trials are going to ask the question: Can we carefully expand the pool of patients who are eligible to receive these therapies? We already know that, to some extent in standard clinical practice, clinicians are going a little bit beyond with what they consider low-risk autoimmune diseases [and can therefore] administered these treatments.

Was there anything else that you wanted to emphasize?

When it comes to stage III locally advanced lung cancer, it's important to remember that this is a substantial proportion of lung cancer cases. We see [stage III cases] a lot, and its treatment is really complex; it will always require more than 1 type of [modality]. It also is the most complicated to diagnose because you've clearly shown that it's not just 1 involved area in the lung; you carefully show [that there could] be disease outside of the chest.

Put all of that together [and] it's pretty complicated. Sometimes, it's frustrating for patients [because of] how long it takes to be diagnosed with stage III disease and then have a treatment plan. Planning thoracic radiation is really complicated. You need to make sure that you get enough radiation to the whole tumor, but you have to limit the amount of radiation to the normal lung, esophagus, spinal cord, and heart. Sometimes it's hard to meet all of those parameters.

Another thing to remember about stage III lung cancer [is] that once a patient is finished with their treatment [whether it is immunotherapy, chemoradiation, and/or surgery] it can be very difficult to judge where there are in terms of potential toxicity and [response to therapy]. Traditionally, only about 15% to 20% of patients treated with thoracic radiation get pneumonitis. Potentially 70% get post-radiation change on their scans, and that can be confused with disease progression or toxicity. In most cases, it's just a normal finding that will gradually resolve over [a few] months. That was a period of uncertainty in terms of what's going on with disease control at that time.

If a patient with stage III disease is later identified to have an EGFR mutation, will that impact their PACIFIC regimen, for example?

We have looked at the idea of giving targeted therapy to stage III disease, and thus far, it [has] not been a very positive experience. A study conducted by the Southwest Oncology Group, administered the EGFR inhibitor gefitinib (Iressa) after the completion of chemoradiation and then after 3 cycles of consolidation docetaxel. Patients got either gefitinib or placebo. Believe it or not, the OS was substantially worse in the group that received gefitinib. It didn't necessarily appear to be toxicity. Granted, that was a molecularly unselected population, so only a very small proportion presumably had EGFR mutations. That gave us a lot of pause about giving targeted therapy after chemoradiation.

Recently, there have been some clinical trials looking at giving targeted therapy before chemoradiation for stage III disease. They're very difficult to conduct and accrue to because a lot of these patients are already waiting to start curative chemoradiation when it's taken so long to finish all of their staging modalities. To try to get them to a clinical trial and enrolled in that treatment underway before radiation can be challenging.

At this point in time, we don't necessarily know that there are better treatments that [patients with stage III disease and harbor EGFR or ALK abnormalities] should be given. Certainly, in my own practice, I would not adopt the findings of ADAURA, which was 3 years of postoperative osimertinib (Tagrisso) given after concurrent chemoradiation. We saw that when we combine osimertinib, an anti–PD-L1 antibody, the rate of pulmonary toxicity was over 50%. Giving it right after thoracic radiation might cause similar problems but we just don't know [yet].


  1. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325