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Justin F. Gainor, MD, highlights the evolving paradigm for the use of immunotherapy in the treatment of patients with unresectable locally advanced non–small cell lung cancer.
Justin F. Gainor, MD
The PACIFIC-2 study (NCT03519971) is examining the use and placement of immunotherapy in the treatment of patients with unresectable locally advanced lung cancer, specifically whether it would be most appropriately delivered after chemoradiation or concurrently, explained Justin F. Gainor, MD.
The initial PACIFIC trial was the landmark study that enrolled patients with locally advanced disease following completion of chemoradiation. Patients were randomized 2:1 to receive either durvalumab (Imfinzi) or placebo. Durvalumab was given once every 2 weeks and led to a 2-year overall survival (OS) rate of 66.3% for patients given durvalumab versus 55.6% for those given placebo.1
In the phase III PACIFIC-2 study, investigators are comparing concurrent delivery of durvalumab plus chemoradiation followed by consolidation durvalumab with placebo/chemoradiation followed by placebo consolidation in patients with locally advanced, unresectable, stage III non—small cell lung cancer (NSCLC).
“We've seen in the chemotherapy space that chemotherapy given concurrently with radiation is better than a sequential approach,” said Gainor, director of Targeted Immunotherapy, Massachusetts General Hospital, and assistant professor of medicine, Harvard Medical School. “We'll have to see if this plays out with immunotherapy. There are arguments on both sides. We know that radiation can have profound effects on the immune system, but those effects may also be negative if given at the same time as delivery of immunotherapy. At the same time, there can also be positive immunogenic effects of radiation.”
In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Gainor highlighted the evolving paradigm for the use of immunotherapy in the treatment of patients with unresectable locally advanced NSCLC.
OncLive: What is the state of locally advanced NSCLC treatment?
Gainor: The management of stage III lung cancer has evolved a great deal over the last 2 years, particularly with regard to patients who have locally advanced disease that is unresectable. The first thing to know about stage III disease is it's a very heterogenous disease. Patients can present with various tumor, node, and metastasis stages that all arrive at stage III disease. The first breakdown is whether a patient is a resection candidate or if are they unresectable.
We've known for some time now that the standard of care for patients with unresectable locally advanced disease is definitive chemoradiation delivered concurrently. What's changed, however, has been the introduction of consolidation immunotherapy. This is based upon the PACIFIC study.
Moving forward, one of the questions is, “How can we improve upon that even more?” In the future, one of the approaches is testing the delivery of immunotherapy given concurrently with chemoradiation. There are a number of ongoing studies specifically exploring that point, including the PACIFIC-2 study.
Since PACIFIC, what have additional studies found in terms of the efficacy of durvalumab?
When looking at the PACIFIC data, it's also important to address the number of key subgroups in that paper. One of the key subgroups was based upon PD-L1 expression analysis. It does look like the higher PD-L1 expression subgroup, which in PACIFIC was defined as ≥25%, tended to have better outcomes with respect to progression-free survival (PFS) and OS. In patients who had lower PD-L1 expression, there was still an improvement in PFS, but not to the same degree. It provides some additional context for the findings, but right now in the United States, the standard of care is to get durvalumab regardless of PD-L1 expression.
In terms of other key subsets, one important subset that did not seem to drive the same degree of benefit were EGFR-mutant patients. We know from the stage IV setting that EGFR-mutant patients tend not to derive significant benefits from single-agent checkpoint inhibitors. It's been seen now in multiple randomized studies and retrospective analyses.
In a key exploratory analysis, the authors of the PACIFIC study did an analysis looking at time to initiation of durvalumab after chemoradiation. They broke it down into 14 days—patients who started durvalumab either before or after 14 days. Patients who started after 14 days had a range [of initiation] between 14 and 42 days. Patients who started durvalumab within 14 days had better outcomes compared with those who started after that 14-day time period.
I should emphasize there are a lot of caveats to that type of analysis. Patients who are able to get started on an additional cancer therapy sooner are likely to be healthier patients at baseline, able to tolerate chemoradiation better, and have lower volume of disease. There is a lot of confounding around that analysis. In my practice, if a patient is fit for starting within 14 days, that would be my preference, but I won't push a patient who has not fully recovered yet based on that analysis.
What is the PACIFIC-2 trial trying to validate?
PACIFIC-2 is trying to address the question of concurrent versus sequential delivery of immunotherapy in patients with locally advanced unresectable lung cancer. Patients are randomized to either chemoradiation plus durvalumab administered concurrently followed by consolidation durvalumab versus chemoradiation with placebo followed by placebo consolidation.
Ultimately, we have to see empiric clinical trial data. One limitation of PACIFIC-2, however, is that the control arm doesn't have consolidation with durvalumab, which is the current standard of care. Therefore, we're going to be left with pretty significant challenges across trial comparisons.
What are your thoughts on using immunotherapy in resectable disease?
Given the profound benefits of checkpoint inhibitors in the stage IV setting, it was natural to try and move these drugs earlier. The findings from the PACIFIC study validate that approach, and we can see profound improvements and outcomes by using checkpoint inhibitors in earlier stages of disease.
The next step would be to look at the role of checkpoint inhibitors in patients with surgically resectable disease. Right now, we've seen 3 studies in this regard with respect to single-agent checkpoint inhibitors.
The first study was published in the New England Journal of Medicine. This looked at giving 2 cycles of neoadjuvant nivolumab (Opdivo) for patients from stage I to stage III disease. That study is proof of concept and showed that the major pathologic response rate was 45%. Major pathologic response is an endpoint that we haven't used commonly in thoracic oncology. One of the reasons this was chosen as an endpoint is that pathological complete responses (pCRs) are really uncommon in lung cancer—at about 4% to 5%. Major pathologic response rate may then be a better endpoint; this hasn't been a validated endpoint for regulatory approvals yet. It's helpful in the sense that it's something we can get early, and it may eventually be a platform for drug development and combination therapies in the neoadjuvant space.
We have seen several other studies looking at neoadjuvant checkpoint blockade. The first was the Lung Cancer Mutation Consortium study, which looked at neoadjuvant and adjuvant atezolizumab (Tecentriq). Some of the key findings were a subset of patients actually had disease progression before going to surgery; several others had disease progression or unresectable at the time of surgery. In total, [the majority of] patients were able to undergo surgical resection. Those tended to be patients with stage I/II disease; they all ultimately had resection.
Finally, we saw one other study of single-agent nivolumab versus nivolumab plus ipilimumab (Yervoy) as induction therapy. This was a study out of The University of Texas MD Anderson Cancer Center. Likewise, it showed that the combination of nivolumab and ipilimumab resulted in a slightly higher major pathologic response rate.
What may be a better path forward based on those 3 studies is the combination of chemotherapy and immunotherapy. In the metastatic setting, we know that produces much higher response rates. In the potentially curative setting, it's going to be important to produce the highest response rates possible in order to downstage patients and ensure that they all eventually have resection. In a series of 2 relatively small studies, we are seeing much higher pathologic response rates with chemotherapy/immunotherapy combinations in the range of 60% to 80%. Moving forward, there are multiple prospective, randomized studies looking at these combinations.
What is an exciting area of ongoing research in the lung cancer research field?
The neoadjuvant space is also an important area for another platform to conduct translational research. It's not just that we can ensure patients are getting therapy before surgery. It can be a robust platform for looking at biomarkers of response because you're giving a pretreatment biopsy; at the end you're getting a resection where you can actually do much more with the tissue. That's an area where we haven't seen a lot of data from translational work, but it is something that I look forward to seeing in the next couple of years.
What is your advice for those who are treating patients with stage III lung cancer?
My greatest piece of advice is that it requires a multidisciplinary approached care. Stage III disease is so heterogenous. It requires multimodality therapy and it requires collaboration among medical oncologists, pulmonologists, radiation oncologists, and surgeons. In our center at Massachusetts General Hospital, these patients are seen together in a multidisciplinary clinic. Commonly, I'm seeing a patient with my colleagues all together in the same room. It is a complicated disease entity and these patients derive a great deal of benefit from that multidisciplinary care.