Findings from the pivotal phase 3 PACIFIC and ADAURA trials have not only led to paradigm shifts and served as the basis for ongoing research for patients with unresectable and resectable non–small cell lung cancer, respectively, but have emphasized the importance of distinguishing treatment options based on the presence or absence of an oncogenic driver.
Findings from the pivotal phase 3 PACIFIC and ADAURA trials have not only led to paradigm shifts and served as the basis for ongoing research for patients with unresectable and resectable non–small cell lung cancer (NSCLC), respectively, but have emphasized the importance of distinguishing treatment options based on the presence or absence of an oncogenic driver, explained Stephen Liu, MD.
“If someone has a driver mutation, I really wouldn’t expect that same degree of benefit with adjuvant immunotherapy and using adjuvant immunotherapy in that setting would really preclude the safe use of a TKI, should relapse occur during therapy. For patients with a driver mutation, targeted therapy is appropriate. For those without, really the immunotherapy studies will be more relevant,” said Liu.
In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, Liu, an associate professor of medicine, director of thoracic oncology, and director of developmental therapeutics at Georgetown Lombardi Comprehensive Cancer Center, discussed the evolution of treatment for patients with early-stage NSCLC.
Liu: Locally advancedstage III NSCLC is an area in lung cancer where outcomes have really been suboptimal. With chemoradiation alone, our goal is cure, but it is not really our expectation. The relapse rates remain unacceptably high. Very few advances [had been made] over the past few decades, but [that] finally changed with the implementation of immunotherapy in this space [because of] the pivotal PACIFIC trial.
PACIFIC was a randomized phase 3 placebo-controlled trial that showed consolidation immunotherapy with the PD-L1 inhibitor durvalumab [Imfinzi] significantly improved progression-free survival [(PFS) compared with placebo], which also translated to an improvement in overall survival [OS].
Updated results presented at the ESMO Virtual Congress 2020 showed that durvalumab improved the median survival from 29 months to 48 months and increased the 4-year survival rate from 36% to 50%. This [approach] is now our standard of care, and durvalumab is approved in this setting after definitive chemoradiation with platinum-based chemotherapy.
Building upon PACIFIC, data from the KEYNOTE-799 trial was presented in early 2021 at the 2020 World Conference on Lung Cancer [WCLC]. The investigators explored a slightly different approach: a single cycle of chemoimmunotherapy followed by concurrent pembrolizumab [Keytruda] with chemoradiation, and then pembrolizumab consolidation. This [approach] showed promising landmark survival rates; in 1 of the arms, the 1-year survival rate was 88%. However, this is a modest sized, nonrandomized phase 2 trial and is not something that will change practice, although it is an interesting approach.
We’re looking forward to results hopefully this year from PACIFIC-2, which is going to randomize patients to concurrent durvalumab with chemoradiation, followed by durvalumab consolidation or chemoradiation alone. Importantly, [investigators are] not randomizing [patients] to the PACIFIC regimen but are randomizing patients to the historic standard based on when this study was launched. Now, that approach will probably lead to more pneumonitis, but because patients are enrolled at diagnosis, it’s going to be relevant to a larger patient pool, and that really is going to increase the impact [of the approach]. We’ll have to balance that potential toxicity with delivering that benefit to more patients and potentially increasing the efficacy [of the historical standard] and building on the synergy of radiation and checkpoint inhibition. When these studies do read out, it will be very difficult to interpret them. The time points are different, and the patient populations are different. But this is an important study to watch and, hopefully, another promising development in the field for unresectable stage III disease.
There is some synergy between the use of radiation and immunotherapy, but its impact on PD-L1 expression and the underlying immune microenvironment is still complex. We’re still unraveling that. I do think there’s the potential for more benefit [with that approach], but I think that will be accompanied by higher rates of pneumonitis, so we’ll have to offset those a bit. When we look at PACIFIC-2 vs PACIFIC, it’ll be difficult and challenging to compare PFS and OS numbers because you’re measuring it from a different point. You’re randomizing patients at a different area, and the population is different. To enroll in PACIFIC, patients had to complete chemoradiation and still have intact organ function, have good performance status, and have no progression.
Chemoradiation is a difficult treatment, and invariably, we lose some patients along the way. If some of those patients would derive long-term benefit from immunotherapy, it would be a shame to deprive them of that opportunity. Therefore, an earlier approach helps ensure that everyone gets the opportunity to get that immune-mediated antitumor advantage that we’re really hoping improves long-term survival. However, the cost at which that will come will be probably a higher pneumonitis rate. The degrees here will be important, and we’ll have to look at these data very carefully.
An area of controversy is the use of immunotherapy in locally advanced stage III NSCLC with an EGFR mutation. Patients with an EGFR mutation were included in PACIFIC, but if we look at the subset [analysis], patients with an EGFR mutation seem to derive less benefit [from durvalumab], with very wide confidence intervals, but crossing unity. [The analysis was based on] small numbers––only about 43 patients––but it’s consistent with what we’ve seen. EGFR mutation––positive lung cancer doesn’t seem to respond as well to immunotherapy. So, it is in line with what we understand about EGFR-mutant lung cancer and its biology.
The hesitation really is not just with the potential lack of efficacy in a small patient subset, but with the consequence at relapse. We know from the TATTON study that when we give durvalumab and osimertinib [Tagrisso] together, it is too toxic. We see very high rates of pneumonitis. We also know from retrospective work that the use of a TKI after immunotherapy in the context of an EGFR-mutant lung cancer is not safe. We see high rates of immune-related adverse effects, and while it can be done carefully, it’s something we like to avoid. If someone is receiving durvalumab for an EGFR-mutant lung cancer, and then suffers relapse, which is still quite common, the use of osimertinib, normally a very well-tolerated and very effective agent, becomes much more toxic, and so withholding durvalumab would allow safer treatment at the time of relapse. Of course, one wonders: Is that a self-fulfilling prophecy? If I withhold durvalumab, am I making relapse more common?
We’ll learn a little bit from the LAURA trial, which is a randomized phase III study enrolling patients with locally advanced unresectable EGFR-mutant lung cancer. [After patients] complete chemoradiation, they will be randomized to osimertinib vs placebo. We won’t answer all the questions there, and the duration of treatment in LAURA is until progression, not a fixed time point, which is another variable that may make the results a little challenging to interpret. However, this is an alternate strategy. In my practice, I do think a TKI is probably more appropriate than immunotherapy in this setting, but we’ll have to wait and see what these results show.
Although the PACIFIC regimen of chemoradiation followed by consolidation durvalumab is our unrefuted standard for unresectable stage III NSCLC, treatment for resectable stage III NSCLC is still evolving. The use of chemoradiation and durvalumab in that setting is also still reasonable and performed at many academic centers, but a lot of university settings, including Georgetown [Lombardi Comprehensive Cancer Center], favor the incorporation of surgery, provided a pneumonectomy is not necessary.
We don’t start with surgery. Our standard at Georgetown has been neoadjuvant chemotherapy alone followed by surgery, but there have been some interesting developments. We’ve had several neoadjuvant targeted therapy trials up and running, such as the Lung Cancer Mutation Consortium [LCMC]-4 trial. These are compelling, and the response rates are high. I think there’s potential for conversion of unresectable to resectable [disease with these approaches], but whether they translates to gains in survival, we won’t know for some time.
The more exciting area of development has been neoadjuvant immunotherapy. Nivolumab [Opdivo] alone or in combination with ipilimumab [Yervoy] has clear activity with encouraging major pathologic response [MPR] rates and pathologic complete response [pCR] rates. The largest data set we have in that space was [presented] at WCLC 2020 from the LCMC-3 study.
The LCMC-3 study is a single-arm, phase 2 study with over 150 patients who received only 2 doses of neoadjuvant atezolizumab [Tecentriq], which is a PD-L1 inhibitor. The MPR rate was 21%, the pCR rate was 7%, and we saw good tolerability, [indicating that just 2 doses of immunotherapy followed by surgery is a] very feasible approach. We’ll see what the survival numbers look like, but more impressive data were seen with neoadjuvant chemoimmunotherapy.
The single-arm phase 2 NADIM trial showed an MPR rate of 83% and really a staggering pCR rate of 63% in patients who went on to resection. We need a randomized study for reference, and we actually have one. CheckMate 816 is a randomized, phase 3 trial where patients with resectable NSCLC are randomized to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone. That study met its primary end point of increasing pCR with nivolumab and chemotherapy vs chemotherapy alone. What we’ll need to see is whether this translates to better survival. Is [pCR] a valid surrogate? Only time will tell.
We’ll typically proceed directly to surgery for stage III NSCLC. We really favor neoadjuvant approaches or maybe even chemoradiation, but there are cases despite proper mediastinal staging, where stage III disease is only identified after surgery. For a resected microscopic stage III NSCLC, our standard of care is platinum-based chemotherapy, which offers a modest but significant improvement in OS. Postoperative radiation therapy is no longer part of my standard treatment. This changed in 2020 when we saw the results of the randomized Lung ART study at ESMO 2020. Patients with resected N2 NSCLC were randomized to postoperative radiation therapy or observation after chemotherapy. Radiation did not improve disease-free survival [DFS] and did not improve the 3-year survival rates. Based on that study, postoperative radiation is only relevant in my practice for patients with positive margins or incomplete resections.
For patients with resected NSCLC that harbor an EGFR mutation, osimertinib is now an approved adjuvant therapy based on the ADAURA trial, where 3 years of osimertinib significantly improved DFS [vs placebo]. We have yet to see if that will translate to an OS benefit, but there may be value in this degree of DFS improvement in and of itself, with a hazard ratio of 0.17 in patients with resected stage II/III disease.
We will have other TKI studies, 1 focusing on ALK fusion–positive NSCLC, but we also have adjuvant immunotherapy approaches, and really, these 2 strategies don’t overlap.
Stage III NSCLC is very heterogeneous. Someone with the same TNM stage could have very different biology and very different outcomes. One person with a stage III lung cancer could walk away with 4 different recommendations from 4 different speakers, and all of them would be very reasonable and valid. Part of the reason there’s so much variation is there is so much heterogeneity within stage III NSCLC, based on location, based on the underlying biology, and now, even more so, based on underlying genomic drivers and the introduction of targeted therapy and immunotherapy as well. This is a disease unto itself. There are many different strategies. We’ll need a lot of careful analysis and a lot of planning before we go down routes for neoadjuvant strategies in stage III lung cancer.