CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: November 17, 2023
Expiration: November 16, 2024
A Role for IO in Treatment of Early-Stage NSCLC
Matthew Gubens, MD, MS:
Surgery remains a mainstay of the SoC for patients with resectable early-stage NSCLC, and there have been many recent advances in the early-stage setting involving both neoadjuvant and adjuvant IO, as well as pairing them together, sometimes referred to as perioperative therapy.
The first FDA approval of an ICI for early-stage NSCLC was for the PD-L1 inhibitor atezolizumab as adjuvant therapy following resection and adjuvant platinum-based CT for adult patients with stage II-IIIA NSCLC whose tumors have PD-L1 expression on ≥1% of tumor cells.68 This approval was based on the positive disease-free survival (DFS) benefit observed with atezolizumab in the phase III IMpower010 trial compared with best supportive care.69
More recently, adjuvant pembrolizumab following resection and adjuvant platinum-based CT was approved by the FDA for adult patients with stage IB-IIIA NSCLC regardless of PD-L1 expression.70 The approval was based on positive DFS outcomes for pembrolizumab compared with placebo in the phase III PEARLS/KEYNOTE-091 study.71
In the neoadjuvant setting, the PD-1 inhibitor nivolumab is approved in combination with platinum-doublet CT for the treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC.72 This approval was based on the positive pathologic complete response (pCR) and event-free survival (EFS) results with nivolumab plus platinum-based CT vs platinum-based CT alone in the phase III CheckMate 816 trial.73
Lastly, we just received an approval from the FDA in October 2023 for perioperative pembrolizumab, specifically as neoadjuvant treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing
CT and then continued as a single agent as adjuvant treatment after surgery.70 This approval was based on the EFS and OS benefit seen in the phase III KEYNOTE-671 trial, with OS recently reported at ESMO 2023, a first in this class of phase III trials.90
We will discuss data reported at WCLC 2023 from the phase III trial AEGEAN trial evaluating perioperative durvalumab next.
AEGEAN Surgery-Related Outcomes: Neoadjuvant Durvalumab + CT Followed by Adjuvant Durvalumab in Resectable NSCLC
Matthew Gubens, MD, MS:
Surgery remains a mainstay of the SoC for patients with resectable early-stage NSCLC, and there have been many recent advances in the early-stage setting involving both neoadjuvant and adjuvant IO, as well as pairing them together, sometimes referred to as perioperative therapy.
The first FDA approval of an ICI for early-stage NSCLC was for the PD-L1 inhibitor atezolizumab as adjuvant therapy following resection and adjuvant platinum-based CT for adult patients with stage II-IIIA NSCLC whose tumors have PD-L1 expression on ≥1% of tumor cells.68 This approval was based on the positive disease-free survival (DFS) benefit observed with atezolizumab in the phase III IMpower010 trial compared with best supportive care.69
More recently, adjuvant pembrolizumab following resection and adjuvant platinum-based CT was approved by the FDA for adult patients with stage IB-IIIA NSCLC regardless of PD-L1 expression.70 The approval was based on positive DFS outcomes for pembrolizumab compared with placebo in the phase III PEARLS/KEYNOTE-091 study.71
In the neoadjuvant setting, the PD-1 inhibitor nivolumab is approved in combination with platinum-doublet CT for the treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC.72 This approval was based on the positive pathologic complete response (pCR) and event-free survival (EFS) results with nivolumab plus platinum-based CT vs platinum-based CT alone in the phase III CheckMate 816 trial.73
Lastly, we just received an approval from the FDA in October 2023 for perioperative pembrolizumab, specifically as neoadjuvant treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing
CT and then continued as a single agent as adjuvant treatment after surgery.70 This approval was based on the EFS and OS benefit seen in the phase III KEYNOTE-671 trial, with OS recently reported at ESMO 2023, a first in this class of phase III trials.90
We will discuss data reported at WCLC 2023 from the phase III trial AEGEAN trial evaluating perioperative durvalumab next.
AEGEAN Surgery-Related Outcomes: Baseline Characteristics
Matthew Gubens, MD, MS:
Although AEGEAN enrolled patients with any PD-L1 expression level, confirmed PD-L1 status was a requirement for this study. As expected, approximately one third of patients on each arm had PD-L1 TPS <1%, 1% to 49%, and ≥50%. Tumor histology in each cohort was divided evenly between squamous and nonsquamous.
AEGEAN Surgery-Related Outcomes: Neoadjuvant Treatment and Surgery Summary in mITT Population
Matthew Gubens, MD, MS:
Initially, there was concern that surgery would take significantly longer following neoadjuvant IO considering the potential for fibrosis associated with receipt of this therapy. However, as was the case with many other trials, including CheckMate 816,76 there does not seem to be a significant difference in terms of duration of surgery with neoadjuvant nivolumab compared with placebo (3.5 hours vs 3.3 hours).75 There also was some worry about delays to surgery or delays to adjuvant therapy following surgery with adjuvant durvalumab, but again, this study did not show significant differences in either.
AEGEAN Surgery-Related Outcomes: Surgical Delay Summary in mITT Population
Matthew Gubens, MD, MS:
Looking in more detail at surgical delays following treatment with neoadjuvant nivolumab vs placebo, there did not seem to be any significant differences in either delay duration or reason for delay between the 2 arms. Delays are very important to evaluate because we do not want to keep people from curative therapy because of either IO toxicities or progressive disease in the meantime.
AEGEAN Surgery-Related Outcomes: Surgical Approach and Type in mITT Population
Matthew Gubens, MD, MS:
In addition to concerns around surgical delays and duration, there has been concern that surgeries may be more complicated and/or invasive following neoadjuvant IO (eg, video-assisted thoracic surgery becomes open thoracotomy or lobectomy becomes pneumonectomy). The results of AEGEAN shown here indicate that this was not the case. If anything, there seems to be a very mild trend toward more minimally invasive surgeries with
AEGEAN Surgery-Related Outcomes: Resection Status in mITT Population
Matthew Gubens, MD, MS:
Equally important is whether patients received a long-term benefit. The goal of surgery is to get to an R0 resection, and it does not appear that neoadjuvant IO compromised the rate of R0 resection compared with neoadjuvant placebo. Again, the durvalumab arm appeared numerically slightly better in this regard compared with the placebo arm.
AEGEAN Surgery-Related Outcomes: Safety
Matthew Gubens, MD, MS:
Finally, the rate of surgery-related AEs in the postsurgery period was very similar between the 2 arms (40.2% vs 39.2%), suggesting no significant adverse safety signal for adding IO prior to surgery.
AEGEAN: Clinical Implications
Matthew Gubens, MD, MS:
Dr Yu, what are your thoughts on these surgical data from AEGEAN?
Helena Yu, MD:
These data corroborate prior presented data (eg, for CheckMate 816) that neoadjuvant IO plus CT, an approach already firmly implanted in the SoC for early-stage disease, is safe and does not seem to lead to inferior surgical outcomes. It adds adjuvant IO after resection, similar to KEYNOTE-671 mentioned above, but neither of these perioperative IO trials answers the question of what value the extra treatment adds for patients. As such, I look forward to the next iteration of studies to determine whether characteristics of the surgical resection sample or new plasma-based assays can help inform which patients do or do not need adjuvant therapy after neoadjuvant IO plus CT and surgery.
Matthew Gubens, MD, MS:
Whether a perioperative IO approach is superior to neoadjuvant IO alone is the million-dollar question in early-stage resectable NSCLC.
SABR: Phase II Study of SABR ± Nivolumab for Untreated Early-Stage or Isolated Lung Parenchymal Recurrent Node-Negative NSCLC
Matthew Gubens, MD, MS:
The next trial we will discuss looks at IO in patients with even earlier-stage NSCLC: those who are candidates for stereotactic ablative radiotherapy (SABR), which was shown to be noninferior to surgery in patients with operable stage IA NSCLC in the prospective revised STARS trial77 and is the SoC for inoperable early-stage disease.31
We know that consolidation durvalumab significantly improves survival in patients with unresectable stage III NSCLC after chemoradiotherapy based on the phase III PACIFIC trial and has become the SoC in this setting.55,78 However, the value of IO following or concurrent to radiation therapy in earlier disease stages is not clear.
The randomized, open-label, single-institution (carried out by MD Anderson at 3 of their hospitals) phase II I-SABR trial compared SABR with or without nivolumab in 156 patients with untreated biopsy-confirmed stage IA/IB/IIA/IIB N0M0 NSCLC or isolated lung parenchymal–recurrent node-negative NSCLC.79,80 Patients were randomized 1:1 to receive SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) with or without 4 monthly cycles of nivolumab. Prior IO was not allowed, and the study was stratified by performance status, tumor size, histology, and lung cancer history. The primary endpoint was 4-year EFS, with secondary endpoints including OS and toxicity and an exploratory analysis of predictive biological or radiomic markers.
Because nivolumab or other IO agents are not currently part of our early-stage SoC absent surgery, this is an interesting study looking at the patients who are curatively treated with SABR.
I-SABR: Patient Disposition
Matthew Gubens, MD, MS:
Of the patients who were screened, 85% were randomized as part of the intention-to-treat (ITT) population. The vast majority received the shorter course of 50 Gy in 4 fractions, and 83% of the SABR plus nivolumab arm received at least 2 of 4 planned cycles of IO. Approximately one half of the patients received a brain MRI, which is bit lower than I would expect for a patient population in this setting.
I-SABR: Baseline Characteristics
Matthew Gubens, MD, MS:
In the treated population, the median age was 72 years, and most were current or previous smokers, with mostly nonsquamous disease. The distribution of the size of tumors is shown in the table, but again, these are all patients with very early-stage, node-negative disease whom we would treat with either surgery or stereotactic radiosurgery.
I-SABR: 4-Year EFS (Primary Endpoint)
Matthew Gubens, MD, MS:
There was a clear EFS benefit for the patients who received SABR plus nivolumab vs SABR alone. An EFS event was defined as local or regional recurrence, distant metastasis, secondary lung malignancy, or death. This was true in both the per-protocol (4-year EFS: 77% vs 53%; HR: 0.38; 95% CI: 0.19-0.75; log-rank P = .004) and ITT (HR: 0.42; 95% CI: 0.22-0.80; log-rank P = .006) populations.
I-SABR: 4-Year EFS by Subgroups
Matthew Gubens, MD, MS:
The EFS benefit with SABR plus nivolumab was seen among all relevant subgroups. However, there were several subgroups whose small size prevented HR estimates (including PD-L1 TPS ≥1%, squamous histology, never smokers, and performance status of 2).
I-SABR: Safety
Matthew Gubens, MD, MS:
Safety signals were as expected with an ICI, especially considering the short course (only 4 cycles) given after radiation.
I-SABR: Pattern of Failure
Matthew Gubens, MD, MS:
In terms of pattern of failure, which is always important to evaluate in radiation studies, the local failure rate was lower with SABR plus nivolumab vs SABR alone. However, these numbers are fairly small, and it will be important as these data mature to see where the pattern of failure finally occurs. But on the whole, this was a positive study.
I-SABR: Clinical Implications
Matthew Gubens, MD, MS:
Dr Yu, what did you think about these data?
Helena Yu, MD:
Although unsurprising, it was very encouraging to see a convincing benefit of adding nivolumab to radiation therapy in very early-stage disease. These data fit well with what we already know about the benefit of IO in resectable early-stage disease, as described above, and concurrent to chemoradiation for more locally advanced disease. We are getting to the point where all patients with early-stage NSCLC without driver mutations likely will receive some amount of IO.
It will be important to validate these results in a broader patient and practitioner population, and several phase III trials evaluating IO plus stereotactic body radiotherapy for stage I or II NSCLC are accruing (eg, KEYNOTE-867 [NCT03924869], PACIFIC-4 [NCT03833154], and SWOG S1914 [NCT04214262]).
Matthew Gubens, MD, MS:
I agree. Showing that there might be benefit with IO even for those really small tumors is important—it is encouraging to see that we potentially can go for an improved cure rate even in very early-stage disease.
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