CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: October 25, 2022
Expiration: October 24, 2023
Heather Wakelee, MD:
One of the studies that was highlighted at WCLC 2022 was the phase III CALGB 140503 (Alliance) trial, which was highly anticipated in the surgical world to help determine whether less extensive surgery in patients with early-stage NSCLC can be considered.1 Instead of the standard full lobar resection, the investigators examined whether sublobar resection would be equivalent for patients who had small tumors. The hope was that we would be able to preserve more lung function with this approach.
Recently, the phase III JCOG0802/WJOG4607L trial from Japan showed significant OS benefit by doing segmentectomy vs lobectomy in patients who had small peripheral stage IA NSCLC with a tumor diameter ≤2 cm.2
In this trial so far, we are not seeing an OS benefit but there was also not a decrement in OS.1 There was also no appreciable difference in lung cancer–related events vs competing deaths when comparing lobar vs sublobar resection in this study.
They were able to show a statistically significant benefit for sublobar resection with a smaller decrease in both FEV1 and FVC from baseline vs with a lobectomy, meaning more pulmonary function was preserved with a sublobar resection.1
Heather Wakelee, MD:
The most important aspect of this second trial comparing lobectomy vs sublobar resection, done predominantly in North America, was that it confirmed that the DFS and OS were not inferior with a sublobar resection vs a lobectomy in patients with stage IA NSCLC with a tumor diameter ≤2 cm and without any nodal metastases and that sublobar resection has the potential for better preservation of lung function.
There was a lot of discussion about this trial after WCLC 2022, with many people saying that this trial helped establish a new standard of care, or at least an option to discuss sublobar resection with patients in this particular subgroup.
Wade T. Iams, MD, MSCI:
I would just note that surgeons at my institution are very excited about these data. Thinking about these data in the context of a tumor board, for a patient with a 2 cm or smaller primary tumor and no nodal involvement who is a borderline surgical candidate, these data show that sublobar resection may be an option for them. In the past, we were not certain whether their survival would be similar to doing a lobectomy, so these data help reinforce that this is a good option for these patients.
Wade T. Iams, MD, MSCI:
For our patients with early-stage NSCLC, not only is the type of resection important, but the risks and benefits for perioperative systemic therapy should also be considered. The randomized phase II NADIM II study assessed neoadjuvant nivolumab plus chemotherapy in patients with locally advanced, potentially resectable stage IIIA/B NSCLC.3 We do have a recent FDA approval of neoadjuvant nivolumab plus chemotherapy for resectable, early-stage NSCLC based on the phase III CheckMate 816 data.4 However, we do not yet have OS data from CheckMate 816, although there was a significantly longer event-free survival and a higher percentage of patients with a pathological CR with nivolumab plus chemotherapy than with chemotherapy alone. This analysis from NADIM II allows us to look at a good dataset with more mature results to start exploring OS results for this treatment option.
Wade T. Iams, MD, MSCI:
These data from NADIM II solidify the recent FDA approval for neoadjuvant nivolumab added to platinum doublet chemotherapy for eligible patients with resectable NSCLC tumors (≥4 cm or node positive), based on the CheckMate 816 study. The data also provide some additional context to this important practice change with excellent survival results.
Heather Wakelee, MD:
NADIM II is not necessarily practice changing because we already had CheckMate 816, which established the addition of neoadjuvant nivolumab to chemotherapy; however, Dr. Iams highlighted a couple of the key features from this trial. I think it is important to remember that this approach should not be considered for all patients; the trial excluded patients who had driver alterations, specifically EGFR mutations or ALK translocations, in their tumor and only included stage III patients. Some healthcare professionals believe that a patient with stage IIIA and especially IIIB NSCLC should not have surgery but should receive concurrent chemoradiation plus additional immune therapy with durvalumab. However, these impressive OS results with neoadjuvant nivolumab added to chemotherapy along with some of the other impressive outcomes of this trial, including pCR rates, do make us pause and they will make our tumor boards continue to have lots of discussions.
When considering both the CheckMate 816 and NADIM II trials, there were some differences to keep in mind. NADIM II only used carboplatin/paclitaxel as chemotherapy, whereas CheckMate 816 allowed various chemotherapy regimens, including cisplatin/pemetrexed or carboplatin/paclitaxel for patients with nonsquamous histology and cisplatin/gemcitabine or carboplatin/paclitaxel for squamous histology. In addition, patients in the chemotherapy-only arm or patients in either treatment group receiving adjuvant chemotherapy could also receive vinorelbine/cisplatin or docetaxel/cisplatin. NADIM II confirmed that using a taxane-based platinum doublet can be a good strategy and lends support for these neoadjuvant strategies.
NADIM II also continued nivolumab in the adjuvant setting for those in the nivolumab arm, while CheckMate 816 offered optional adjuvant chemotherapy for both arms. Now, one of our bigger unanswered questions is the importance of continuing immunotherapy after resection as adjuvant therapy vs only as a part of neoadjuvant therapy, as was done in CheckMate 816.
Heather Wakelee, MD:
The Presidential Plenary session at WCLC 2022 was focused on early‑stage lung cancer because we had some great data from new trials and updated trials. One of the trial updates was from IMpower010, which was the first randomized phase III trial to prove a benefit with adjuvant immune checkpoint inhibitor therapy.
The results from IMpower010 were initially presented at the 2021 American Society of Clinical Oncology (ASCO) annual meeting and showed a significant DFS improvement with adjuvant atezolizumab vs BSC for patients with completely resected stage IB-IIIA NSCLC after platinum-based chemotherapy.5 Based on these data, atezolizumab was approved as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II-IIIA NSCLC with PD-L1 expression on ≥1% of tumor cells in countries including the United States, China, and Japan.
The updates at WCLC 2022 included a prespecified interim analysis of the OS events.
Additional follow-up is needed to determine if a significant difference in OS emerges, but these data suggest that it is trending in that direction. These data were reassuring to many who have been questioning whether there will actually be a survival benefit. Looking at the OS curve separation at 3 years, 82% of patients remain alive with atezolizumab vs 79% with BSC. When you get out toward 5 years, more patients are censored, leading to some instability of the numbers, but 77% of patients remain alive with atezolizumab vs 68% with BSC.6
These patient subgroups are small, but it highlights the need to use biomarker testing, even in early-stage disease, to make sure that we are not including patients with ALK translocations (and probably ROS1 alterations) or EGFR mutations for treatment with immune checkpoint inhibitors in the perioperative setting.
For patients with 1% to 49% of tumor cells expressing PD-L1, the HR approaches 1 and it is not clear whether there is any benefit. Furthermore, in patients who do not have PD‑L1 expression on their tumors (<1% of tumor cells), there is actually potential harm with an HR of 1.36 when including EGFR/ALK-positive patients or 1.21 when excluding EGFR/ALK-positive patients.
When we look just at the stage II-IIIA patient population with high PD‑L1 expression excluding the EGFR- and ALK-positive population, the separation of OS curves is quite striking.6 Again, at this point we cannot call this statistically significant based on the way the study was powered, but we do see a trend toward OS improvement.
Heather Wakelee, MD:
The current analysis of IMpower010 includes data at nearly 4 years of follow-up and suggests a trend toward improvement in OS with adjuvant atezolizumab, with the OS curves continuing to separate. Currently, there is not a statistically significant difference in OS at this time, and we need to continue to analyze this trial with longer follow-up.
Wade T. Iams, MD, MSCI:
These data are important to continue to assess for this FDA-approved regimen of adjuvant atezolizumab in patients with ≥1% PD‑L1 expression. The OS results can help solidify the practice in patients whose tumors have ≥50% PD‑L1 expression and the separation of the OS curves is impressive.
In the subgroup of patients with 1% to 49% PD-L1 expression, the benefit of adjuvant atezolizumab has been questioned and it remains a question based on these data. As the data continue to mature, it will be helpful to see if there continues to be a difference in the groups of patients with ≥50% vs 1% to 49% PD-L1 expression.
There is also another subgroup analysis that I will be interested to watch over time, particularly in patients with 1% to 49% PD-L1 expression where the benefit from adjuvant atezolizumab hasn’t been as clear—using circulating tumor DNA (ctDNA) to define measurable residual disease (MRD) negativity. There was an interesting early analysis from the IMpower010 data based on ctDNA results and, potentially, patients with ≥1% PD-L1 expression who are ctDNA positive may show a more pronounced DFS improvement with adjuvant atezolizumab vs placebo compared with the ctDNA-negative population.7 I look forward to seeing more mature data from IMpower010 as the MRD field matures.
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