CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: November 18, 2021
Expiration: November 17, 2022
Thomas E. Stinchcombe, MD:
Patients with early-stage NSCLC who lack EGFR mutations still face a high unmet need for improved neoadjuvant/adjuvant treatment options. Immunotherapy has shown promising results in advanced disease, and the phase III IMpower010 study is the first to evaluate it in the adjuvant setting.9,10
This phase III trial enrolled 1280 patients with completely resected stage IB-IIIA NSCLC per Union for International Cancer Control/American Joint Committee on Cancer version 7 staging criteria. This included stage IB tumors ≥4 cm. All patients received 1‑4 cycles of adjuvant chemotherapy, which was cisplatin plus choice of pemetrexed, gemcitabine, docetaxel, or vinorelbine based on histology. Patients were then randomized to receive atezolizumab at 1200 mg every 3 weeks for 16 cycles or best supportive care (BSC).
The primary endpoint is investigator-assessed disease-free survival (DFS). The statistical design is a bit complex using a hierarchical design in which the first evaluation was DFS in patients with stage II to IIIA disease with PD‑L1 tumor cells (TC) ≥1%, and if that analysis was positive, followed by evaluation of all patients with stage II to IIIA disease, and then in the intention-to-treat (ITT) population, which included patients with stage IB to IIIA disease.
Thomas E. Stinchcombe, MD:
Looking at the patient demographics in IMpower010, approximately 12% of patients had stage IB disease, 30% stage IIA, approximately 15% to 20% stage IIB and, of note, approximately 40% of patients had resected stage IIIA disease.10 It is also important to look at the type of surgery patients received, because that is really the focus of this analysis. Approximately three quarters of patients had a lobectomy, approximately 15% to 17% had a pneumonectomy, and the remaining patients had a bilobectomy. The median time from surgery to the first dose of atezolizumab or BSC was very similar between the 2 arms (5.1 and 5.2 months, respectively). The chemotherapy selection was also similar between the treatment arms, with cisplatin/docetaxel used in approximately 15% of patients, cisplatin/gemcitabine in 16% to 17%, cisplatin/vinorelbine in 30%, and cisplatin/pemetrexed in approximately 40% of patients, probably those with nonsquamous histology, as per the protocol.
Thomas E. Stinchcombe, MD:
The primary analysis of DFS was presented at the 2021 American Society of Clinical Oncology annual meeting.9 In patients with stage II-IIIA disease and PD‑L1 TC ≥1%, atezolizumab significantly prolonged DFS compared with BSC, with an HR of 0.66 (95% CI: 0.50-0.88; P = .004). As you can see on the curves, median DFS for this group of patients was 35.3 months in the BSC arm but was not yet reached in the atezolizumab arm. Based on these data, the FDA approved atezolizumab for adjuvant treatment following resection and platinum-based chemotherapy for adults with stage II-IIIA NSCLC with PD-L1 ≥1% on tumor cells in October 2021.11
As a result of this trial meeting its primary endpoint, the second analysis on all patients with stage II-IIIA disease was done. In this group, atezolizumab showed a benefit vs BSC, although the results were a little bit less robust than in the PD‑L1 TC ≥1% subgroup, with an HR of 0.79 (95% CI: 0.64-0.96; P = .02). The third analysis (of the ITT population including all stage IB-IIIA patients) is descriptive but is not mature enough to draw any conclusions from because there have not yet been enough events.
Thomas E. Stinchcombe, MD:
In the subgroup analysis of DFS in the patients with stage II-IIIA disease and PD‑L1 TC ≥1%, there is a benefit with atezolizumab regardless of the type of surgery, although the benefit appears to be largest in those who had lobectomy.10 When interpreting this subanalysis, however, it is important to remember that certain disease characteristics may impact the decision to perform a pneumonectomy vs a lobectomy. Among patients receiving different chemotherapies, there appears to be a benefit with atezolizumab in those who received cisplatin plus docetaxel, vinorelbine, or pemetrexed, but not among the 75 patients who received cisplatin plus gemcitabine, where the HR was 1.14 (95% CI: 0.50-2.61).
Anne Chiang, MD, PhD:
Yes, there does appear to be differences in DFS among the various adjuvant chemotherapy regimens given to patients prior to their starting adjuvant atezolizumab, with cisplatin/gemcitabine not being as effective as the other platinum doublets evaluated. I don’t typically use cisplatin/vinorelbine in my practice; instead, I usually use cisplatin/pemetrexed or cisplatin/docetaxel. Now based on these findings, I would lean more toward using cisplatin/docetaxel.
Based on these findings, I would lean toward using docetaxel over gemcitabine. I think it’s important to remember that this study advises atezolizumab after chemotherapy, not in place of chemotherapy.
Thomas E. Stinchcombe, MD:
Looking at all randomized stage II‑IIIA patients, we still see a benefit with atezolizumab among the patients who underwent lobectomy (HR: 0.77; 95% CI: 0.61-0.97), but in this larger analysis, we don’t see an atezolizumab benefit in the subsets who had pneumonectomy or bilobectomy. As in the previous analysis, we see a benefit or trend toward benefit with atezolizumab among patients who received cisplatin with docetaxel, vinorelbine or pemetrexed, but not among those who received cisplatin/gemcitabine, where the HR is closer to 1.
Thomas E. Stinchcombe, MD:
The analysis of the full ITT population, which includes all randomized patients with stage IB IIIA disease, is a bit harder to interpret. The general trends here look very similar to the previous analyses at this point, but the data are immature.
Thomas E. Stinchcombe, MD:
IMpower010 is a landmark trial in bringing the advances of immunotherapy to the adjuvant setting, driving the first approval of adjuvant atezolizumab for patients with stage II-IIIA NSCLC with PD-L1 ≥1% on tumor cells.9,11 We know from the metastatic setting there is a subgroup of patients with NSCLC who achieve a durable benefit with atezolizumab, and I’m eager to follow the DFS curves for adjuvant atezolizumab longer and look at OS. With the focus on DFS as an endpoint, one concern in the field is that we could be delaying recurrence in some patients rather than preventing it, so it will be important to watch for longer-term follow-up. For example, consider the phase III PACIFIC trial of consolidation durvalumab following concurrent chemoradiation in unresectable stage III NSCLC. With reported 5-year follow-up data, we can feel more confident in the demonstrated OS benefit with immunotherapy.12
The data from the subgroup analyses presented this year at WCLC, such as type of surgery and chemotherapy, are interesting hypothesis‑generating questions but are unlikely to affect my prescribing patterns at this point. With confounding factors and other aspects that make the subgroup analyses hard to interpret, I would to follow the FDA-approved indication for adjuvant atezolizumab.
As immunotherapies start to move into the early-stage setting, it’s interesting to consider how that might affect treatment in the metastatic setting where these agents are standard of care (SoC). Hopefully, adjuvant immunotherapy will reduce the number of patients who progress to metastatic disease, but it will raise some questions. If a patient received adjuvant immunotherapy after surgery, and has disease progression, should they be considered immunotherapy naive for metastatic treatment decisions or immunotherapy resistant? I think most of us are going to have to decide on a case-by-case basis. It may matter whether the patient progresses while receiving immunotherapy or whether they complete the defined duration of treatment, for example. If someone completes 1 year of immunotherapy, then relapses 12, 18, or 24 months later, I’m more inclined to treat them as immunotherapy naive and enroll them on a clinical trial as well as give SoC treatment for advanced disease.
Anne Chiang, MD, PhD:
I agree. IMpower010 is a very important trial as adjuvant atezolizumab (ie, after chemotherapy) will now be our new SoC for patients with stage II-IIIA NSCLC with PD-L1 ≥1%. In my own clinical practice, these subset analyses may help inform the type of adjuvant chemotherapy that I offer my patients.
Another relevant question that has already come up in our tumor boards is whether you should use adjuvant atezolizumab for patients with EGFR mutation–positive disease or whether you should give adjuvant osimertinib, which is FDA approved as adjuvant therapy after resection in adults with early-stage NSCLC and EGFR exon 19 deletions or exon 21 L858R mutations. I would favor osimertinib for these patients based on a prior subgroup analysis from IMpower010 that suggested adjuvant atezolizumab was not as beneficial in patients with EGFR mutations.9
Thomas E. Stinchcombe, MD:
Another study in the setting of early-stage NSCLC that I’d like to discuss is the long‑term follow-up of chemotherapy and immunotherapy in the phase II NADIM trial.13 In this single-arm study, patients with resectable stage IIIA NSCLC received neoadjuvant therapy with carboplatin, paclitaxel, and nivolumab every 3 weeks for 3 cycles before surgery. After resection, patients received adjuvant nivolumab at 240 mg every 2 weeks for 4 months, then at 400 mg every 4 weeks for 8 months. The primary endpoint was PFS at 24 months in the modified ITT population, which included all patients who received neoadjuvant therapy, and in the per protocol population, which included patients who had resection and at least 1 cycle of adjuvant therapy. The follow up was for 3 years.14
At WCLC, Provencio and colleagues13 presented the long‑term follow-up, with a median follow-up of 38 months. PFS was 69.6% at 36 and 42 months in the modified ITT population and 81.1% at 36 and 42 months in the per protocol population. The median PFS of patients with progressive disease was 21.4 months. Beyond these timepoints, if you look at the Kaplan-Meier PFS curve, there is a lot of censoring in the 30‑ to 50-month time period. And there seems to be a real plateau, which suggests these patients may have been cured with this strategy. The OS curves mirror the PFS curves, with an OS rate of 78.9% at 42 months. Although this is a single‑arm phase II trial, these outcomes are much better than what we would anticipate in this patient population based on historical evidence.
These results are encouraging and provide what I would call preliminary evidence that this strategy has merit as a way to improve outcomes in patients with resectable stage IIIA disease. The investigators also did some exploratory analyses looking at complete vs major-plus-incomplete pathologic response and circulating tumor DNA clearance. The take-home message is that patients who had a complete pathologic response had a longer PFS, which was statistically significant (HR: 0.25; P = .05). This provides additional evidence that patients who have a complete pathologic response are deriving greater benefit from nivolumab than those patients who do not achieve a complete pathologic response.
Overall, these results build on other single‑arm phase II trials of either immunotherapy alone or in combination with chemotherapy as neoadjuvant therapy. However, it’s important to remember that patients had postoperative immunotherapy as well. When both neoadjuvant and adjuvant strategies are contained within one trial, it’s very hard to tease out the effect of the neoadjuvant vs adjuvant approach.
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