The announcement of Phase III CheckMate 816 results appears to open the door to neoadjuvant treatment of early-stage NSCLC. While it is not yet clear whether neoadjuvant treatment leads to a survival benefit, endpoints such as pathologically complete response indicate an important clinical effect. Furthermore, the treatment appears to lead to only limited delay or cancellation of surgical treatment. Pulmonologist Dr. Jeroen Hiltermann (UMCG) puts the findings into perspective.
CheckMate 816 participants included 358 patients with newly diagnosed resectable NSCLC (IB to IIIA according to TNM classification 7th edition; see box).1 Patients had no EGFR or ALK abnormalities and were randomized to receive three cycles of neoadjuvant chemotherapy or three cycles of neoadjuvant chemotherapy plus nivolumab immunotherapy. Patients underwent surgery within six weeks of treatment and may subsequently receive adjuvant chemotherapy or radiotherapy.
The primary endpoints of the study were event-free survival and pathologically complete response, defined as the absence of viable tumor cells in both the primary tumor and lymph nodes. This endpoint was achieved in approximately one-quarter of patients in the chemotherapy-nivolumab arm (24%) compared with only 2% in the chemotherapy-only arm. Looking only at patients who actually underwent a resection, the number of pathologically complete responses was even higher than 30%. Median event-free survival was also significantly longer in the immunotherapy group, at 31.6 months versus 20.8 months, respectively (HR 0.63).
Jeroen Hiltermann predicts that achieving a complete pathological response will become an important concept in the treatment of early stage NSCLC. “A pathologically complete response is a new concept in the context of NSCLC and means that there is no visible tumor when the pathologist systematically examines the tissue sample. I expect this to be important reading. This has yet to be associated with overall survival – those data are still immature – but this is expected to have a strong positive relationship. The question then is whether the group should still be operated on with a pathologically complete response. We do not know. But these are patients who benefit greatly from this induction treatment. In general, you also see that patients who received chemo-immunotherapy have much stronger tumor shrinkage than patients who received chemotherapy alone. So it really seems like a much more effective treatment.
Surgical delay acceptable
Furthermore, a reassuring result is that neoadjuvant treatment did not have a major impact on subsequent surgery. “There were concerns about it before,” says Hiltermann. “If you pre-treat patients, can you still operate on them properly? Won’t you enter areas of necrosis that could cause problems during surgery? But this doesn’t seem to be all that bad and this is a very important result of this study.” Finally, of all patients randomized to the chemotherapy-nivolumab arm, 83.2% underwent surgery and 75.4% to the chemotherapy arm.
Hiltermann: “17% therefore did not undergo surgery, and of these 7% had progression and 1% had side effects. The latter is obviously undesirable, because you certainly don’t want that to happen, but I don’t find these numbers scary. Additionally, there appear to be surgical benefits associated with neoadjuvant chemoimmunotherapy, Hiltermann points out. “Patients who had received chemoimmunotherapy were more likely to have a lobectomy instead of a pneumonectomy and were also more likely to be treated with minimally invasive surgery. And if they had minimally invasive surgery, it was less likely that it would need to be converted to a thoracotomy. So the operation was easier. And this was also evident, for example, from the average operation time. Additionally, there was a half-hour gain over chemotherapy (185 minutes and 214 minutes).”
A comparison with the current standard of adjuvant chemotherapy is also favourable, says Hiltermann. “At the moment we operate and then we do adjuvant chemotherapy. But a recent large study in JAMA Oncology with more than 2800 patients, real-world data has been used to examine the number of patients who ultimately receive full adjuvant chemotherapy, and that’s just 34%.2 So only 34% of that population, the same population as the CheckMate-816, received the adjuvant treatment, which offers a survival advantage of the order of 5-7%. In the CheckMate 816, 94% received full induction treatment. Thus, systemic treatment appears to be better tolerated if administered preoperatively rather than postoperatively.”
Downstaging
Since the use of neoadjuvant chemoimmunotherapy leads to a considerable number of pathologically complete responses, an important question for the near future is what the policy should be for patients who meet or fail to meet this endpoint. “I expect that patients who have a pathologically complete response may have completed treatments and you can follow them up,” Hiltermann said. “And that this group shows good five-year survival that is better than what we’ve seen so far in stage II and III NSCLC. But what to do with patients who do not have a pathologically complete response? You will certainly want to operate on him and then you will want to do adjuvant treatment, probably in the first instance in a study setting. But how it will be is still speculative. For example, what the discussion will be about is patients who are downstaging but still have a tumor in a gland, for example. Will you operate on him or will you continue him on chemoradiotherapy?
For stage III NSCLC in particular, the approach could change as a result of the findings, Hiltermann predicts. “Stage IIIA and IIIB patients currently receive chemoradiation often, but some of these patients, particularly relatively young patients and otherwise healthy patients, will more often have surgery as an option. This does not mean that chemoradiation will be dispensed with, but patients will more often receive an induction course and then possibly surgery, especially if there is down-staging of the mediastinal glands. That would really mean a change in clinical policy. Surprisingly, an exploratory analysis shows that only patients who have had a complete pathological response actually benefit from treatment. The future will show exactly what that will mean for practice.”
Using the old TNM classification somewhat obscures the beneficial effect
In the CheckMate 816, patients were classified with the seventh edition of the TNM classification. This affects how the results should be interpreted, Hiltermann points out, because the NWT 8th edition is currently in use. Hiltermann: “In the CheckMate 816, the majority of patients – 63% – had stage IIIA, but IIIA according to the seventh TNM classification. So these are actually patients of whom a large percentage would currently have stage IIIB, whose five-year survival is only 24%. But those patients were included in this study. When you look at the positive results of the CheckMate 816 in this light, they seem very important.”
This interview appeared on MedNet Oncology – Lung Cancer Special 2022-2. These articles also appeared in Special Lung Cancer:
References:
- Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N English J Med 2022; 386:1973-85.
- Kehl KL, Zahrieh D, Yang P, et al. Rates of guideline-conformant surgery and adjuvant chemotherapy among patients with early-stage lung cancer in the US ALCHEMIST study (Alliance A151216). JAMA Oncol. 2022;8:717-28.
