Bringing immune-checkpoint inhibitors earlier in the management of non-small cell lung cancer

Surgical resection followed by adjuvant cisplatin-based chemotherapy has long been the standard of care for resectable non-small-cell lung cancer (NSCLC), based on the results of phase III trials (1,2) and a meta-analysis showing an absolute benefit of 5.7% in overall survival (OS) at 5 years for tumors of more than 4 cm or with positive lymph nodes (3). On the contrary, the adoption of neoadjuvant chemotherapy in NSCLC was probably hampered by the earlier adoption of adjuvant therapy, based on high quality data (4). Several trials have however evaluated neoadjuvant chemotherapy in NSCLC, alone and in adjunction to radiotherapy, with a comparable benefit to that observed with the adjuvant approach (5,6), although only one directly compared neoadjuvant vs. adjuvant chemotherapy (5). The theorical advantage of a neoadjuvant approach is the possibility to treat more patients, as some individuals will not be able to receive post-operative treatment due to surgical complications or altered performance status after surgery. Other advantages stand in the earlier treatment of micro-metastatic disease, and the opportunity to facilitate surgery through tumor shrinkage. On the other hand, the major theoretical drawback of neoadjuvant therapy is that serious adverse events could preclude a patient from reaching surgery. The 2017 European Society of Medical Oncology (ESMO) guidelines recommended adjuvant cisplatin-based chemotherapy after surgical resection and to consider a neoadjuvant strategy in locally advanced or borderline resectable situations, such as stage III disease. It is important to mention that there is no universal definition of resectability and that practice for stage III disease varies in different centers and different countries (7). In this debate, the results of the PACIFIC trial (8), that established chemoradiotherapy followed by adjuvant durvalumab as the standard of care for unresectable stage III NSCLC, probably led to a shift in practice from surgery and (neo)adjuvant therapy to radio-chemotherapy, especially for borderline cases. Of note, the PACIFIC trial was the first study to demonstrate the efficacy of immune-checkpoint inhibitors (ICIs) in non-metastatic NSCLC.

Since the results of the PACIFIC trial and the subsequent shifts in clinical practices it introduced, the role of ICI in early-stage NSCLC has continued to evolve. Adjuvant pembrolizumab demonstrated a benefit in disease-free survival (DFS) vs. placebo in stage IB–III resected NSCLC in the Keynote-091/PEARLS trial. Interestingly, programmed death-ligand 1 (PD-L1) expression did not correlate with outcome. Atezolizumab was also investigated as an adjuvant treatment in the IMpower010 trial, in which, contrarily to Keynote-091, all patients also received adjuvant chemotherapy before ICI. DFS was improved with atezolizumab in PD-L1 positive patients. The benefit was driven by high PD-L1 expressors (9), leading to the approval of atezolizumab only for patient with PD-L1 ≥50%, by the European Medicines Agency (EMA), United Kingdom and Canada. Similarly, the updated results show an OS benefit only in this exploratory subgroup, without any trends towards a benefit in other PD-L1 expression subsets (10).

As mentioned earlier, as a neoadjuvant approach can carry some advantages, the role of ICI therein was of great interest. The administration of ICI when the tumor antigens and the lymph nodes are still in place, can theoretically enhance the antitumor immune response (11).

In their paper, Wakelee et al. tested the efficacy of perioperative pembrolizumab in resectable NSCLC (12). Patients with stage II–IIIB NSCLC according to the tumor-node-metastasis (TNM) American Joint Committee on Cancer (AJCC) 8^th edition, with upfront resectable disease after case discussion at multi-disciplinary tumorboard, were included. Molecular testing for epithelial growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangement or other oncogene-addiction was not mandatory. Indeed, the presence of EGFR mutation or ALK rearrangement was not even an exclusion criterion, and 7% of the patients had an EGFR mutation or ALK alteration. Patients were randomized between perioperative pembrolizumab and a placebo arm, with stratification by disease stage (stage II vs. III), histology (squamous vs. non-squamous), PD-L1 status (≥ or <50%), region of the world (East Asian vs. not-East Asian). In the intervention arm, patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks in combination with cisplatin-based chemotherapy, for four cycles, followed by surgery, and adjuvant pembrolizumab for thirteen cycles. The choice of chemotherapy was restricted to cisplatin, and pemetrexed and gemcitabine for non-squamous and squamous histology respectively. In the control arm, patients received neo-adjuvant chemotherapy with placebo, and one year of adjuvant placebo. The co-primary endpoints were OS and event-free survival (EFS), defined as the time from randomization to the first occurrence of local progression precluding the planned surgery, an unresectable tumor, distant progression or recurrence, or death. After a median follow-up of 25 months, EFS was improved in the intervention arm with a hazard ratio (HR) of 0.58 [95% confidence interval (CI): 0.46–0.71, P<0.00001]. OS data were immature at the time of this primary analysis. The rate of major pathological response (MPR), defined as 10% or less of viable tumor cells, was significantly higher with pembrolizumab-chemotherapy compared to chemotherapy alone, 30.2% vs. 11.1%, as was pathological complete response (pCR): 18.1% and 4%. Adverse events were slightly more frequent in the intervention arm; however, there were no significant differences between adverse events precluding surgery in both groups, and 82.1% and 79.4% of patient underwent surgery in the pembrolizumab and placebo group respectively.

Three other phase III trials and one randomized phase II trial have recently compared neoadjuvant ICI in combination with chemotherapy in early NSCLC. The different characteristics of these trials are summarized in Table 1, for better comparison. Checkmate-816 compared nivolumab and chemotherapy with chemotherapy alone, for three preoperative cycles (13). Interestingly, this is the only phase III trial which did not include an adjuvant phase. The coprimary outcome of EFS was improved with nivolumab with an HR of 0.68 (95% CI: 0.49–0.93). The other coprimary endpoint, pCR, was also improved with nivolumab, at 24.0% (95% CI: 18.0–31.0%) vs. 2.2% (95% CI: 0.6–5.6%). With a similar design to the Keynote-671 trial, the phase III AEGEAN trial evaluated the combination of durvalumab-chemotherapy vs. placebo-chemotherapy for four cycles in the preoperative setting, followed by adjuvant durvalumab or placebo for one year (14). EFS and pCR were superior with durvalumab compared to placebo with an EFS HR of 0.68 (95% CI: 0.53–0.88, P=0.003902). The NEOTORCH trial, conducted in Asia, tested the combination of toripalimab with chemotherapy to placebo-chemotherapy for three pre-operative cycles, followed by one post-operative cycle of toripalimab-chemotherapy or placebo-chemotherapy, and one year of toripalimab or placebo (15). The primary outcome of MPR and EFS in stage III disease were met, HR of 0.40 (95% CI: 0.277–0.565, P<0.0001). Finally, in the phase II randomized trial, NADIM-2, patients were randomized between nivolumab-chemotherapy and chemotherapy alone (16). Only patients with resectable stage III disease were included. Patient with R0 resection in the intervention group received 6 months of adjuvant nivolumab. The primary outcome of pCR was improved with nivolumab, at 37% vs. 7% in the control group. The secondary endpoints of PFS and OS were also improved with nivolumab. Despite its modest size, NADIM-2 was the first study to show a survival benefit for a neoadjuvant ICI-chemotherapy combination in NSCLC.

In terms of safety, as in Keynote-671, the addition of ICI to chemotherapy did not lead to a major increase in toxicity in these phase III studies. Grade 3 or 4 treatment-related adverse events did not differ between the two groups in Checkmate-816: 33.5% vs. 36.9%. In AEGEAN study the all-cause grade 3 or 4 adverse events were similar with durvalumab or placebo: 42.3% vs. 43.4%, during the whole treatment-period. In the NEOTORCH trial, the incidence of grade 3 or more all causes adverse events was slightly increased with toripalimab compared to placebo: 63.4% vs. 54.0%, as was the rate of immune-related adverse event: 42.1% vs. 22.8%. It is also worth mentioning that in all these trials, the addition of ICI did not negatively affect the feasibility of surgery, with around 80% of patient undergoing surgery in the AEGEAN trial, and even a slight increase in the surgery rate in patients treated with ICI and chemotherapy in the NEOTORCH (83% vs. 73.3%) and Checkmate-816 trials (83.2% vs. 75.4%).

While there is no doubt that preoperative ICI and chemotherapy combination has improved anti-tumor activity in operable NSCLC, several questions remain.

First, there is the question of the impact and efficacy of the choice of the chemotherapy partners for ICI. The Keynote-671 trial restricted chemotherapy to cisplatin-pemetrexed for non-squamous and cisplatin-gemcitabine for squamous tumors, and did not include taxanes, which are an active drug in NSCLC. The NADIM-2 trial, on the other hand, restricted the choice to carboplatin and paclitaxel, while the other phase III trials mentioned above offered a more diverse choice, with the possibility to use cisplatin or carboplatin, and pemetrexed, paclitaxel, gemcitabine or vinorelbine, depending on the histology. At the moment, it is difficult to determine whether the chemotherapy regimen used in combination with ICI affects the effectiveness of ICI.

Second, the role of PD-L1 expression as a predictive biomarker in the neoadjuvant setting remains a matter of debate. PD-L1 expression is a well-known predictive factor of ICI efficacy in metastatic NSCLC, where patients with PD-L1 negative tumors derive less benefit from ICI (17-19). The subgroup analysis of Keynote-671 stays in line with this observation, with a benefit that seemed higher in PD-L1 positive subgroup. The subgroup analysis of Checkmate 816 goes in the same direction: patients with PD-L1 negative disease seemed to derive less benefit from the addition of nivolumab to chemotherapy, with an HR for EFS of 0.85 (95% CI: 0.54–1.32). While the Food and Drug Administration (FDA) has approved the use of nivolumab with neoadjuvant chemotherapy regardless of PD-L1, strictly following the inclusion criteria of the originator study, the EMA has decided to restrict its use to patients with PD-L1-positive disease, based on this subgroup analysis. Whether this distinction will also be made for pembrolizumab remains to be seen. On the question of biomarkers, the presence of an oncogenic mutation should probably discourage the use of an ICI-based perioperative strategy, as it is well described that these patients respond poorly to immunotherapy (20). For these patients, several perioperative strategies using targeted therapies are being developed (21,22).

Third, the relative contribution of the adjuvant component of the treatment remains unknown. A post-hoc and unplanned analysis compared the outcome of patients with and without MPR and pCR in the Keynote-671 trial and showed that pembrolizumab appears to offer an EFS benefit even without a deep neoadjuvant response, suggesting a potential benefit of the adjuvant component of therapy. Of note, with this post-hoc unplanned analysis, it is still unclear whether these patients derive a benefit from the adjuvant component, or only from the preoperative treatment. A discrepancy between image-based response assessment and progression-free survival or OS has also been described for immunotherapy in other settings (23), possibly due to the delayed impact of immunotherapy, highlighting the fact that neoadjuvant ICI may have a prolonged or delayed impact. Even though cross trial comparisons should be avoided, in terms of absolute numbers, the EFS rate at 2 years appears comparable in the Keynote-671 and Checkmate-816 trials. New prospective data will be needed to determine if some patients could undergo less than a full year of adjuvant treatment or even totally avoid adjuvant treatment. These future studies should, as far as possible, focus on identifying those patients at higher risk, most likely to benefit from additional adjuvant therapy, with biomarkers that go beyond simple pathological response, such as circulating tumor DNA or minimal residual disease (16).

Fourth, in Keynote-671 as in the other trials, the benefit of neoadjuvant ICI and chemotherapy seem to be higher for stage III disease. The NADIM-2 trial shows a significant EFS and OS benefit in stage III disease, confirming the hypothesis that ICI and chemotherapy are effective in this setting. On the other hand, the benefit in stage II disease seems more nuanced, even though this observation should be interpreted with caution, as it is based on a subgroup analysis. In patients presenting with stage II disease with easily resectable tumors, especially those without lymph node involvement, the risk of precluding surgery must be considered. In this respect, it is worth mentioning that about 20% of patient did not undergo surgery in the Keynote-671 trial, the main reasons being adverse events, progressive disease and physician’s choice. These numbers are consistent with other neoadjuvant chemo-immunotherapy trials.

Finally, the question of which treatment to give at relapse for these patients is still open to debate (24). Current treatment choices will probably depend on the time between ICI exposure and relapse. Data collected from the efficacy of ICI rechallenge after progression in the experimental arms of the trials discussed herein could be valuable for guiding clinical practice. Regarding treatment at progression, one major limitation of the Keynote-671 trial is that only 57% of patients in the control arm received ICI as further systemic therapy at relapse. This is probably substandard, as ICI represent a standard of care in metastatic NSCLC, except for patients with oncogene addicted tumors. This limitation could influence the validity of OS results in the future, as the control arm is likely inadequate.

In conclusion, ICI are now part of the treatment algorithm for early-stage NSCLC. Their role in certain situations, such as locally advanced stage III disease is now indisputable. As discussed, several questions remain, such as strategies to better identify patients who are likely to benefit from ICI, particularly regarding the adjuvant therapy in a perioperative approach. Finally, this progress underlies the paramount importance of a good collaboration between all medical specialties involved in the management of NSCLC patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-466/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-466/coif). A.F. received payments from Amgen, AstraZeneca, Roche, Astellas, Takeda, Bristol-Myers Squibb, Merck Sharpe Dohme, Pfizer, Merck, Novartis and Janssen, outside the scope of this manuscript. A.A. reports advisory board fees from Amgen, AstraZeneca, Roche, Astellas, Takeda, Merck Sharpe Dohme, Pfizer, Bristol-Myers Squibb, Merck and Novartis; and speaker’s bureau fees from Eli-Lilly, AstraZeneca, Amgen and Novartis. The other author has no conflicts of interest to declare.

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