In 2012, a phase I study was conducted to determine the safety and efficacy of nivolumab in patients with certain types of cancers. Surprisingly, this trial showed a response rate of 18% among patients with NSCLC and led to further clinical development and other anti-PD(L)1 agents in NSCLC [52]. Checkmate-017 was a landmark phase III trial that examined the safety and efficiency of nivolumab versus docetaxel. The trial showed significantly improved overall survival (OS), overall response rate (ORR), and progression-free survival (PFS) with nivolumab over docetaxel in patients who had received one prior line of therapy [21]. In March 2015, Checkmate-017 together with Checkmate-057, which had the same study design but was conducted in patients with non-squamous NSCLC [53], led to the approval by the FDA of nivolumab as the first ICI for the treatment of patients with advanced NSCLC after platinum-based chemotherapy. The five year outcomes of pooled data from both these trials revealed that at five years, nivolumab continued to demonstrate a survival benefit compared with docetaxel, with an OS of 13.4% versus 2.6%, and a PFS of 8.0% versus 0% [54]. This is a significant and life-changing advance for patients with NSCLC.

The approval of nivolumab was quickly followed by the approval of subsequent ICIs (Table 1). In October 2016, results from the KEYNOTE-010 [23] and KEYNOTE-024 [22] trials led to the approval of the PD-1 inhibitor, pembrolizumab, for the treatment of patients with metastatic NSCLC. In KEYNOTE-024, pembrolizumab was compared with cytotoxic chemotherapy as a first-line treatment for patients with advanced NSCLC and a PD-L1 tumour percentage score of 50% or greater. Pembrolizumab was shown to have significantly longer PS and OS and fewer adverse effects compared with platinum-based chemotherapy and so became a new standard of care for the first-line treatment of patients with ‘PD-L1 high’ NSCLC [22]. Following positive results from the POPLAR and OAK trials, another ICI inhibitor, atezolizumab, was approved for second-line treatment for patients with locally advanced or metastatic NSCLC [24,25]. While anti-PD-(L)1 monotherapy had demonstrated benefit in a subset of patients with pre-treated NSCLC, it was also postulated that combination immunotherapy may be a useful strategy in NSCLC.

Name	Approval	Type of MA	Action	Usage	Reference
Nivolumab	March 2015	IgG4	PD-1	Stage III OR IV metastatic NSCLC.	[21]
Pembrolizumab	October 2016	Humanized IgG4-K isotope antibody.	PD-1	Stage IV metastatic NSCLC.	[22,23]
Atezolizumab	October 2016	IgG1	PD-L1	Stage III or IV metastatic NSCLC.	[24,25]
Durvalumab	February 2018	IgG1 k	PD-L1	Stage III NSCLC	[26]
Ipilimumab	May 2020 (in combination with nivolumab)	IgG1	CTLA-4	NSCLC	[27]
Cemiplimab	November 2022 (in combination with platinum-based chemotherapy)	IgG4	PD-L1	Stage III OR IV metastatic NSCLC	[28]
Tremelimumab	November 2022 (in combination with durvalumab and platinum-based chemotherapy)	IgG2	PD-L1	Stage III OR IV metastatic NSCLC	[29]

Ipilimumab and tremelimumab are CTLA-4 inhibitors previously used in metastatic melanoma. In a phase II trial conducted more than 10 years ago, single agent ipilimumab combined with chemotherapy demonstrated modest benefit compared with ipilimumab monotherapy in NSCLC [55]. However, the combination of ipilimumab and nivolumab had demonstrated deep and durable responses in patients with melanoma [56], and it was hoped this could be recapitulated in NSCLC. In early phase studies of this combination, it was clear that the doses used for melanoma resulted in unacceptable toxicity in patients with NSCLC. After modification of this dose to ipilimumab every 6 weeks, the Checkmate-227 explored this combination in a complex eight-arm clinical trial. Broadly, this study demonstrated a significant benefit in PFS and OS as well as durable responses in patients with both PD-L1 > 1% and PD-L1 < 1% NSCLCs, and is approved as a ‘chemotherapy-free’ option in the first-line treatment for patients with advanced PD-L1 > 1% NSCLC [27]. In addition, a novel regimen from the Checkmate 9LA trial incorporating two doses of platinum-doublet chemotherapy in addition to ipilimumab and nivolumab also resulted in both PFS and OS benefits for this combination compared with chemotherapy alone, and is also an approved treatment option for first-line advanced NSCLC in all-comers for PD-L1 status [57]. This regimen is thought to potentially provide the ‘neoantigen release’ of cytotoxic chemotherapy alongside the long-term durable outcomes seen with ipilimumab and nivolumab.

While the use of ICIs has undoubtably changed the landscape of patient care for NSCLC, there remains an urgent need to transform more patients from immunotherapy non-responders to responders. Hence, current research strategies are focused on improving the response rate of ICIs, and these efforts are mainly centred around creating effective combination regimens with chemotherapy, radiotherapy, and other anti-cancer drugs (Table 2). In 2018, the FDA approved the use of pembrolizumab in combination with chemotherapy for first-line treatment of metastatic non-squamous NSCLC, independent of PD-L1 tumour expression status. This approval was based on the results of the KEYNOTE-189 trial which demonstrated a longer OS and PFS in patients receiving pembrolizumab in addition to standard chemotherapy of pemetrexed and a platinum-based drug compared with patients receiving chemotherapy alone [58]. This combination regimen was also approved for first-line treatment in metastatic squamous NSCLC following the results of the KEYNOTE-407 trial, again independent of PD-LI tumour expression status [59]. The positive results from the Impower150 trial led to the approval of atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC [60]. Interestingly, it has been demonstrated that the combination of chemotherapy with bevacizumab induces proliferation of peripheral CD8 T cells, particularly memory and effector subsets [61], perhaps offering the rationale for combining chemotherapy and bevacizumab with ICIs. This is also now an approved option for first-line treatment of advanced NSCLC independent of PD-L1 status, based on the phase III IMPower150 trial [60].

Immunotherapy and immunotherapy combination strategies are now an accepted standard of care, with 5-year survival data supporting these approaches. The future of immunotherapy research in this disease setting will focus on improving treatment for subsets for patients with advanced disease, developing approaches for the PD-L1 pre-treated setting, and conducting biomarker discovery of the mechanisms of response and resistance.

While immunotherapy has changed the management of advanced NSCLC, its use in early-stage NSCLC has only begun to emerge. In February 2018, the FDA approved the use of durvalumab for patients with unresectable stage III NSCLC whose disease had not progressed following concurrent platinum-based chemotherapy and radiation therapy. This was the first approval of an immunotherapy agent for the treatment of earlier stage NSCLC and was based on the results of the phase III PACIFIC trial, which demonstrated prolonged PFS and OS in patients treated with 1 year of consolidation durvalumab versus a placebo [26]. In recent years, much effort has also centred around designing effective uses of immunotherapy for the treatment of resectable NSCLC (Table 3).

In October 2021, the FDA approved atezolizumab for adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II and IIIA NSCLC whose tumours have a PD-L1 expression of greater than/equal 1% of tumour cells. This approval came about following the Impower010 trial which demonstrated a DFS benefit with atezolizumab versus best supportive care after adjuvant chemotherapy [102]. This was the first phase III trial to demonstrate a benefit from immunotherapy in patients with early-stage resectable NSCLC. In 2023, the KEYNOTE-091/PEARLS trial investigated pembrolizumab for adjuvant treatment of early-stage NSCLC following resection and optional platinum-based chemotherapy for patients with stage IB-IIIA NSCLC. This is approved for this indication, independent of tumoural PD-L1 expression [103].

Researchers have also recently witnessed the use of immunotherapy in the neoadjuvant setting for NSCLC. The Checkmate-816 trial was a phase III trial examining the use of nivolumab plus platinum-based chemotherapy versus chemotherapy alone, followed by resection in patients with stage IB to IIIA resectable NSCLC; patients were enrolled regardless of PD-L1 status [112]. The results demonstrated that nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. Similar results have also been observed in the NADIM trial, for patients with resectable stage IIIA NSCLC [113]. The trial compares the effect of nivolumab with chemotherapy against chemotherapy as a monotherapy. While the trial is still ongoing, current results show an improved overall survival in patients treated with chemo-immunotherapy compared with chemotherapy alone, with overall survival at 24 months showing 85.3% vs. 64.8%.

In March 2022, the Checkmate-816 data led to the FDA approval of neoadjuvant nivolumab and platinum-doublet chemotherapy for the treatment of early-stage resectable NSCLC. The NEOSTAR trial was also performed in the neoadjuvant setting, examining the effect of nivolumab or nivolumab and ipilimumab followed by surgery in patients with resectable NSCLC. The data from this trial indicate that neoadjuvant nivolumab and ipilimumab-based therapy enhances pathological response, tumour immune infiltrates and immunological memory [111].

For patients with resectable NSCLC, the goal of therapy is cure. In the context of a curable disease, ICIs are used to reduce the risk of relapse, but it is critical that they do not interfere with the curative portion of the treatment paradigm, that is, surgery. This is a particular challenge for patients being treated in the neoadjuvant setting (e.g., CHECKMATE-816) in which the use of neoadjuvant therapy could be associated with delays to surgery. Encouragingly, an increased risk of surgical complications has not been observed in most neoadjuvant studies involving ICIs and NSCLC. For example, in the CHECKMATE-816 study, the authors reported surgical complications of 41.6% in the nivolumab plus chemotherapy arm and 46.7% in the chemotherapy arm [116]. Encouragingly, only 3.4% of patients had delayed surgery in the nivolumab plus chemotherapy arm and 5.1% in the chemotherapy alone arm.

For patients in the adjuvant setting (e.g., PEARLS/IMPower010), different challenges emerge compared with the neoadjuvant setting [102,117]. Given that the cancer is already surgically resected, irAEs will not interfere with patients’ curative procedure. However, unlike in the metastatic setting, it is our expectation that the majority of these patients will be cured of their disease. In this regard, the risk of inducing a chronic or multi-organ toxicity may be associated with significant and long-term impact on patients’ quality-of-life. The risks and benefits of such adjuvant therapy pose challenges in weighing the low risk of long-term toxicity versus the survival benefit of disease control. Decisions regarding the most appropriate treatment option need to be made in a collaborative manner between patients and the multidisciplinary team.

Adjuvant/neoadjuvant studies in resectable NSCLC have to date demonstrated impressive event-free/disease-free survival for patients, which we hope will translate to an overall survival benefit. Long-term follow-up and further studies will provide more data on the efficacy of adjuvant/neoadjuvant ICI and the risks of delays to surgical resection/long-term toxicity. We eagerly await the publication of further studies in this field and long-term follow-up.

3. Future Outlook for the Use of Immunotherapy in NSCLC