Lung carcinoma is the main cause of cancer-related mortality worldwide – in 2018, approximately 1.76 million deaths were in direct relation with lung cancer. Concurrently, in Eastern Europe and Romania, statistics imply that lung cancer incidence and mortality rates have been on a rising trend since 1990(1). In Europe, in 2018, lung-cancer mortality ranked highest, with 24.8% for males and 14.2% for females(2).
Lung cancer is comprised of two main subtypes: 20% of the disease cases are classified as small-cell lung cancer (SCLC) and the rest of 80% of the disease is categorized as non-small-cell lung cancer (NSCLC). Globally, the most common histology of NSCLC is represented by adenocarcinoma, although Romania has insufficient incidence data regarding the histology of lung cancer cases. Lung adenocarcinoma has been further classified into non-squamous lung carcinoma subgroup. The so-called “classical chemotherapy” in NSCLC is selected based on the main histological and pathological descriptions.
But with the recent introduction of immunotherapy into lung cancer treatments, the therapy options have been truly transformed. This kind of therapy presents efficacy in both non-squamous and squamous carcinomas.
Clinical trials demonstrated that patients with NSCLC and driver mutation – such as epidermal growth factor receptor (EGFR) gene mutation or anaplastic lymphoma kinase (ALK) rearrangements – do not respond to immunotherapy(3).
Currently, the main compounds used in the immunotherapy of lung cancer lacking a driver mutation are the inhibitors of programmed death-1 (PD-1) and programmed death-1-ligand 1 (PD-L1) proteins. These proteins are also being investigated for applicability as predictive biomarkers for the indication of immunotherapy, despite the fact that much remains to be yet discovered(4).
In this review, we discuss the main studies with PD-1 and PD-L1 inhibitors in lung cancer, studies that demonstrated the superiority of PD-1 and PD-L1 inhibitors to chemotherapy. We also present the combinations of these compounds with chemotherapy, and the attempts to introduce immunotherapy with PD-1 and PD-L1 inhibitors for patients with EGF gene mutations.
2. Immunotherapy versus chemotherapy in advanced nsclc
Anti-PD-1 therapy studies have documented an overall survival benefit and improved quality of life with immunotherapy in metastatic and/or previously treated NSCLC populations(5).
A member of the immune blockade PD-1/PD-L1 is nivolumab, a fully human IgG4 isotype antibody which has been first studied in the metastatic, pre-treated NSCLC setting. Given the positive results and the encouraging median overall survival odds(6), nivolumab has been furthermore tested in different settings.
CheckMate 017 confirmed the highly anticipated favorable results, concluding that nivolumab versus docetaxel in pretreated, advanced or metastatic squamous cell lung carcinoma was superior, with a median overall survival of 9.2 months (95% confidence interval [CI]; 7.3 to 13.3) for the nivolumab arm as compared with the docetaxel arm: 6 months (95% CI; 5.1 to 7.3)(7). Similarly, for the non-squamous histology subtype of NSCLC, in the CheckMate 057 trial, nivolumab was superior to docetaxel regarding overall survival. The median overall survival was 12.2 months (95% confidence interval [CI]; 9.7 to 15) in the nivolumab group, and 9.4 months (95% CI; 8.1 to 10.7) in the docetaxel group (hazard ratio for death: 0.73; 95% CI; 0.59 to 0.89; P=0.002)(8).
But as for first-line therapy in advanced NSCLC with PD-L1 positive staining (≥1%), CheckMate 026 did not show the superiority of nivolumab over chemotherapy, with a median progression-free survival of 4.2 months for nivolumab, compared to 5.9 months for chemotherapy (stratified hazard ratio [HR]=1.15; 95% CI; 0.91-1.45; p=0.25)(9). Currently, the available data do not support the use of nivolumab in the first-line setting of advanced NSCLC, indicating that it is best used when mutational burden increases, as is with tumor progression after chemotherapy. Also, new biomarkers and predictors of response to specific clinical therapies (e.g., tumor mutational burden [TMB], PD-L1 presence in the tumor microenvironment and CD8+ tumor infiltrating lymphocytes) are emerging along with clinical research regarding immunotherapy(10,11).
In this respect, KEYNOTE-024 and KEYNOTE-010 studies further concluded that the anti-PD-1 monoclonal antibody pembrolizumab has antitumor activity on cancer cells that overexpresses the PD-L1 protein on their surface, in advanced or metastatic chemotherapy-naïve NSCLC, without ALK-translocation or EGFR-sensitizing mutations(12,13). KEYNOTE-010 compared pembrolizumab to docetaxel in pretreated, advanced NSCLC with at least 1% PD-L1 expression on tumor cells, subsequently displaying pembrolizumab superiority with regards to overall survival. The median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel.
The overall survival (OS) was substantially longer for pembrolizumab 2 mg/kg compared to docetaxel (hazard ratio [HR] 0.71; 95% CI; 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg compared to docetaxel (HR: 0.61; 0.49-0.75; p<0.0001).
KEYNOTE-024 confronted pembrolizumab versus platinum backbone chemotherapy in advanced and untreated setting of NSCLC with PD-L1 expression of at least 50% and no ALK/EGFR driver mutation present with similar findings; the estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (HR for death: 0.60; 95% CI; 0.41 to 0.89; P=0.005).
In October 24, 2016, pembrolizumab received the FDA approval for the first-line therapy of metastatic NSCLC tumors that harbor high surface PD-L1 overexpression (tumor proportion score ≥50%), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations, and also for the therapy of metastatic NSCLC patients whose tumors have PD-L1 overexpression of ≥1% and progressive disease on or upon previous platinum-containing regimens(14).
Furthermore, atezolizumab, a fully engineered human anti-PD-L1 antibody which inhibits both PD-1 and B7-1, has been studied for efficacy and safety profile: FIR phase II study showed high response rates for IIIB/IV NSCLC patients, consistently with tumor PD-L1 expression, in both chemotherapy-naïve patients and also in pretreated ones. The duration of the objective response (DOR) according to RECIST v1.1 in a timeframe up to 20 months in chemotherapy-naïve cohort was 9.2 months, 17.2 months for patients who had previously received one or more platinum-containing therapy line, and not reached (NR) for the cohort of patients who had asymptomatic pretreated brain lesions and one or more platinum lines of therapy(15).
In POPLAR study, the favorable results of atezolizumab have been compared to standard docetaxel in platinum pre-treated, metastatic/locally advanced NSCLC setting. The duration of response (DOR) in a timeframe of 28 months (first data cutoff) was 7.2 months for docetaxel arm, and 18.6 months for atezolizumab arm (HR=0.32; CI 95%; 0.15 to 0.70; p=0.0028)(16).
Improved efficacy and safety profile were noted among subgroups with high PD-L1 expression (OS HR=0.46; PFS HR=0.57 and ORR=38% versus 13%) compared to patients with low PD-L1 levels (OS HR=1.12; PFS HR=1.17; ORR=8% versus 10%)(17).
These conclusions were further confirmed by the first phase III study OAK(18), with anti-PD-L1 therapy (atezolizumab) showing superiority to standard chemotherapy (docetaxel) in previously treated advanced NSCLC, regardless of PD-L1 expression. In the intention-to-treat (ITT) population, the median survival was higher in atezolizumab arm versus docetaxel arm (13.8 months [95% CI; 11.8-15.7] versus 9.6 months [8.6-11.2]; hazard ratio [HR] 0.73 [95% CI; 0.62-0.87]; p=0.0003). The patients with low or undetectable PD-L1 also benefited from the treatment with atezolizumab (median overall survival 12.6 months versus 8.9 months; HR 0.75 [95% CI; 0.59-0.96]). Grade 3/4 toxicities were higher in the docetaxel arm – 247 (43%) of 578 patients(19).
Anti-PD-L1 immunotherapy is reserved at this moment for metastatic NSCLC that have previously progressed during or after platinum-containing chemotherapy(20).
3. Immunotherapy in the preoperative (neoadjuvant) setting
Immunotherapies have received ratification and have now changed the algorithms of therapeutic approaches. Currently, there is a rising interest in exploiting this new approach also in the early stages of lung disease. There are a number of ongoing studies that aim to document whether immunotherapy in neoadjuvant setting could prove beneficial:
NCT03158129 – a phase II, randomized, open label study with the primary goal of determining which induction therapy is best for stage I-IIIA NSCLC amenable for curative resection (the combinations tested are (1) nivolumab alone, (2) nivolumab + ipilimumab, (3) nivolumab + platinum-combination chemotherapy).
NCT03081689 – a phase II, open label, single arm study of combined neoadjuvant chemotherapy and immunotherapy with nivolumab + paclitaxel and carboplatin in resectable stage IIIA-N2 NSCLC, followed by adjuvant immunotherapy for 12 months with nivolumab.
NADIM II: Neo-Adjuvant Immunotherapy (NADIMII) – NCT03838159 – a phase II, randomized open label, two-arm trial assessing the pathological response in surgical specimens of IIIA/IIIB NSCLC patients treated with chemo-immunotherapy versus chemotherapy alone.
NCT03366766 – a phase II, interventional, open label, non-randomized trial to assess the major pathologic complete response in newly diagnosed stage I-IIIA NSCLC with neoadjuvant (1) nivolumab, cisplatin and pemetrexed in non-squamous lung carcinoma and (2) nivolumab, cisplatin and gemcitabine in squamous lung carcinoma.
CheckMate 816 (NCT02998528) – a phase III, open label, randomized trial of nivolumab and ipilimumab versus nivolumab plus platinum doublet therapy in IB-IIIA resectable NSCLC.
NCT03217071 (PembroX) – a phase II, interventional, open label randomized trial of neoadjuvant pembrolizumab (1) and pembrolizumab concurrently with single dose (12 Gy) of stereotactic radiation therapy (2) followed by curative intent surgical resection of I-IIIA NSCLC patients. The primary endpoint is the change in number of T CD3+ cells in tumor tissue from before/after pembrolizumab and the secondary endpoint is overall survival (time-frame: 1 year from surgery).
NCT02818920 (TOP1501) – a phase II, open label, interventional, single-group assignment of neoadjuvant pembrolizumab (two cycles) followed by curative intent surgery and by adjuvant standard chemotherapy (the physicians’ choice) for IB-IIIA NSCLC patients. Primary endpoint: surgical feasibility rate. Secondary endpoint: percentage of patients having complete/partial response rate (RECIST 1.1).
KEYNOTE-671 – a phase III, interventional, randomized (parallel assignment), double-blind study assessing (1) neoadjuvant pembrolizumab concurrently with platinum-doublet chemotherapy followed by surgery and (2) neoadjuvant platinum-doublet chemotherapy + placebo followed by surgery for resectable IIB-IIIA NSCLC cases. The primary endpoint was the event-free survival and the overall survival.
IMpower 030 (NCT03456063) – a phase III, multi-center, randomized, double-blind trial assessing (1) neoadjuvant atezolizumab plus combination platinum-containing chemotherapy versus (2) neoadjuvant placebo plus combination platinum-containing chemotherapy in II-IIIA and selected IIIB NSCLC patients suitable for surgery. Primary endpoint: major pathological response (≤10% residual viable tumor). Secondary end-point: overall survival.
NCT02927301 – a phase II, open-label, multicenter, non-randomized clinical trial evaluating the major pathologic response for neoadjuvant (two cycles prior to surgery) and adjuvant (up to 12 months for those demonstrating clinical benefit) atezolizumab in IB-IIIA and selected IIIB NSCLC amenable to curative surgery.
4. Immunotherapy in driver mutation positive NSCLC
C.Y. Yang et al. found that there was no correlation between PD-L1 expression and ALK, EGFR, KRAS and BRAF in pulmonary adenocarcinoma resected specimens (stage I)(21), but K. Azuna et al. found that the high expression of PD-L1 was associated with the presence of EGFR mutations in surgically resected NSCLC (stages I-IIIB)(22). However, retrospectively, EGFR activation mutation has been found to influence PD-L1 expression via an incompletely known pathway on tumor cell surface and to be significantly strongly correlated with adenocarcinoma histology, never/former smoker status and female gender(23). The various opinions could reflect the tumor versus host microenvironment and the evolution from stage I to IV, but there is more yet to be clarified.
Both overall survival (OS) and progression-free survival (PFS) were improved in patients with EGFR-mutant non-squamous cell lung cancer (NSCLC) who were treated with the combination of atezolizumab (Tecentriq®), bevacizumab (Avastin®), and chemotherapy compared with bevacizumab plus chemotherapy, according to an exploratory analysis of the IMpower150 study(24).
IMpower150 is focused on the combination of check-point inhibitors with chemotherapy and VGFR inhibitors, a combination which could give better results in the treatment of non-squamous NSCLC with EGFR mutation and ALK translocation.
To our knowledge, OAK is the first randomized phase III study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel, in previously treated, non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favorable safety profile(25,26).
Also, the OAK study and subgroup assessments of several phase III trials comparing immunotherapy to docetaxel (CheckMate 057, KEYNOTE-001) showed no difference in the overall survival with immunotherapy in EGFR-mutant patients compared to docetaxel.
5. Combination with other therapies
The striking success of checkpoint inhibition in the treatment of certain tumors has reinvigorated cancer research into therapeutic vaccines. Although, historically, lone vaccine treatments for cancer hold a modest track record, combining them with checkpoint inhibitors, which override a tumor’s ability to escape detection, may turn “hot cancers even hotter,” said James Gulley (MD, PhD), chief of the genitourinary malignancies branch at the National Cancer Institute in Bethesda, Maryland, USA(27).
KEYNOTE-189 data: FDA granted approval for the combination of the PD-1 inhibitor pembrolizumab (Keytruda®) plus standard-of-care chemotherapy (i.e., pemetrexed [Alimta®] plus cisplatin or carboplatin) in the first-line setting for patients with stage IV non-squamous NSCLC and no EGFR, or ALK genomic tumor aberrations(28).
The European Commission approved Merck’s Keytruda® (pembrolizumab) in combination with pemetrexed and platinum chemotherapy for the first-line treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations (press release; Kenilworth, NJ: Merck; September 10, 2018)(29).
FDA approved the first-line pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane®) for patients with metastatic squamous NSCLC. The approval is based on the results from the phase III KEYNOTE-407 trial, in which combining pembrolizumab with chemotherapy reduced the risk of death by 36% compared with chemotherapy alone in this population. The median overall survival was 15.9 months (95% CI; 13.2 – not evaluable) with pembrolizumab versus 11.3 months (95% CI; 9.5-14.8) with chemotherapy alone (HR: 0.64; 95% CI; 0.49-0.85; P=0.0017)(30).
The integration of immunotherapy with radiotherapy has been a subject of a multiple preclinical studies which have demonstrated that RT induced immunomodulatory effects in the local tumor microenvironment, supporting a synergistic combination approach with immunotherapy to improve the systemic control. Immunotherapy options that could be combined with RT include programmed cell death-1/programmed cell death ligand-1 blockers, as well as investigational agents such as OX-40 agonists, toll-like receptor agonists, indoleamine 2,3-dioxygenase-1 inhibitors and cytokines. We can also discuss at this point about the post chemo-radiotherapy combination of “consolidation therapy” with durvalumab. FDA approved durvalumab for the aforementioned indication, following the results from PACIFIC trial(31).
At this moment, there is not clear for which patients the combination of radio- and immunotherapy could bring the greatest benefit regarding the response rate and the overall survival. We wait for ongoing studies to answer these questions, and future research is also needed(32).
Nivolumab, pembrolizumab and atezolizumab achieved amazing results for patients who progressed to a first-line setting with squamous and non-squamous histology. All these three agents improve survival when compared with standard docetaxel. The correlation of response with PD-L1 expression is not reliable, but still in use in clinical practice.
At present, these immunotherapy agents were moved from the second-line to the front-line setting, with a statistically significant benefit survival when compared with platinum-based chemotherapy.
Nowadays, a multitude of clinical trials are ongoing to evaluate different immune checkpoint agents in first line, in monotherapy or in combination therapy with chemotherapy or other immunotherapy agents with or without PD-L1 expression analysis as an inclusion criterion. We have already seen approvals of these drugs combined with chemotherapy.
Another important finding of immunotherapy is that lung cancer patients who smoke show a better response to immunotherapy than non-smokers, but non-smokers also respond to immunotherapy.
The study with checkpoint inhibitors agents demonstrated that some of them have activity in the second-line therapy and also for patients treated before with TKIs and ALKs inhibitors. For this last category of patients, the combination of chemotherapy and PD-L1 inhibitors demonstrated efficacy in terms of response rate and survival.
For these reasons, we consider that immunotherapy has changed the paradigm of treatment in advanced non-small-cell lung cancer.
Conflict of interests: The authors declare no conflict of interests.