Risk and safety profile in checkpoint inhibitors on non-small-cell lung cancer: A systematic review

ABSTRACT

Treating non-small-cell lung cancer (NSCLC) has gained increased importance in recent years due to the high mortality rate and dismal five-year survival rate. Immune checkpoint inhibitors (ICI) are a promising approach with exceptional outcomes in NSCLC thanks to the antigenic nature of cells. Conversely, immune system over-stimulation with ICI is a double-edged sword that can lead to various negative effects ranging from mild to life-threatening. This review explores current breakthroughs in nanoparticle-based ICI and their limitations. The PubMed, Scopus and Web of Science were examined for relevant publications. Thirty-eight trials (N = 16,781) were included in the analyses. The mixed effects analyses on quantifying the treatment effect contributed significantly to the subgroups within studies for ICI treatment effect. Models confirmed ICI’s higher impact on treatment effectivity and the decrease in respondents’ mortality compared to conventional treatment regiments. ICI might be used as first-line therapy due to their proven effectiveness and safety profile.

KEYWORDS:

• Adverse event
• anti-tumor immunity
• checkpoint inhibitors
• non-small-cell lung cancer
• review

Background

Lung cancer has the highest rates of morbidity and mortality, with an estimated 2.3 million diagnoses and 1.8 million deaths in 2021.^1,2 Non-small cell lung cancer (NSCLC) is its most common histological type, with a 5-year survival rate of 2.8%; having a poor prognosis, since most afflicted persons are diagnosed at an advanced stage, making it difficult to treat.^3–5

Immune checkpoint inhibitors (ICI) are perspective innovative immunotherapeutic drugs that work by blocking the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) or CTLA-4 pathways to reactivate T-lymphocytes targeting tumors. An accumulating amount of evidence shows that ICI may improve clinical outcomes in patients with advanced NSCLC.^6,7 ICI provide long-lasting responses in an increasing percentage of patients with metastatic cancer and are widely employed in (neo)adjuvant situations. Based on these results, the United States Food and Drug Administration (FDA) approved ICI as first-line therapies for advanced NSCLC. When used as first-line therapy, ICI have a 5-year survival rate of 23% compared to other treatments with survival below 16%.⁸

However, immunostimulants can cause targeted hyperactivation of the immune response, which may lead to normal tissue damage.⁹ While acute toxicities are more prevalent, chronic immune-related adverse events (irAEs) are becoming more recognized, as they may occur in up to 40% of patients.¹⁰ Other long-term concerns include fatal irAEs (FAEs), occurring in 0.4%–1.2% of patients.¹⁰ The occurrence of irAEs like rashes, colitis, hepatitis, myocarditis, endocrinopathies, and pneumonitis has been regularly documented.¹¹ Although FAEs are uncommon, they may occur due to overwhelming autoinflammation resistant to steroids and/or other immunosuppressive agents.¹⁰ When deciding treatment, oncologists should evaluate the FAEs possibility.

Pneumonitis, also known as checkpoint inhibitor pneumonitis (CIP), is one of the most serious irAEs.^12–14 Immune checkpoint inhibitors cause immune dysregulation, which is associated with CIP, despite their unclear mechanism of action. Even while CIP is documented to occur in 3% to 5% of the population, it is associated with a mortality rate of 10% to 17%; conversely, CIP morbidity varies from 7% to 13% in NSCLC patients.^12–15–17 CIP is most frequent in the first 6 months after a course of therapy.^12,18 Although most irAEs are moderate (grade 1 or 2), in less than 10% of patients treated with immune checkpoint inhibitors, severe (grade 3 or 4) and possibly life-threatening irAEs (grade 5) may occur.¹⁹ Meta-analyses indicate they occur at a modest incidence, ranging from 0.4% with monotherapy to 1.2% with combination anti- regimens.¹⁰ It is possible that growing levels of pre-existing autoantibodies are responsible for the development of immune-related adverse events.²⁰ However, particular antibodies related to CIP are now being investigated in more depth than either of these conditions. Additionally, a rise in inflammatory cytokines is associated with the irAEs development. NSCLC patients after receiving atezolizumab who developed CIP exhibited greater C-reactive protein and interleukin-6 (IL-6) levels than those who did not develop CIP.²¹ Cytokines may also be used as predictors of negative outcomes, and their elevated expression is linked with significant ICI toxicity.^22–24 While patients receiving chemotherapy had a greater risk of mortality due to myelosuppression and infection, those receiving immunotherapy faced a greater risk of death due to CIP.^25–27

Survival, efficiency, together with irAEs are the most relevant markers for the safe and sufficient NSCLC treatment when comparing the ICI risk versus benefit. Thus, the aim of this systematic review was to explore and compare the effectiveness and safety profile of ICI alone or in combination with conventional agents against an active comparator or placebo between and across clinical trials and moderated by the grades of Common Terminology Criteria for Adverse Events (CTCAE). Furthermore, objective response rate of ICI was to validate on the treatment effect and the absolute number of deaths across study arms subgroups.

Methods

Sources of data and search

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. We examined PubMed, Scopus and Web of Science (WoS) from January 2015 to December 2021 for relevant articles published in English. The preliminary results were checked by ClinicalTrials.gov. Non-small lung cancer, adverse event, immune checkpoint inhibitors (anti-programmed cell death 1, anti-programmed cell death ligand 1, anti-cytotoxic T-lymphocyte associated antigen 4), and particular ICI medication names were included in the search approach (ipilimumab, selumetinib, tremelimumab, nivolumab, pembrolizumab, atezolizumab, cemiplimab, durvalumab). We further evaluated possibly relevant papers (N = 512) after a preliminary review of titles and abstracts.

Selection of studies with quality control

Due to the absence of specific safety data and first-hand clinical results, conference abstracts, posters, reviews, position statement, not written in English and reports not retrieved, case studies, and editorials were eliminated (n = 305). Additionally, laboratory, non-clinical studies, papers on more malignancies than NSCLC, and findings on quality of life, as well as studies assessing other immune therapies on a summary, but did not provide data on site, organ, or system-level toxicity, retrospective and observational studies, and purposes of the study were omitted (n = 169). Only randomized controlled studies in individuals with NSCLC comparing therapies that included an ICI medicine or comparing an ICI agent to conventional monotherapy were eligible. Additionally, studies comparing various dosages or administration locations (pharmaceutical forms, effectiveness, and administration sites) of a single ICI medication were considered. In addition, high-quality single-arm and placebo-controlled studies were chosen to form a validation group. The ongoing study with preliminary results on survival or results on irAEs was also included into analyses. Finally, studies were controlled with a technique provided by the Cochrane Collaboration Handbook, which evaluated the bias risk from the original research.^28,29 The appropriateness of five areas was evaluated: the production of random sequences, the concealment of allocations, the blinding procedure, the evaluation of outcomes, and the reporting of findings.²⁸ Each element was given a risk of bias assessment index assessed as yes, no, or uncertain based on the bias likelihood. With the use of the modified Jadad scale, it was possible to statistically measure the investigations’ method quality (high quality, four points and over; or low quality, three points and under).³⁰ Every opinion difference about the selection of studies, data extraction, and control of the data quality was handled via discussion to reach a common understanding. Only scores three and up were chosen for final analyzed models. In total, 38 studies were included in the definite analyses. (Please, see Figure 1 for detailed information.)

Figure 1. Flowchart diagrams of design and study selection procedure.

Data extraction

Despite the fact that irAEs were assumed to represent the result of interest, it was discovered that this phrase was inadequate for describing the toxicity associated with standard treatment. In line with that, some AE may not be due solely to immunotherapy, but to other potential causes. It was decided that all adverse events would be utilized if treatment-related adverse events (TEAEs) were not available in research. We chose TEAEs as the main outcome, along with survival data, because they were consistent with most studies and considered a viable alternative to immune-related adverse events. The primary text was analyzed to conduct a comprehensive and thorough data extraction procedure on the clinical trials database. The original articles represented in a single trial were built-in the mixed effects analyses. However, TEAE was retrieved that had provided the most comprehensive report. The other data were used to augment rudimentary information. Data were extracted as well as summarized based on the following information from the studies reports: authors, ClinicalTrials.gov number, phase of clinical trial, year of publication, follow-up time, total number of patients, number of patients in safety analysis, treatment regimens, survival up to 12 months, overall survival and hazard ratio as an indicator of treatment effect, absolute number of deaths, TEAEs, the presence of CIP, and the CTCAE. Treatment regiments of studies papers were divided into three basic groups: i) immune checkpoint inhibitors, ii) active comparator, like cytostatics and immunotherapies (monoclonal antibodies, biological therapy, mRNA vaccine) as well as radiotherapy, and iii) placebo. Moreover, ICI were split up by using their target. (Please, see Figure 2 for detailed information).

Figure 2. Flowchart of treatment regimens used in the studies papers.

The standardized CTCAE is the most widely used instrument in clinical practice for irAEs severity assessing, due to including a grading system and explicit descriptions for each irAE category.³¹ All grades of side events imply total, severe, and life-threatening toxicity, according to their severity.³¹ The CTCAE displays grades 1 through 5 with unique clinical descriptions of severity for each immune-related adverse event: grade 1: mild, asymptomatic, or mild symptoms; clinical or diagnostic observations only; intervention not indicated; grade 2: moderate, minimal, local, or noninvasive intervention indicated; grade 3: severe or medically significant, but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; grade 4: life-threatening consequences, urgent intervention indicated; grade 5: death related to irAEs.³¹ Presence of CIP and CTCAE Grade were defined by more than or equal to 10% of the study sample, significant prevalence in cohorts, and/or as positive presentation in the analyzed paper.

Involvement of patients and the general public

Patients were not involved in the formulation of the review question or results evaluation. No patients were contacted for input on the interpretation or writing up of the data. The outcomes will not be shared with research participants or the relevant patient group. All studies included into analyses were in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments, or comparable ethical standards in the informed consents for clinical trials included into this review.

Data synthesis and statistical analysis

Frequencies, durations, percentages, total numbers, medians, means, and standard deviations were calculated for the descriptions. Two different perspectives evaluated TEAEs: overview and detail, based on the total number of all TEAEs and the number of each specific TEAE, respectively. Regardless of the irAE grading, general safety was used to indicate the TEAEs overview without distinguishing between their specific classifications. Next, grades (1–5) of CTCAE were stratified into two groups: G-I: low (grade 1 + 2) and G-II: serious (grade 3 + 4); grade 5 was only confirmed in 4 studies; therefore, it was allied to the serious stratified group (G-II). Study subgroups were stratified according to the study arms: interventional drug versus comparator. Firstly, two studies with more than 3 study arms were split into 3 subgroups; secondly, arms were divided in two divisions: interventional and conventional therapy. Finally, we performed mixed effects analyses. A random effects model was used to combine studies within each subgroup, and a fixed effect model was used to combine subgroups and yield the overall effect. Regardless of the study arms, subgroup analyses were performed for the total number of TEAEs, survival with the presence of checkpoint inhibitor pneumonitis, hazard ratio, as well as the absolute number of deaths. So far, analyzed models were moderated by G-I versus G-II of CTCAE. Forrest plots were generated depicting the risk ratio, and 95% confidence interval of study models using mixed effects analyses and p-values lower than or equal to 0.01 were considered significant. GraphPad Prism 9.3.0 and Comprehensive Meta Analysis version 3.0 were used for statistical analyses.

Results

Systematic review and characteristics of the reviewed studies

After checking all inclusion and exclusion criteria, 38 papers (N = 16,781) published between January 2015 and December 2021 were included into analyses definitely (please, see Figure 1). Studies duration occurred from 3 to 53 months (29 ± 9). Survival up to 12 months varied from 18% to 69% (28 ± 8%) and median of overall survival between 6.0 and 20.2 months (9.1 ± 2.2). 94.7% (36/38) of included studies were in advanced (III-IV) stage of disease and consisted of 21 different active drugs with different doses and cycles as well as different combinations; 6 studies evaluated one interventional treatment with one dose without any comparator, 9 trials had one study arm with solo ICI or not only ICI, 2 studies were controlled by combination with placebo, and 1 study was compared with solo placebo. So far, monotherapy with Nivolumab (n = 2332) was controlled by six comparators, Atezolizumab (n = 2006) by 8, Pembrolizumab (n = 2078) by 6, Durvalumab (n = 1473) by 8, CTLA-4 inhibitors (Tremelimumab, Selumetinib) (n = 60) by 3, combination of 2 ICI (n = 1253) by 3, and combination of ICI with conventional therapy (n = 2313) by 10 comparators. Conventional therapy (n = 3150) was linked to 14 ICI (monotherapy or its combinations), two or more conventional therapies (n = 1308) to 6 ICI combinations and pooled conventional therapy with placebo (n = 808) was connected with ICI 4-times. Mixed effects analyses based on total number of TEAEs was firstly conducted to investigate the comparability of TEAEs. In the consistency model, we found non-significant differences in the total number of TEAEs between studies independent of stages of NSCLS. The results obtained using the consistency model fit well with the results using the inconsistency model. These results showed that the safety of all investigated and compared drugs in the studies was similar. (Please, see Table 1 for detailed information of the studies characterization).

Table 1. Characteristic of included studies.

First Author Publication year	ClinicalTrials.gov Clinical phase	Study sample	Tumour stage	Treatment regiment		Survival (median in months)	TEAE (total No)		CIP (yes/no)		CTCEA (Grade)
Brahmer et al., 2015^Citation6	NCT01642004 phase 3	272	IIIB-IV, NA	NIVO 3mg/kg IV Q2W	9.2			9		yes		3–4
				TXT 75 mg/m^2 IV Q3W	6.0
Shu et al., 2020^Citation32	NCT02716038 phase 2	30	IB-IIIA	ATE 1200 mg/kg IV Q3W	12.9			5		no		3–4
				NP 100 mg/m^2 IV Day1, 8, 15 Q3W	14.3
				CBP AUC 5 IV Q3W	17.9
Garon et al., 2015^Citation33	NCT01295827 phase 1	495	III-IV	PEM 2 or 10 mg/kg IV Q3W	10.9			4		yes		3–4
				PEM 10mg/kg IV Q2W
Gandhi et al., 2018^Citation34	NCT02578680 phase 3	616	III-IV	PEM 200 mg IV + PEME 500 mg/m^2 + CIS 75 mg/m^2 IV or CBP AUC 5 IV Q3W 4 cycles, then PEM 200 mg IV + PEME 500 mg/m^2 Q3W	12			11		no		3
				PEM 100 mg IV Q3W + SBRT	11.3
Rizvi et al., 2015^Citation35	NCT01721759 phase 2	117	IIIB-IV	NIVO 3 mg/kg IV Q2W	8.2			4		yes		1–2
Rizvi et al., 2020^Citation36	NCT02453282 phase 3	1118	IIIB-IV	DUR 20mg/kg IV Q4W	16.3			7		no		3–4
				DUR 20mg/kg IV Q4W + TREM 1mg/kg IV Q4W up to 4 doses	11.9#
				DUR 20mg/kg IV Q4W + PTX + CBD	12.9
Chen et al., 2020^27	NCT0223900 phase 1	241	IV	anti-CTLA-4 3 mg/kg IV Q3W 2 cycles + SBRT	10.7			8		no		3–4
	NCT02444741 phase 1+2			PEM 100 mg IV Q3W + SBRT	8.3
Planchard et al., 2020^Citation37	NCT02352948 phase 3	595	IV	DUR 10mg/kg IV Q2W	11.7			11		yes		3
				ERL 150mg PO QD + VIN 30 mg/m^2 IV Day1, 8, 15, 22 or GEM 1000 mg/m^2 IV Day1, 8, 15	6.8
				DUR 20mg/kg IV Q2W + anti-CTLA-4 1mg/kg IV Q4W, then DUR 10mg/kg IV Q2W	11.5
				DUR 10mg/kg IV Q2W up to year	10.1
				anti-CTLA-4 10mg/kg IV Q4W 24 weeks, then by Q12W up to 9 doses	6.9
				ERL 150mg PO QD + VIN 30 mg/m^2 IV Day1, 8, 15, 22 or GEM 1000mg/m^2 IV Day1, 8, 15	8.7
Soria et al., 2017^Citation38	NCT01750281 phase 2	212	III-IV	SEL 75mg PO BID + TXT 60 mg/m^2 IV Q3W	5.7			5		yes		3
				SEL 75mg PO BID + TXT 75 mg/m^2 IV Q3W	7.7
				Placebo PO BID + TXT 75 mg/m^2 IV Q3W	11.5
Vergnenegre et al., 2020^Citation39	NCT03801304 phase 2	12	IV	ATE 1200mg IV Q3W + VIN 40mg PO QD Day1,3,5 Q3W	NA			4		no		1–2
Garassino et al., 2020^Citation40	NCT02087423 phase 2	444	III-IV	DUR 10mg/kg IV Q2W up to year	13.2			7		yes		3–4
Felip et al., 2020^Citation41	NCT02409368 phase 2	811	III-IV	NIVO 3mg/kg IV Q2W	10.0			6		yes		3–4
von Pawel et al., 2019^Citation42	NCT02008227 phase 3	1225	III-IV	ATE 1200 mg IV Q3W	11.9			15		yes		3
				TXT 75 mg/m^2 IV Q3W	16.0
Gettinger et al., 2015^Citation43	NCT00730639 phase 1	129	IV	NIVO 1 mg/kg IV Q2W 8 cycles up to 96 weeks	9.2			4		yes		3–5
				NIVO 3 mg/kg IV Q2W 8 cycles up to 96 weeks	14.9
				NIVO 10 mg/kg IV Q2W 8 cycles up to 96 weeks	9.2
Gettinger et al., 2021^Citation44	NCT02785952 phase 3	252	IV	NIVO 3mg/kg IV Q2W	10			10		yes		3
				NIVO 3mg/kg IV Q2W + anti-CTLA-4 1mg/kg IV 3 cycles	11
Herbst et al., 2020^Citation45	NCT02409342 phase 3	572	IV	ATE 1200mg/kg IV Q3W	20.2			6		yes		3–4
				CIS 75 mg/m^2 IV or CBP AUC 6 IV 4or6 cycles Q3W + PEME 500mg/m^2 IV Q3W	13.1
				CIS 75 mg/m^2 IV + GEM 1250 mg/m^2 IV Q3W or CBP AUC 5 IV Q3W 4or6 cycles + GEM 1000 mg/m^2 IV Q3W
Herbst et al., 2016^Citation46	NCT01905657 phase 2+3	1034	III-IV	PEM 2mg/kg IV Q3W	10.4			9		yes		3–4
				PEM 10mg/kg IV Q3W	12.7
				TXT 75 mg/m^2 IV Q3W	8.5
Fehrenbacher et al., 2016^Citation47	NCT01903993 phase 2	287	III-IV	ATE 1200mg IV Q3W	9.7			13		no		3
				TXT 75 mg/m^2 IV Q3W	12.6
Jabbour et al., 2021^Citation48	NCT03631784 phase 2	216	III	CBP AUC 6 IV + PTX 200 mg/m^2 IV + PEM 200 mg IV, then CBP AUC 2 IV + PTX 45 mg/m^2 IV QW 6 weeks, then PEM 200 mg IV Q3W + TRT 2 cycles	9.1^§			4		no		3–5
				CIS 75 mg/m^2 IV 3 cycles + PEME 500 mg/m^2 IV + PEM 200 mg IV Q3W + TRT 2+3 cycles, additional PEM 200 mg IV Q3W 14 cycles	7.7^§
Peters et al., 2019^Citation49	NCT02434081 phase 2	82	III	NIVO 360mg IV + SBRT	NA			3		yes		3–5
				Platinum-based IV 3 cycles
Hellmann et al., 2019^Citation50	NCT02477826 phase 3	1189	III-IV	NIVO 3 mg/kg IV Q2W + anti-CTLA-4 1 mg/kg IV Q6W	17.1			7		no		3–4
				NIVO 240mg IV Q2W
				Platinum-doublet Q3W 4 cycles	14.9
Besse et al., 2020^Citation51	NCT02451930 phase 1	71	III-IV	PEM 200 mg IV Q3W, then NECI 800 mg IV Day 1, 8 Q3W	NA			12		no		2
Borghaei et al., 2015^Citation52	NCT01673867 phase 3	582	III-IV	NIVO 3 mg/kg IV Q2W	12.2			14		no		3
				TXT 75 mg/m^2 IV Q3W	9.4
Wu et al., 2019^Citation53	NCT02613507 phase 3	504	III-IV	NIVO 3 mg/kg IV Q2W	12			8		yes		3
				TXT 75 mg/m^2 IV Q3W	9.6
Wu et al., 2021^Citation54	NCT02220894 phase 3	1274	III-IV	PEM 200mg IV Q3W 35 cycles	20.1			10		no		3–5
				CBP AUC 5 Q3W + PTX 200mg/m^2 IV Q3W or TXT 75 mg/m^2 IV +PEME 500mg/m^2 IV Q3W	12.2
Kowanetz et al., 2018^Citation55	NCT01846416 phase 2	1092	III-IV	ATE 1200 mg IV Q3W				15		yes		1–2
	NCT01903993 phase 2			TXT 75 mg/m^2 IV Q3W	9.7
				ATE 1200mg IV Q3W	13.2
	NCT02031458 phase 2			ATE 1200mg IV Q3W
Sakai et al., 2020^Citation56	JIPANG-TR phase 3	374	II-IIIA	PEM 500mg/m^2 IV + CIS 75 mg/m^2 IV	52.5^§			NA		NA		NA
				VIN 25 mg/m^2 IV Day1,8 + CIS 80 mg/m^2 IV	72^§
Ready et al., 2019^Citation57	NCT02477826 phase 3	324	III-IV	NIVO 3mg/kg IV Q2W + anti-CTLA-4 1mg/kg IV Q6W	4.2			5		no		3–4
				NIVO 360mg IV Q3W + anti-CTLA-4 1mg/kg IV Q6W + Platinum doublet 2 cycles	8.7
Ouwens et al., 2021^Citation58	NCT02125461 phase 3	713	III	DUR 10mg/kg IV Q2W up to year	34.7			9		no		3
				Placebo Q2W up to year	22.9
Provencio et al., 2020^Citation59	NCT03081689 phase 2	46	IIIA	PTX 200mg/m^2 + CBP AUC 6 + NIVO 360mg Q3W, then surgery, followed by NIVO 240mg IV Q2W 4 months, followed by NIVO 480mg IV Q4W 8 months	24			6		yes		3–4
Osorio et al., 2017^Citation60	NCT01295827 phase 1	51	III-IV	PEM 1mg/kg IV Q2W	40			1		no		2
Paz-Ares et al., 2021^Citation61	NCT03215706 phase 3	719	IV	NIVO 360mg IV Q3W+ anti-CTLA-4 1mg/kg IV Q6W+ 2 Platinum-based IV Q3W 2 cycles	14.1			7		yes		3–4
				Cytostatics IV Q3W 4 cycles	10.7
Antonia et al., 2016^Citation62	NCT02000947 phase 1	102	III-IV	DUR 3, 10, 15 or 20mg/kg Q4W + TREM 1, 3 or 10mg/kg Q4W 6 cycles, then Q12W 3 cycles	47^§			5		no		3–4
Rudin et al., 2020^Citation63	NCT03066778 phase 3	453	III-IV	PEM 200mg IV Q3W 35 cycles + EP IV 4 cycles	10.8			6		yes		3–4
				Placebo 35 cycles + EP IV 4 cycles	9.7
Arrieta et al., 2020^Citation64	NCT02574598 phase 2	78	III-IV	PEM 200mg IV Day 8 Q3W + TXT 75 mg/m^2 IV Q3W	9^$			9		no		1–2
				TXT 75 mg/m^2 IV Q3W	5^$
Stratigos et al., 2021^Citation65	NCT03132636 phase 2	84	III-IV	CEM 350 mg IV Q3W 93 weeks	19^§			3		no		3–4
Middleton et al., 2020^Citation66	NCT02733159 phase 2	^Citation36	IV	PEM 200 mg IV Q3W maximum 2 years	NA			10		no		3–4
Reck et al., 2016^Citation7	NCT02142738 phase 3	305	III-IV	PEM 200 mg IV Q3W 35 cycles up to 2 years	8.0^‡			11		yes		3
				Platinum-based IV 4–6 cycles	6.3^‡

Abbreviations: ATE - Atezolizumab, AUC – area under the curve, BID – twice a day, CBP – Carboplatin, CEM - Cemiplimab, CIP - checkpoint inhibitor pneumonitis, CIS - Cisplatin, CTCEA - the Common Terminology Criteria for Adverse Events, CTLA-4 - cytotoxic T lymphocyte associated protein 4, DUR – Durvalumab, EP - Etoposide and platinum, ERL - Erlotinib, GEM - Gemcitabine, IV – intravenous, NA – not applicable, NIVO - Nivolumab, N^o – number, NP - Nabpaclitaxel, PEM - Pembrolizumab, PEME - Pemetrexed, PO – peroral, PTX – Paclitaxel, QD – once a day, QxW – each x week, SBRT - Stereotactic body radiotherapy, TERM - Tremelimumab, TRT - Thoracic radiotherapy, TXT - Docetaxel, VIN - Vinorelbine, # - ns vs DUR study arm, § - treatment, no survival, $ - approximately because of still ongoing (median for both groups is 8.9 months), ‡ - objective response rate because overall survival was not reached.

Analysis of drug-based treatments and treatment-related adverse effects

For all studies (n = 27; N = 14,609) in these mixed effects analyses, NSCLC patients were randomized according to their treatment subgroups. The study by Ready et al.⁵⁷ (p < .01) contributed significantly to random as well as fixed models on the subgroup analysis for total number of TEAEs. Moreover, risk ratio (RR) of trial by Ready et al.⁵⁷ for the interventional arms when compared to the conventional comparators was lower than 0.1. All other studies also showed that RR for the interventional arms versus the conventional comparators were lower than or equal to 1.0; however, they did not contribute significantly to the model. Standardised residual clarified no contrast in results between the fixed and random models. (Please, see Figure 3 for detailed information of the models). The similar summary for the subgroup with two study arms and the summary across all studies were obtained when the mixed effects analysis was grouped by study arms subgroups. (Please, see Figure 4 for detailed information of the models).

Figure 3. The model of drug-based network and TEAEs. Fixed-effect and randomised-effect models on the study arms subgroups containing the total number of TEAEs. Forrest plots depict the risk ratio of the favourable treatments versus comparators. The standardised residuals of both models are displayed.

Figure 4. The model of drug-based network and TEAEs. Fixed-effect and randomised-effect models on the study arms subgroups grouped by these subgroups containing the total number of TEAEs. Forrest plots depict the risk ratio of the favourable treatments versus comparators. The standardised residuals of both models are displayed.

Next, CTCAE Grades I vs II were defined as a categorical moderator variable; thus, the model was grouped by that variable and heterogeneity values was provided because of an analysis being run within each grade and an overall analysis across grades as well as within groups and between groups. As a result, the study by Ready et al.⁵⁷ (p < .01) contributed significantly to random and fixed models on the subgroup analysis for total number of TEAEs in Grade II of CTCAE as well as in overall model. RR for all studies across groups were lower or equal to 1.0 for the interventional arms versus the conventional comparators. Standardised residual clarified no contrast in results between models, like it was in the previous analysis. (Please, see Figure 5 for detailed information of the models).

Figure 5. The model of drug-based network and TEAEs. Fixed-effect and randomised-effect models on the study arms subgroups containing the total number of TEAEs were moderated by CTCEA Grade (G-I against G-II). The models were grouped by CTCEA Grade and heterogeneity values was provided because of an analysis being run within each grade and an overall analysis across these grades as well as within groups and between groups. Forrest plots depict the risk ratio of the favours treatments versus comparators. The standardised residuals of both models are displayed.

Analysis based on the survival rate and general life prosperity of NSCLC patients

Firstly, the analysis across groups for survival involved all studies (n = 38) and 16,781 patients. Secondly, all included trials compared their survival (in months) with one common comparator that is the most serious and fatal immune-related adverse event in clinical practice, such as checkpoint inhibitor pneumonitis, which has been the common comparator in many trials. Finally, only study by Ready et al.⁵⁷ (p < .001) contributed significantly to random and fixed models on survival analysis compared by CIP. Standardised residual clarified the contrast in results between models. (Please, see Figure 6 for detailed model information).

Figure 6. Model on survival compared by CIP between studies. Fixed-effect and randomised-effect models on clinical trials (n=38) containing survival were compared by the presence of CIP. Forrest plots depict the risk ratio of the favours treatments versus comparators. The standardised residuals of both models are displayed.

Next, 27 studies (N = 14,609) in this analysis on quantifying the treatment effect across studies using survival data was the log hazard rate. The study by Brahmer et al.⁶ (p < .001), Gandhi et al.³⁴ (p < .001), von Pawel et al.⁴² (p < .01), Herbst et al.⁴⁶ (p = .01), Borghaei et al.⁵² (p < .01), both studies by Wu et al.^53,54 (p < .01), Ouwens et al.⁵⁸ (p < .001), Paz-Ares et al.⁶¹ (p < .001), Arrieta et al.⁶⁴ (p < .001), and Reck et al.⁷ (p < .001) contributed significantly to random as well as fixed models on the subgroups within studies for ICI treatment effect. Standardised residual clarified the contrast in results random versus fixed models. (Please, see Figure 7 for detailed information of the models).

Figure 7. Model on survival compared by ICI treatment effect. Fixed-effect and randomized-effect models containing quantifying the ICI treatment effect across studies using survival data by the log hazard rate. Forrest plots depict the risk ratio of the favorable treatments versus comparators. The standardized residuals of both models are displayed.

In line with the previous finding, analysis on mortality was conducted to investigate the risk of death in patients underwent ICI therapy versus conventional drugs. Majority of investigated trials on ICI showed significant decreasing of total number of deaths in patients who underwent ICI therapy. Standardised residual clarified the contrast in results between random and fixed models. (Please, see Figure 8 for detailed information of the models).

Figure 8. Models on survival compared by mortality across studies. Fixed-effect and randomised-effect models on mortality across studies investigated the total number of deaths in ICI subgroup against conventional drugs. Forrest plots depict the risk ratio of the favours treatments versus comparators. The standardised residuals of both models are displayed.

Discussion

This systematic review examined recent advances in nanoparticle-based immune checkpoint therapy, as well as the limits of this therapeutic approach. To commence, the total number of irAEs was undertaken to determine the comparability of irAEs between reviewed trials. We confirmed no variations in the safety of all investigated and conventional therapy between reviewed trials. This finding is an important demonstration for comparable safety of investigated and causal therapy according to actual European Society for Medical Oncology (ESMO) Clinical Practice Guidelines on diagnosis, treatment and follow-up for NSCLC,⁶⁷ which depend on asymptomatic or symptomatic process, staging with risk assessment, efficacy by evaluations of genes and biomarkers, or treatment response and potential follow-up therapy.

The next step of analyses across study arms subgroups on the total number of irAEs and grouping by CTCEA Grades because of an analysis was run within each grade and an overall analysis across grades as well as within subgroups and between CTCEA grades showed that only study by Ready et al.⁵⁷ decreased significantly of immune-related adverse events. Moreover, the sole substantial difference on survival compared with the most serious and fatal immune-related adverse events, such as checkpoint inhibitor pneumonitis, across study arms subgroups was also confirmed only by trial of Ready et al.⁵⁷ This study⁵⁷ described a first-line therapy for advanced and/or metastatic NSCLC, nivolumab with low-dose ipilimumab proved efficacious and tolerated. Tumors with PD-L1 expression of 1% or greater and tumors with less than 1%, have been identified as potentially relevant cutoffs for nivolumab plus ipilimumab therapy, with the total number of mutations concentrations of more than ten being associated with improved response and prolonged progression-free survival.⁵⁷ The similar combination and dosages were studied by Gettinger et al.⁴⁴ in advanced NSCLC; however, their patients were pre-treated with standard platinum-based chemotherapy, and they used different scheme for treatment cycles (every two versus every six weeks). The next reason why outcomes of trial by Ready et al.⁵⁷ seem to be safer might be data on checkpoint inhibitor pneumonitis. While the presence of CIP was stated in respondents of Gettinger’s study⁴⁴ sufficiently (approximately equals to 10% of participants), CIP in Ready’s trial⁵⁷ was presented insufficiently (less than 10% of responders). This should be in line with revealing that CIP is associated with a mortality rate of 10% to 17%.^12–15–17 Moreover, CIP patients’ bronchoalveolar lavage samples showed increased lymphocytosis, which was mostly composed of CD4+ T-cells.^14,68 This indicates NSCLC has been progressing due to extensive underlying lung cancer with lymphangitic spread and alveolar damage.^14–17–68

In terms of the effectiveness and treatment impact on survival or plasticity reduction, we verified a substantial difference between immune checkpoint inhibitor and conventional therapy, which is corroborated by the treatment effectivity and decrease in respondents’ mortality in the subgroups with interventional checkpoint (cell surface) inhibitors against comparator agents. We confirmed that receiving ICI therapy had a greater probability of survival because of treatment effect and plasticity reduction (11/27) and dying less (15/27) often. These findings are in line with the latest guidelines on metastatic non-small cell lung cancer.⁶⁷ Definitely, since benefit was shown with PD-1 blockade in lung cancers, three PD-1 inhibitors and PD-L1 inhibitors have been approved by the United States Food and Drug Administration and the European Medicines Agency in the second-line setting.^69–71 The three approved agents in the immunotherapy-naive, second-line setting include atezolizumab, nivolumab and pembrolizumab.⁶⁷ They have been approved on the basis of phase 3 trials demonstrating improved overall survival in comparison with docetaxel.^6,37,42,53 Improving survival under ICI therapy might be explained by showing a link between the development of irAEs and increased survival in NSCLC and other malignancies, as well as a link between longer immune checkpoint inhibitor treatment duration and the development of irAEs^50,72–74 The outcomes of Shankar et al. established that multisystem irAEs are related to better overall survival and/or progression free survival, and that this connection becomes stronger as the number of irAEs increases.⁷⁴ Although patients with multisystem irAEs experienced a longer ICI treatment course, the link between immune-related adverse event count and increased survival remains after correcting for ICI duration, indicating that patients obtain a stronger therapeutic impact, yet are at a higher risk of irAEs.⁷⁴

Regardless of the activity of PD-1/PD-L1 inhibitors in NSCLC, only 20% of responders ultimately react to treatment.⁷⁵ Therefore, patients with a PD-L1 tumor percentage score of 50% or above had a 5-year survival rate of 29.6%.⁸ The similar results were showed in the phase 3 KEYNOTE-024 study that established the pembrolizumab as first-line treatment in NSCLC individuals with untreated, advanced NSCLC and tumor characterized by PD-L1 expression more than 50% in absence of the epidermal growth factor receptor mutation and anaplastic lymphoma kinase translocation.^7,37,67 Furthermore, results of the phase 3 trials KEYNOTE-189 showed in patients with previously untreated metastatic NSCLC without epidermal growth factor receptor mutation and/or anaplastic lymphoma kinase mutations, the addition of pembrolizumab to pemetrexed and cisplatin or carboplatin resulted in significantly better treatment effect and longer overall survival and progression-free survival than solo chemotherapy.^34,37,67 In line with that, CTLA-4 and PD-1 commonly seen on activated T-cells are the most reliable targets for the treatment of cancer.⁷⁶ Gianchecchi and Fierabracci⁷⁷ reported an increase in central memory T-cells and a decrease in the expression of CTLA-4 and PD-1 in the Treg population. PD-1+ and CTLA-4+ Tregs have a detrimental effect on CD8+ T-cells, conventional T-cells (such as Tcms), and macrophage proinflammatory responses in various ways.⁷⁷ In this way, increasing the number of activated alveolar T-cells while lowering the anti-inflammatory Treg phenotype may lead to dysregulation of T-cell activity. It is also possible that anti-CTLA-4 antibodies directly bind to CTLA-4 expressed on normal tissues, such as the pituitary gland, which could also lead to immune-related adverse events. This might explain why pituitary inflammation is a well-documented adverse effect of anti-CTLA-4 antibody treatment.⁷⁸ It is necessary to study and verify other potential mechanisms. Updating guidelines on early and locally advanced NSCLC have to focus on treatment recommendations, including follow-up and survivorship. The latest studies have started to accumulate evidence for ICI in elderly responders with advanced NSCLC. Although no studies dedicated to elderly patients were reported yet, it can be inferred that overall response rates as well as survival are not different between patients lower than 65 years and those with age higher than 65 years, based on subgroup analysis of the randomized second-line trials.⁶⁷ This is one of the many important demonstrations,⁶⁷ which call for new personalized medicine recommendations and new treatment algorithms that should be updated as soon as possible, in accordance with approving of their safety and efficacy. The extension of ICIs from advanced NSCLC to earlier stages in NSCLC has resulted in benefits for long-term responders.⁵²

Strengths and limitations

The strengths of this systematic review are based on electronic sources from January 2015 to December 2021 and mixed effects analyses of included clinical trials results, and precise specified inclusion criteria, such as minimum responders in the study sample, type of therapy (including conventional monotherapy and/or placebo), as well as comparing various dosages or administration locations and data on immune-related adverse events, survival, and mortality. These inclusion criteria were chosen to prevent bias because of improving ICI guidelines over studied decade. Moreover, this review aggregated effects from several studies and yielded an average treatment effect, with its efficacy and safety more precise than the individual study results.

On the other hand, there are several weaknesses. Not realizing analyses on different drugs, variety of dosage across identical agents as well as across different drugs between studies and timing of the change in dosage due to difficult statistical elaboration with potential bias in outcomes. Moreover, certain trials have insufficient data and information about the variables and comorbidities under investigation, which could potentially affect the risk of adverse events, morbidity, and mortality. Some AEs may not be due solely to immunotherapy, but to other potential causes. This might be a potential confounding factor. Therefore, we decided to use all adverse events in research if TEAEs were unavailable. Because it was consistent with the majority of studies and considered a viable alternative to immune-related adverse events, treatment-related adverse events (TEAEs) were chosen as the main outcome, together with data on survival.

Implications and further research

Importantly, prevention the first. After undergoing an early diagnosis procedure, the most essential is to compile a comprehensive toxicity profile, a toxicity spectrum, and a rating of the ICI safety used in NSCLC therapy. Except for optimal supportive care or experimental therapy in clinical trials, there are no conventional therapies for such individuals. Thus, novel molecules with higher treatment effect and lower number of irAEs are urgently required. The goal of future researches and their analyses should be to determine best practice and areas of uncertainly in the diagnosis, treatment and follow-up of NSCLC. Additionally, researchers must be able to optimize the design of future studies, with an emphasis on antitumour efficacy and safety as two critical success factors.

Conclusions

We verified no variations in the safety profiles of all investigated and conventional agents across this review. Our finding demonstrated the comparability of investigated and causal therapy according to actual guidelines for NSCLC treatment recommendations. Only one study significantly contributed to the total number of immune-related adverse events across study arms and CTCEA grades within each grade, and an overall analysis across grades. Additionally, the difference in survival compared with checkpoint inhibitor pneumonitis across studies subgroups was confirmed in the same study. Its interventional focus was based on advanced and/or metastatic NSCLC with dual ICI agents as the first-line therapy in a longer period between treatment cycles. Conducted mixed effects analyses showed that ICI might have a greater impact on treatment efficacy and the decrease in respondents’ mortality compared to conventional treatment regiments. These findings suggest patients with NSCLC should undergo relevant clinical and laboratory assessment followed by targeted and personalized treatment to reduce their high risk of mortality. Immune checkpoint inhibitors were confirmed as the first-line therapy due to their proved effectiveness and safety profile.

Authors’ contributions

Sara Maria Majernikova wrote the main manuscript text, did the analyses and created all Figures and Tables.

Availability of data and materials

We examined the PubMed, Scopus and Web of Science from January 2015 to December 2021 for relevant articles and conferences meetings published in English. Non-small lung cancer, lung cancer, biomarkers, immune checkpoint inhibitors (anti-programmed cell death 1, anti-programmed cell death ligand 1, anti-cytotoxic T-lymphocyte associated antigen 4), and particular ICI medication names were included in the search approach (ipilimumab, selumetinib, tremelimumab, nivolumab, pembrolizumab, atezolizumab, cemiplimab, durvalumab).

Ethics approval and consent to participate

No patients were contacted for input on the interpretation or writing up of the data. All studies included into analyses were in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments, or comparable ethical standards in the informed consents for clinical trials included into this review.

No third party participated in this study

The datasets analyzed during the current study available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this published article.

List of abbreviations

ATE	=	Atezolizumab
AUC	=	area under the curve
BID	=	twice a day
CBP	=	Carboplatin
CEM	=	Cemiplimab
CIP	=	checkpoint inhibitor pneumonitis
CIS	=	Cisplatin
CTCAE	=	Common Terminology Criteria for Adverse Events
CTLA-4	=	anti-cytotoxic T-lymphocyte-associated protein 4
DUR	=	Durvalumab
EP	=	Etoposide and platinum
ERL	=	Erlotinib
FAE	=	fatal immune-related adverse event
FDA	=	the United States Food and Drug Administration
GEM	=	Gemcitabine
ICI	=	Immune checkpoint inhibitors
irAE	=	immune-related adverse event
IV	=	intravenous
NA	=	not applicable
NIVO	=	Nivolumab
No	=	number
NP	=	Nabpaclitaxel
NSCLC	=	non-small-cell lung cancer
PD-1/PD-L1	=	the programmed cell death protein 1/ligand 1
PEM	=	Pembrolizumab
PEME	=	Pemetrexed
PO	=	peroral
PTX	=	Paclitaxel
QD	=	once a day
QxW	=	each x week
SBRT	=	Stereotactic body radiotherapy
TEAEs	=	treatment-related adverse events
TERM	=	Tremelimumab
TRT	=	Thoracic radiotherapy
TXT	=	Docetaxel
VIN	=	Vinorelbine

Acknowledgments

Go to Dr. Dean Willis (Department of Neuroscience, Physiology and Pharmacology, Division of Biosciences, Faculty of Life Sciences, University College London, London, United Kingdom) for his suggestions regarding Methods.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.