Clinical Trials for Oral, Inhaled and Intravenous Drug Delivery System for Lung Cancer and Emerging Nanomedicine-Based Approaches

Figures & data

Figure 1 Schematic representation showing current status of clinical trials of lung cancer through delivery pathway. Created with Biorender.com.

Figure 2 Diagram representing human lungs and their anatomy. On the left side of the diagram, a set of healthy lungs is shown while on the right side, a pair of diseased lung illustrates the effects of lung disease. Created with Biorender.com.

Table 1 The Synopsis and Results of Clinical Studies on Drugs Administered Orally

Phase/Setting	Cancer Type	Treatment Dose	Outcome	Comments
Stage (III B-IV)/ First line treatment^Citation63	NSCLC	Gemcitabine - 1000 mg/m^2 (I.V) ^VS Vinorelbine - 60 mg/m^2 (oral) On days 1 and 8. Cycle repeated every 21 days until disease progression/ patient withdrawal	Efficacy - 88.8% Less adverse events - 90.7% Easily managed - 92.5%	Improved cognitive functioning with IV gemcitabine. Improved role functioning, emotional functioning, emotional functioning and social functioning with oral vinorelbine.
Stage (III/IV)/ mostly pretreated^Citation64	NSCLC	NVBo (20–50 mg/d) for 21 days of each 4-week cycle	Median DoDC - 8.7 months (95% CI: 4.9–27.3 months). Median TTP - 1.7 months (95% CI: 1.4–2.1 months) Median OS - 5.7 months (95% CI: 3.5–9.6 months).	Feasible and safe at the recommend dose level (30–40 mg/d), but dose-limiting toxicities observed at 50 mg/d.
Stage (III B/ IV)/ local treatment^Citation65	NSCLC	Cisplatin 80 mg/m^2 + NVBiv 30 mg/m^2 on day 1 and NVBo 80 mg/m^2 on day 8 every 3 weeks, after a first cycle of NVBiv 25 mg/m^2 on day 1 and NVBo 60 mg/m^2 on day 8 VS Cisplatin 75 mg/m^2 and DCT 75 mg/m^2 on day 1 every 3 weeks, for a maximum of six cycles.	Median TTF: NP arm - 3.2 months (95% CI: 2.96–4.24), DP arm: 4.11 (95% CI: 3.45–4.5). No significant difference in OS between NP and DP arm.	Similar response, time-related parameters, and quality of life between NVBiv/NVBo- Cisplatin and Docetaxel-Cisplatin, but oral Vinorelbine was more effective than IV Vinorelbine.
Stage III/ untreated^Citation66	NSCLC	Induction chemotherapy NVB iv = 25 mg/m^2 NVB oral = 60 mg/ m^2 Cisplatin = 80 mg/m^2 Concomitant chemo-radiotherapy (CT-RT) NVB oral = 20 mg Cisplatin = 80 mg/m^2	Median progression-free survival: 14.58 months (95% CI: 10.97–18.75). PFS rate at 12 months: 58.6% (95% CI: 47.0–70.1). Median overall survival: 17.08 months (95% CI: 13.56–29.57).	Combination of oral Vinorelbine with Cisplatin during concomitant CT-RT is well tolerated compared to I.V Vinorelbine-based chemoradiotherapy regimen.
NA^Citation67	Lung Cancer Cachexia	Thalidomide = 150 mg + Cinobufagin = 2000 mg Vs Cinobufagin = 2000 mg	At the end of week 4, EORTC QLQ-C30 score (p < 0.001) was significantly improved in the trial group. At the end of week 12, EORTC QLQ-C30 score (p < 0.001) and grip strength (p < 0.001) were significantly improved in the trial group.	Cinobufagin combined with thalidomide is well tolerated and improves the nutritional status and quality of life of the patient compared to Cinobufagin alone.
NA^Citation68	Advanced Lung cancer + EGFR T790M mutation	AZD9291 20 mg to 240 mg	Overall objective tumor response rate was 51% (95% CI: 45–58). Patients who confirmed EGFR T790M showed 61% response rate (95% CI: 52–70). Patients without EGFR T790M shown 21% response rate (95% CI: 12–34).	Adverse events observed in 10% patients, increased with increasing dose.
Phase I/II^Citation69	EGFR mutated NSCLC	Rociletinib 500 mg daily twice 625 mg daily twice 750 mg daily twice	46 patients with centrally confirmed T79M positive tumors were 59% (95% CI: 45–73). Estimated median progression-free survival - 13.1 months (95% CI: 5.4–13.1).	Rociletinib exceeds objective response rates of 45% with a dose-limiting toxic effect of less than 33%. Treatment-related adverse events were mild. Hyperglycemia was only observed in a few patients, which was controlled by decreasing the dose.
Phase I/II single Arm^Citation70	ALK+ NSCLC	Brigatinib 30–300 mg/d	The median and maximum time on treatment were 5.5 months and 29 months.	Side effects were observed
Phase I^Citation71	NSCLC	Trametinib 0.5, 1, 1.5, 2, 15, 30 mg	15 patients were treated. 12 patients among them completed trametinib	The combination of cCRT and trametinib, with a maximum tolerated dose of 1.5 mg was well tolerated in locally advanced, nonmetastatic, KRAS-mutated NSCLC patients, showing preliminary outcomes in terms of progression-free survival and overall survival.
Phase III^Citation72	EGFR mutation-positive stage IIIB/IV lung adenocarcinoma	Afatinib Cisplatin/pemetrexed	Each study showed an increased overall survival rate compared to Cisplatin and pemetrexed.	These independent Phase 3 studies have demonstrated an improved overall survival rate.
Phase III^Citation73	Advanced NSCLC EGFR-activating mutations	Dacomitinib Gefitinib	During a median follow-up period (31.3 months), a lower death rate (45.4%) in patients who took dacomitinib was shown compared to patients who took gefitinib (52%).	Dacotinib showed significant improvement in overall survival rate compared with a standard-of-care.
Phase III^Citation74	Advanced ALK-positive lung cancer	Lorlatinib Crizotinib	Improved disease progress rates were evaluated; 78% (95% confidential interval, 70–84) in the lorlatinib group Versus 39% (95% confidential interval, 30–48) in the crizotinib group.	Patients with previously untreated advanced ALK-positive NSCLC who received lorlatinib had longer progression-free survival and a higher response.
Phase I/II^Citation75	ROS1 fusion-positive NSCLC	Entrectinib	Improved median duration of response	Showed active durable disease control rate in patient with ROS1 fusion-positive NSCLC.

Abbreviations: DoDC, Duration of disease control; TTP, time to progression; OS, overall survival; CI, confidence interval; NVBo, Navelbine^®oral; TTF, time to treatment failure; PFS, progression free survival; DR, duration of response; EORTC QLQ-C30, European organization for research and treatment quality of life questionnaire; EGFR, epidermal growth factor receptor; NA, Not available; ALK, Anaplastic lymphoma kinase.

Figure 3 Schematic depiction of the different routes for nanoparticle drug delivery, particularly emphasizing oral administration and interactions within the intestinal barrier.⁸⁹ Figure (a) depicts various routes for nano-drug delivery (b) highlights challenges in oral delivery such as enzymatic degradation (pepsin, lipase, peptidase, amylase), mucus entrapment, and pH variations in the gastrointestinal tract. The enterocyte transport mechanisms involve transcytosis, direct passage, and paracellular routes, while M cells in the gut associated lymphoid tissue (GALT) play a role in antigen detection for immune response.

Notes: Reprinted with permission from Vitulo M, Gnodi E, Meneveri R, Barisani D. Interactions between nanoparticles and intestine. International Journal of Molecular Sciences. 2022 Apr 14;23(8):4339. Copyright © 2022.⁸⁹ This image even after increasing resolution words are blurred because it’s the same in original article also.

Figure 4 Illustration of diverse Nanodrug designs for oral administration: A Spectrum of Vesicle, Micelle, Solid, Hollow, Pored microparticles, Tube, Mesoporous and Hydrogel Architectures.

Notes: Reprinted with permission from Homayun, Bahman, Xueting Lin, and Hyo-Jick Choi. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics 11.3 (2019): 129. Copyright © 2019.⁶⁰

Table 2 The Synopsis and Results of Clinical Studies on Drugs Administered Through Respiratory Inhalation

Phase/Setting	Histology	Treatment Arm	Outcome	Comments
Phase I, II/ untreated NSCLC^Citation114	NSCLC	Inhaled doxorubicin plus i.v docetaxel and cisplatin	29% response rate among 24 evaluable patients (95% CI: 12.6–51.5%)	Only 24 patients received at least two courses and 3 patients had progressive disease after the first-course treatment. The survival of the 34 patients was quite robust.
Phase II/untreated primary NSCLC^Citation115	NSCLC	Carboplatin, docetaxel (Group B: 1/3 Carboplatin inhaled,2/3 via i.v administration	Group B showed significant survival benefit against control group (carboplatin and docetaxel administered via i.v (p < 0.001).	Group B delivers high concentration of chemotherapy regimen to the tumor site, lymph nodes and systemic circulation simultaneously.
Phase I/with or without previous chemotherapy^Citation116	NSCLC	Gemcitabine	No significant analysis mentioned	One patient experienced bronchospasm during the second cycle, and the other experienced fatigue, dyspnea, and vomiting.

Figure 5 Barriers that impact the effectiveness for treating lung infection via pulmonary drug delivery is depicted. (a) Mucociliary clearance (b) biofilm (c) pulmonary surfactant and (d) alveolar macrophage clearance.

Notes: Reprinted with permission from He S, Gui J, Xiong K, Chen M, Gao H, Fu Y. A roadmap to pulmonary delivery strategies for the treatment of infectious lung diseases. Journal of nanobiotechnology. 2022 Mar 3;20(1): 101. Copyright © 2022.¹²³

Figure 6 Nanoparticle – guided journey: The microenvironment of (A) healthy and (B) tumor tissues are compared. The chaotic components of the tumor microenvironment (hypoxic core, obstructed lymphatic drainage, insufficient pericyte population, disorganized basement membrane, and broad fenestration are used to enhance the EPR effect.

Notes: Reprinted with permission from Ejigah V, Owoseni O, Bataille-Backer P, Ogundipe OD, Fisusi FA, Adesina SK. Approaches to improve macromolecule and nanoparticle accumulation in the tumor microenvironment by the enhanced permeability and retention effect. Polymers. 2022 Jun 27;14(13):2601. Copyright © 2022.¹²²

Table 3 The Synopsis and Results of Clinical Studies on Drugs Were Administrated by Vein

Phase/Setting	Histology	Treatment Arm	Outcome	Comments
Phase III/ previously treated (second-line treatment)^Citation126	SCLC	Amrubicin vs Topotecan	Similar survival: amrubicin (7.5 months; 95% CI, 6.8–8.5) Topotecan (7.8 months; 95% CI, 6.6–8.5).	OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with Amrubicin.
Phase II/ untreated NSCLC^Citation127	NSCLC	S-1 plus Cisplatin	Overall response rate - 47% (95% CI; 34–61%). Median survival time - 11 months 1-year survival rate - 45% (95% CI; 32–59%) 2-year survival rate - 17% (95% CI; 6–27%).	The incidence of side effects such as neutropenia and vomiting appear to be lower with the S-1 plus cisplatin combination than with platinum-based two-drug combination chemotherapy.
Phase II^Citation128	Stage IIIA/B NSCLC	Chemoradiotherapy using Cetuximab	24-month progression failure rate - 55.2% (95% CI; 44.6–65.7%). 24 months survival rate - 49.3% (95% CI; 38.3–59.3%) MS - 22.7 months (95% CI; 15.3–30.4 months).	The median and overall survival of the combination of Cetuximab with chemoradiotherapy were longer than previously reported by the Radiation Therapy Oncology Group.
Phase III/ untreated SCLC^Citation129	SCLC	TP vs TE vs PE	PE group: median OS - 40.9 weeks (95% CI 36.7–46.1) TP group: median OS - 44.9 weeks (955 CI 41.4–48.1)	TP is not inferior to PE in overall survival, but hematologic toxicity is slightly higher. The TE arm was closed after recommendations by the Independent Data Safety Monitoring Board.
Phase I/ previously treated^Citation130	NSCLC or SCLC	DOTAP: chol-TUSC2	Median duration - 5 months (95% CI 2.0–7.6) Median survival rate - 8.3 months (95% CI 6.0–10.5) Mean survival time - 13.2 months (95% CI 8.9–17.5)	This was the first trial to test the TUSC2 gene therapy approach in humans.
Phase III/ untreated NSCLC^Citation131	NSCLC	Chemoradiotherapy using Cisplatin and Vinorelbine	Objective response rate - 82.0% (95% CI 74.5–89.1%) Median PFS - 13.4 months (95% CI 9.8–16.4) Median survival time - 30.0 months (95% CI 24.5–38.8)	Approximately 15% of patients with stage III NSCLC could be cured without severe toxicities.
Phase II/ previously treated^Citation132	NSCLC	Pemetrexed Plus Bevacizumab	24 patients with 3 months PFS - 57% (95% CI–41–72%) Median PFS time - 4.0 months (95% CI 2.8–4.7)	The study did not meet its primary endpoint (3-month PFS).
Phase I/ untreated NSCLC^Citation133	NSCLC	Nivolumab	12 months OS rate - 73% (95% CI 59–83%) 24-week PFS rate - 41% (95% CI 27–54%)	First line Nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC.
Phase III/ untreated SCLC^Citation134	SCLC	Atezolizumab plus Carboplatin and Etoposide vs Carboplatin plus Etoposide	Atezolizumab group: OS rate - 12.3 months (95% CI 10.8–15.9) PFS - 5.2 months (95% CI 4.4–5.6) Placebo group - OS rate 10.3 months (95% CI 9.3–11.3) PFS - 4.3 months (95% CI 4.2–4.5)	Combining checkpoint inhibition (atezolizumab group) with cytotoxic chemotherapy resulted in significantly lower survival and progression-free survival than chemotherapy alone.
Phase I/II^Citation135	NSCLC	APX005M plus Nivolumab	One of 4 immunotherapy patients had complete response (CR) and 2 had stable disease (SD)	Binds to CD40 which is an immune-activating tumor necrosis factor (TNF) receptor.
Phase III^Citation136	SCLC	Pembrolizumab plus Etoposide and Platinum	Improved PFS; extended PFS of 13.6% was estimated compared to 3.1% in the control group.	Show significantly improved PFS compared with placebo plus etoposide and platinum.

Abbreviations: CI, confidence interval; OS, overall survival; S-1, tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate; TP, topotecan plus cisplatin; TE, topotecan plus etoposide; PE, cisplatin plus etoposide; DOTA P, chol-TUSC2 (cholesterol nanoparticles encapsulating a TUSC2 expression plasmid); PFS, Progression Free survival.

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