Real-world study on the effect of nab-paclitaxel treatment on clinical outcomes and laboratory parameters in patients across metastatic tumor sites

INTRODUCTION

Managing cancer is an ever-evolving journey marked by the ongoing development of innovative treatment options. Conventional treatment approaches for cancer consist of surgery, chemotherapy, and radiotherapy, whereas contemporary methods encompass hormone therapy, anti-angiogenic treatments, stem cell therapy, immunotherapy, and dendritic cell-based immunotherapy.^[1] For years, chemotherapy has played a central role in treating metastatic cancers, with a widely recognized consensus that taxanes are among the most potent individual agents.^[2]

Paclitaxel is a commonly employed pharmaceutical preparation derived from natural anti-cancer compounds extracted from a plant source, Taxus brevifolia. It holds significant importance in the treatment of various cancer types, including breast cancer, lung cancer, pancreatic cancer, and more, making it a typical and essential component in chemotherapy.^[3] The solvent-based paclitaxel may require premedication with prophylactic steroids, antihistamines, and H2 receptor blockers due to a risk of hypersensitivity. In addition, it has limitations in terms of slower tissue penetration and elimination, which results in lower intratumoral drug concentrations.^[4,5] In January 2005, the United States Food and Drug Administration approved nanoparticle albumin-bound paclitaxel (nab-paclitaxel), Abraxane^®, which uses albumin to deliver paclitaxel, as a safer alternative to toxic solvents. It is indicated for the treatment of various cancers, including metastatic breast cancer (MBC), after failed combination chemotherapy or relapse within six months of adjuvant chemotherapy, locally advanced or metastatic non-small-cell lung cancer (NSCLC) in combination with carboplatin for patients’ ineligible for curative surgery or radiation therapy, and metastatic adenocarcinoma of the pancreas in combination with gemcitabine as a first-line treatment.^[6] In 2011, DCGI India approved PacliALL^TM as an anti-cancer treatment, which is a cost-effective generic alternative to Abraxane^® based on a series of pre-clinical studies in which it established comparable tumor regression benefits and a multi-centric bioequivalence study in MBC comparing Abraxane^®.

The nab-paclitaxel offers numerous practical benefits, such as a reduced infusion duration of only 30 min and the elimination of the need for pre-medications to prevent hypersensitivity reactions. Furthermore, nab-paclitaxel exhibited quicker and more extensive tissue penetration, a briefer period of elevated systemic exposure, and delayed elimination of paclitaxel in comparison to cremophor EL-paclitaxel.^[7] In addition, it exhibits improved response rates and enhanced tolerability in patients with advanced MBC and NSCLC.^[8,9] Evidence suggests that the nab formulations of paclitaxel achieve 49% higher dose delivery and 33% higher intratumoral concentration of paclitaxel as compared to solvent-based paclitaxel formulations.^[4,10] A randomized, open-label, two-period, two-treatment, single-dose, crossover, and bioequivalence study comparing generic nab-paclitaxel (PacliALL) and originator nab-paclitaxel (Abraxane^®) was conducted in MBC patients across 15 centers in India. The 90% confidence interval (CI) of the relative mean Cmax (90.33%, 121.47%), AUC_t (84.74%, 113.80%), and AUC_i (82.68%, 112.02%) of the generic nab-paclitaxel to originator product formulation was within the bioequivalence criteria, thus indicating that generic nab-paclitaxel is bioequivalent to originator nab-paclitaxel along with comparable safety profile. The bioequivalence study in MBC holds the most promising alternative for originators in India at an affordable cost.

Although several clinical studies from the US and Europe have demonstrated the efficacy and safety of nab-paclitaxel in various cancer types, including head and neck, ovary, gallbladder, and biliary tract,^[3,11-15] the real-world Evidence demonstrating effectiveness and tolerability is limited, especially from India. Therefore, to address these gaps in the real-world evidence of nab-paclitaxel use in Indian settings, this study aimed to assess the effects of nab-paclitaxel (PacliALL) on clinical outcomes in patients diagnosed with different metastatic cancers.

MATERIAL AND METHODS

This retrospective study was carried out in patients with metastatic cancers who underwent treatment with nab-paclitaxel injection in a tertiary care hospital from Kanpur, Uttar Pradesh, India, from January 2022 to June 2023. It was conducted in accordance with ethical principles that are consistent with the Declaration of Helsinki. The study protocol was approved by the Institutional Ethics Committee.

Patients with metastatic cancers who underwent treatment with PacliALL (nab-paclitaxel) injection, a bioequivalent to Abraxane^®, were selected and retrospectively analyzed for this study. The detailed inclusion criteria were patients aged between 18 and 85 years diagnosed with metastatic cancer (any stage) that was histopathologically/cytologically confirmed, refractory/recurrent to the previous treatment, with Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2, with at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors, with a known case of type 2 diabetes, hypertension, or dyslipidemia and treated with nab-paclitaxel for six cycles. Patients with a known history of hypersensitivity to paclitaxel or any other taxane or compounds chemically/biologically related to paclitaxel or excipients, known central nervous system lesions (brain metastasis or carcinomatous meningitis), active infections, systemic corticosteroid use in a year or with hematologic malignancies, life expectancy more than six months, or with any other medical condition, in which the opinion of the investigator would prohibit the patient’s inclusion in the study and pregnant or lactating women were excluded from the study.

RESULTS

The data of 73 patients diagnosed with metastatic cancer and who were initiated with nab-paclitaxel injection were analyzed in this study. The mean (standard deviation) age of the study population was 54.6 (12.0) years with a male predominance (52.7%) [Table 1]. The mean height, weight, and body surface area were 157.9 cm, 70.6 kg, and 1.7 m², respectively. The majority of the patients presented with an ECOG performance scale score of 0 (84.3%), followed by those with a score of 1 (14.3%) and a score of 2 (1.4%). The primary site of cancer in the majority of the patients was the oral cavity (40.8%), followed by the breast (15.3%) and ovary (15.3%). All patients did not receive prior treatment except one patient who had received prior treatment with chemotherapy.

The analyses of response to treatment were done at week eight and week 17, with the majority of the patients demonstrating a partial response (87.1% and 76.8%, respectively), followed by those with progressive disease (11.4% and 14.5%, respectively). Complete response was observed in 1.4% of patients at week 8, while stable disease was observed in 8.7% of patients at week 17.

Patients received nab-paclitaxel over a mean period of 18 weeks in six cycles. None of the patients required a pre-medication while administration of nab-paclitaxel. None of the patients required a treatment change during the study period. Weekly analysis over a period of six cycles revealed no significant differences in hemoglobin, neutrophil, serum creatinine, RBG, and SGOT levels [Table 2] (P > 0.05). The majority of patients reported anemia at week 0 (97.1%), week 8 (90.0%), and week 17 (85.1%). The majority of the patients documented high levels of neutrophils (>60%) at week 8 (53.5%) and week 17 (62.7%). Similarly, greater number of patients had creatinine levels within normal limits at week 8 (68.6%) and week 17 (73.2%). Compared to baseline, at week 8, the percentage of patients with RBG levels exceeding 125 mg/dL was higher (80.0%) and further increased (88.1%) at week 17 [Table 3]. No serious adverse reactions leading to drug discontinuation were documented during the study period.

DISCUSSION

The nab-paclitaxel is a solvent-free version of paclitaxel crucial in treating breast, lung, pancreatic, and other cancers. Nab formulations of paclitaxel demonstrate enhanced tumor-targeting activity through the binding mechanisms of Gp60 (a 60-kDa sialoglycoprotein) and secreted protein acidic and rich in cysteine (SPARC). On the surfaces of endothelial and cancer cells, Gp60 and SPARC are present.^[16] Intratumoral delivery of nab-paclitaxel is higher than polymer-based formulations, which indicates higher targeted drug delivery, resulting in higher efficacy and lesser side effects due to better targeting of cancer cells.^[17] Further, PacliALL is inherently present in an albumin-bound form, rendering it readily available for action without subjecting the patient to the exposure of synthetic polymeric formulations.

This study gathered real-world Evidence of the utilization of nab-paclitaxel in metastatic cancers and the key findings were as follows: (i) primary cancer sites were the oral cavity, breast, and ovary in a greater number of patients; (ii) weekly analysis over six cycles showed no significant differences in hemoglobin, neutrophil, creatinine, RBG, and SGOT levels; (iii) response at week eight and week 17 showed most of the patients reporting a partial response and smaller percentage reported progressive disease, and (iv) no major adverse reactions leading to discontinuation were reported during the study treatment.

In this study, the common sites of cancers reported were the oral cavity (40.8%), breast cancer (15.3%), and ovary (15.3%). A previously conducted retrospective study demonstrated a higher number of patients with breast (16.8) and ovarian (14.1%) cancer who were treated with nab-paclitaxel in metastatic cancers.^[3] Furthermore, a prior Japanese study assessed paclitaxel’s efficacy as a third-line treatment in patients who failed gemcitabine-cisplatin and fluoropyrimidine, indicating a promising disease control rate (83%) and a median overall survival of 9 months.^[13] In the present study, the mean laboratory findings, including hemoglobin, neutrophil count, creatinine, SGOT, and RBG, were comparable from cycle 1 to cycle 6 of nab-paclitaxel treatment, indicating a relatively stable metabolic profile during the treatment. However, few studies have proposed a potential correlation between the utilization of nab-paclitaxel and an elevated likelihood of developing metabolic disorders. Nab-paclitaxel at a dose of 100 or 125 mg/m²/w exhibits fewer or comparable grade 3/4 specific adverse events than traditional taxanes, with a lower incidence of allergy. Despite fractional dosage analyses suggesting an increased risk of neurotoxicity, the median recovery times for neurotoxic events were notably shorter at 25 days for nab-paclitaxel versus 64 days for solvent-based paclitaxel. This underscores the importance of considering dosage and recovery timelines in evaluating the overall safety profile of nab-paclitaxel.^[18] Another retrospective real-world study of MBC patients treated with nab-paclitaxel monotherapy also reported the absence of grade 3/4 hypersensitivity reactions, with only 1.9% of patients reporting low-grade hypersensitivity reactions.^[19] Similarly, various other studies have reported better efficacy and tolerability of nab-paclitaxel in metastatic cancers.^[10,20-22] Furthermore, Zheng et al. found a significant increase in the neutrophil count from baseline to cycle two during nab-paclitaxel treatment. In addition, they demonstrated a decrease in SGOT and creatinine in contrast to this study.^[3] This variation warrants larger studies to be conducted in patients with metastatic cancers.

Anemia was reported in 97.1% at the baseline, which reduced to 90.0% and 85.1% of patients at weeks 8 and 17, respectively. These observations indicate that nab-paclitaxel treatment had no negative impact on anemia incidences. The average hemoglobin levels were higher in patients undergoing nab-paclitaxel treatment compared to those receiving paclitaxel for breast and pancreatic cancer.^[23] Contrastingly, a decrease in hemoglobin was reported over two cycles of nab-paclitaxel.^[3] Another study also demonstrated contrasting observations wherein anemia was documented in a greater number of patients with NSCLC who were on nab-paclitaxel as compared to those on solvent-based paclitaxel.^[24]

In this study, at baseline, 63.4% of patients already had high RBG (>125 mg/dL), and further, a modest proportion of increase in patients with high RBG was reported at week 8 (80.0%) and week 17 (88.1%) from baseline (63.4%) indicating a slight increase in blood sugar levels post nab-paclitaxel treatment. However, it is crucial to highlight that hyperglycemia was observed in fewer patients undergoing nab-paclitaxel treatment as opposed to those receiving cremophor-based paclitaxel for breast cancer.^[25] Similarly, in patients with ovarian cancer on nab-paclitaxel, high blood glucose was reported in only 5.0% of patients.^[11]

At week 17, 76.8% of patients showed a partial response to treatment, and 14.5% had progressive disease. The partial response rate observed in this study is relatively higher than in the literature. A previous study in patients with metastatic head-and-neck squamous cell carcinoma treated with nab-paclitaxel, cetuximab, and carboplatin for three weeks, followed by nab-paclitaxel and cetuximab for three weeks until progression found that the overall response rate was 60%.^[26] A meta-analysis documented the cumulative overall response rate to be 40%, followed by the cumulative partial remission reaching 38% and stable disease of 28% in patients with MBC who were treated with nab-paclitaxel monotherapy.^[27] Furthermore, patients with NSCLC demonstrated a partial response (41.2%) to nab-paclitaxel treatment and progressive disease in 25.6% of patients.^[28] In patients with ovarian cancer, the use of nab-paclitaxel was associated with progression-free survival (Hazards ratio = 0.411, 95% CI (0.224–0.753), P = 0.004).^[11]

CONCLUSION

The retrospective evaluation found that nab-paclitaxel had been employed in a range of solid tumor sites, with the most common ones being ovarian, breast, and oral malignancies. The majority of patients reported essentially a partial response to therapy, and there were no serious side effects that necessitated discontinuing the medication. Throughout the course of six cycles, nab-paclitaxel therapy did not significantly alter hemoglobin, neutrophil percentage, creatinine, or SGOT levels; nevertheless, a greater proportion of patients endured increased RBG. Overall, the data from patients with various types of metastatic cancers signify the safety and efficacy of generic nab-paclitaxel use in Indian patients.