Update on taxanes in the first-line treatment of advanced non-small-cell lung cancer

Abstract

Based on demonstrated favourable risk–benefit profiles, taxanes remain a key component in the first-line standard of care for advanced non-small-cell lung cancer (nsclc) and nsclc subtypes. In 2012, a novel taxane, nab-paclitaxel (Abraxane: Celgene Corporation, Summit, NJ, U.S.A.), was approved, in combination with carboplatin, for the first-line treatment of locally advanced or meta-static nsclc. The approval was granted because of demonstrated improved antitumour activity and tolerability compared with solvent-based paclitaxel–carboplatin in a phase iii trial. This review focuses on the evolution of first-line taxane therapy for advanced nsclc and the new options and advances in taxane therapy that might address unmet needs in advanced nsclc.

1. INTRODUCTION

Non-small-cell lung cancer (nsclc) is a heterogeneous disease with multiple subtypes, including squamous cell carcinoma (scc), which accounts for 20%–30% of all nsclcs^1,2. A large number of patients with nsclc are elderly, and 30% or more have a poor Eastern Cooperative Oncology Group (ecog) performance status (≥2)^1,3,4. Outcomes for patients with advanced nsclc remain poor, with the 5-year survival rate being less than 4%¹. The goals of treating advanced nsclc are therefore to prolong survival and to palliate symptoms.

Platinum-based doublet regimens, the current standard of care for the treatment of advanced nsclc, yield a 1-year survival rate of 30%–40% and are superior to single-agent therapy^5,6. However, a plateau in efficacy has been reached with current standard-of-care options, and no single standard-of-care regimen is superior in the treatment of advanced nsclc^7–10. Thus, physicians rely on numerous factors to optimize treatment strategies, including histology, age, performance status, cost, tolerability, and convenience. The combination of a platinum agent with a taxane—either solvent-based (sb) paclitaxel (Taxol: Bristol–Myers Squibb, Princeton, NJ, U.S.A.) or docetaxel (Taxotere: Sanofi–Aventis, Bridgewater, NJ, U.S.A.)—has a proven efficacy and safety profile in advanced nsclc⁶. The sb-paclitaxel–carboplatin regimen is among those most commonly used for the first-line treatment of advanced nsclc in the United States¹¹.

Recently, nab-paclitaxel, a 130-nm albumin-bound (“nab”) form of paclitaxel designed to use endogenous albumin pathways to increase intratumoural concentrations of the active drug, demonstrated improved antitumour activity and tolerability compared with sb-paclitaxel when both were used in combination with carboplatin in the first-line treatment of patients with advanced nsclc¹². Based on the results of a phase iii trial, nab-paclitaxel in combination with carboplatin was approved in 2012 as first-line therapy for the treatment of locally advanced or metastatic nsclc in patients who are not candidates for curative surgery or radiation therapy^12,13. The present review summarizes the clinical experience to date with taxanes in the first-line treatment of nsclc.

2. DISCUSSION

2.1. Taxane–Platinum Combinations

In landmark nsclc studies, overall response rates (orrs) were higher with taxane–platinum combinations than with other chemotherapy regimens (Table i). Historically, sb-paclitaxel given in combination with carboplatin or cisplatin demonstrated a median overall survival (os) of 7.7–10 months and an orr of 17%–41%^{7–9,11,14,16–18,22}.

TABLE I.

Landmark studies of taxanes in the first-line treatment of non-small-cell lung cancer

Reference	Pts (n)	Dose and schedule	Median os (months)	p Value	orr (%)	p Value
Solvent-based paclitaxel
Giaccone et al., 199814	332	Paclitaxel 175 mg/m2 plus cisplatin every 3 weeks	9.7	ns	41	<0.05
		Teniposide 100 mg/m2 days 1, 3, 5, plus cisplatin every 3 weeks	9.9		28
ecog 5592, 200015	599	Etoposide 100 mg/m2 days 1–3, plus cisplatin day 1 every 3 weeks	7.6	nsa	12.4	<0.05a
		Paclitaxel 250 mg/m2 plus cisplatin plus filgrastim every 3 weeks	10.0		27.7
		Paclitaxel 135 mg/m2 plus cisplatin every 3 weeks	9.5		25.3
Gatzemeier et al., 200016	414	Cisplatin every 3 weeks	8.6	ns	17	<0.05
		Paclitaxel 175 mg/m2 plus cisplatin every 3 weeks	8.1		26
swog 9509, 20017	444	Vinorelbine 25 mg/m2 weekly, plus cisplatin every 4 weeks	8.1	ns	28	ns
		Paclitaxel 225 mg/m2 plus carboplatin every 3 weeks	8.6		25
Rosell et al.,200217	618	Paclitaxel 200 mg/m2 plus carboplatin every 3 weeks	8.5	<0.05	25	ns
		Paclitaxel 200 mg/m2 plus cisplatin every 3 weeks	9.8		28
Scagliotti et al., 20029	612	Gemcitabine 1250 mg/m2 2 of every 3 weeks, plus cisplatin every 3 weeks	9.8	ns	30	ns
		Paclitaxel 225 mg/m2 plus carboplatin every 3 weeks	9.9		32
		Vinorelbine 25 mg/m2 weekly for 12 weeks, then every 2 weeks, plus cisplatin every 4 weeks	9.5		30
eortc 08975, 200318	480	Paclitaxel 175 mg/m2 plus cisplatin every 3 weeks	8.1	nsb	31.8	nsb
		Gemcitabine 1250 mg/m2 2 of every 3 weeks, plus cisplatin every 3 weeks	8.9		36.8
		Paclitaxel 175 mg/m2 every 3 weeks, plus gemcitabine 1250 mg/m2 2 of every 3 weeks	6.7		27.7
Belani et al., 200811	444	Paclitaxel 100 mg/m2 3 of every 4 weeks, plus carboplatin every 4 weeks	9	nr	27.6	<0.05
		Paclitaxel 225 mg/m2 plus carboplatin every 3 weeks	10		19.2
Docetaxel
tax 326, 200310	1218	Docetaxel 75 mg/m2 plus cisplatin every 3 weeks	11.3	<0.05	31.6	<0.05
		Vinorelbine 25 mg/m2 weekly, plus cisplatin every 4 weeks	10.1		24.5
		Docetaxel 75 mg/m2 plus carboplatin every 3 weeks	9.4	ns	23.9	ns
		Vinorelbine 25 mg/m2 weekly, plus cisplatin every 4 weeks	9.9		24.5
Georgoulias et al., 200419	339	Docetaxel 100 mg/m2 plus cisplatin every 3 weeks plus filgrastim	10.5	ns	36.5	<0.01
		Docetaxel 100 mg/m2 every 3 weeks	8.0		21.7
Kubota et al., 200420	311	Docetaxel 60 mg/m2 plus cisplatin every 3–4 weeks	11.3	<0.05	37.1	<0.01
		Vindesine 3 mg/m2 3 of every 4 weeks, plus cisplatin every 4 weeks	9.6		21.2
btog 1, 200621	433	Docetaxel 75 mg/m2 plus carboplatin every 3 weeks	9.5	ns	32	ns
		micor mvpc every 3 weeks	8.7		32
Solvent-based paclitaxel and docetaxel
ecog 1594, 20028	1207	Paclitaxel 135 mg/m2 plus cisplatin every 3 weeks	7.8	nsd	21	nsd
		Gemcitabine 1000 mg/m2 days 1, 8, 15, plus cisplatin every 4 weeks	8.1		22
		Docetaxel 75 mg/m2 plus cisplatin every 3 weeks	7.4		17
		Paclitaxel 225 mg/m2 plus carboplatin every 3 weeks	8.1		17

^aNo significant difference was observed between either paclitaxel arm and etoposide, but the orr for both paclitaxel arms was significantly higher than that for the etoposide arm.

^bTwo pairwise comparisons were performed.

^cPatients received either micor mvp.

^dComparison with the paclitaxel–cisplatin arm.

Pts = patients; os = overall survival; orr = overall response rate; ns = nonsignificant; ecog = Eastern Cooperative Oncology Group; swog = formerly the Southwest Oncology Group; eortc = European Organisation for Research and Treatment of Cancer; nr = not reported; btog = British Thoracic Oncology Group; mic = mitomycin, ifosfamide, cisplatin; mvp = mitomycin, vinblastine, cisplatin.

The efficacy of sb-paclitaxel–cisplatin was established in several large phase iii trials in advanced nsclc^14–16. The efficacy and safety of sbpaclitaxel–cisplatin and sb-paclitaxel–carboplatin were compared in a large phase iii trial in patients with advanced nsclc¹⁷. In that trial, both regimens demonstrated similar response rates [28% vs. 25%, p = nonsignificant (ns)], the primary study endpoint, and manageable toxicity. Overall survival was longer with sb-paclitaxel–cisplatin than with sb-paclitaxel–carboplatin [median: 9.8 months vs. 8.5 months; hazard ratio (hr): 1.2; 90% confidence interval (ci): 1.03 to 1.40]. Based on that survival advantage, the authors recommended sb-paclitaxel–cisplatin for the treatment of advanced nsclc, with sb-paclitaxel–carboplatin as a viable alternative based on its safety profile and ease of administration.

First-line docetaxel plus cisplatin or carboplatin has also demonstrated efficacy, with a median os of 7.4–11.3 months and an orr of 17%–37% in phase iii trials in patients with advanced nsclc^8,10,19–21. In the tax 326 trial, docetaxel in combination with cisplatin or carboplatin was compared with vinorelbine (Navelbine: Píerre Fabre Médicament, Boulogne, France) plus cisplatin (Table i)¹⁰. The orrs in the docetaxel–cisplatin, docetaxel–carboplatin, and vinorelbine–cisplatin arms were 32%, 24%, and 25% respectively; the difference in response was significant only for docetaxel–cisplatin compared with vinorelbine–cisplatin (p = 0.029). Additionally, docetaxel–cisplatin was associated with improved survival compared with vinorelbine–cisplatin (median os: 11.3 months vs. 10.1 months, p = 0.044); however, docetaxel–carboplatin did not show a survival advantage over vinorelbine–cisplatin (median os: 9.4 months vs. 9.9 months, p = ns). The docetaxel–platinum arms were also associated with improved tolerability, resulting in fewer grades 3 and 4 adverse events (aes) than resulted with vinorelbine–cisplatin. Those findings were consistent with findings in other phase iii trials comparing docetaxel–platinum combinations with other chemotherapy regimens^8,10,19–21. The most common grades 3 and 4 aes reported with docetaxel–platinum combinations were neutropenia, leucopenia, and nausea and vomiting^8,10,19–21.

The relative clinical benefit of various taxane–platinum regimens was evaluated in the landmark phase iii study ecog 1594, which compared the efficacy and safety of sb-paclitaxel plus cisplatin or carboplatin, docetaxel–cisplatin, and gemcitabine–cisplatin⁸. Although no survival advantage was noted for any of the 4 arms, the rate of aes was lower with sb-paclitaxel–carboplatin than with the other regimens⁸. Based on those findings, the sb-paclitaxel–carboplatin regimen became the reference regimen for future phase iii studies.

The effect of the taxane schedule on outcomes and tolerability has also been evaluated in the setting of advanced nsclc. Although an every-3-weeks schedule is indicated for sb-paclitaxel in the treatment of advanced nsclc²³, a lower incidence of myelosuppression and neuropathy has been reported with weekly regimens. Thus, the weekly schedule might allow for delivery of a higher dose intensity of paclitaxel with less toxicity. Additionally, low-dose sb-paclitaxel has demonstrated proapoptotic and antiangiogenic effects in vitro²⁴. Evidence from several phase ii/iii trials comparing the every-3-weeks and weekly schedules of sb-paclitaxel and docetaxel have demonstrated no significant difference in orr or survival in patients with advanced nsclc^11,25–30. In those studies, the weekly schedule of sb-paclitaxel resulted in a higher incidence of anemia, and the every-3-weeks schedule resulted in a higher incidence of neuropathy^11,25,29. Similarly, no difference in outcomes was noted between the every-3-weeks and weekly schedules of docetaxel in the second-line setting in patients with advanced nsclc, but hemato-logic events were more common in the every-3-weeks arms, with the exception of anemia in one study^26–28.

2.2. Taxanes in Combination with Other Third-Generation Chemotherapy Agents

The advent of newer therapies has opened up a greater number of options for patients. Accordingly, the efficacy and safety of taxanes in combination with other third-generation chemotherapy agents such as gemcitabine and vinorelbine have also been assessed^31–35.

No difference in efficacy outcomes were reported in a phase iii trial comparing sb-paclitaxel–gemcitabine with sb-paclitaxel–vinorelbine in patients with advanced nsclc, but more patients in the vinorelbine arm than in the gemcitabine arm experienced severe leucopenia, neutropenia, and febrile neutropenia (p < 0.001)³². Similarly, no survival advantage has been reported in phase iii trials comparing gemcitabine–carboplatin, gemcitabine–sb-paclitaxel, and sb-paclitaxel–carboplatin as first-line treatment for patients with advanced nsclc^33,34.

In general, the incidence of grades 3 and 4 aes was higher with gemcitabine–carboplatin than with other regimens, but sb-paclitaxel–containing regimens resulted in a higher incidence of grades 3 and 4 sensory neuropathy³⁴.

Current evidence suggests that a taxane plus gemcitabine is as effective as taxane–platinum doublets in the first-line treatment of advanced nsclc. However, the ae profiles of taxane doublets vary by agent and should be considered when a first-line therapy is chosen. In general, a taxane plus gemcitabine can be considered when a platinum agent is contraindicated^6,31.

2.3. Taxanes in Combination with Molecularly Targeted Agents

The addition of molecularly targeted agents to taxane–platinum regimens, including agents targeting the angiogenesis pathway or known mutations associated with advanced nsclc, has been evaluated in several studies^36–41.

In a phase ii trial of patients with advanced nsclc, the addition of bevacizumab to sb-paclitaxel–carboplatin resulted in a median os of 17.7 months compared with 14.9 months with sb-paclitaxel–carboplatin alone⁴⁰. Toxicity was greater overall with the addition of bevacizumab, and a greater number of life-threatening pulmonary hemorrhagic events was observed, especially in patients with scc. Thus, patients with scc were excluded from the subsequent phase iii ecog 4599 trial³⁷. In that trial, the addition of bevacizumab to sb-paclitaxel–carboplatin significantly improved median os (12.3 months vs. 10.3 months with the chemotherapy alone, p = 0.003), but was associated with greater toxicity and a greater incidence of treatment-related deaths. Based on those results, bevacizumab was approved for patients with nonsquamous nsclc⁴². More recently, a large open-label phase iii trial (PointBreak) evaluated the addition of bevacizumab to first-line sb-paclitaxel–carboplatin or pemetrexed–carboplatin with respect to survival outcomes in patients with advanced nonsquamous nsclc⁴³. No significant difference in os was observed (median: 12.6 months in the pemetrexed arm vs. 13.4 months in the sb-paclitaxel arm; hr: 1.00; 95% ci: 0.86 to 1.16; p = 0.949), the primary endpoint of the study. However, a statistically significant improvement in progression-free survival (pfs) favouring the pemetrexed arm was noted (median pfs: 6.0 months vs. 5.6 months; hr: 0.83; 95% ci: 0.71 to 0.96; p = 0.012). The orr (34.1% vs. 33.0%) and the disease control rate (65.9% vs. 69.8%) were similar in the treatment arms. Patients whose disease did not progress after first-line treatment received maintenance therapy with pemetrexed–bevacizumab in the pemetrexed arm (n = 292); patients in the sb-paclitaxel arm received bevacizumab as a single agent (n = 298). In a prespecified noncomparative survival analysis of patients who received maintenance therapy in the pemetrexed and sb-paclitaxel arms, median os was 17.7 months and 15.7 months respectively, and median pfs was 8.6 months and 6.9 months respectively. Toxicity profiles in the two regimens differed, with significantly more (p ≤ 0.025) treatment-related grades 3 and 4 anemia (14.5% vs. 2.7%), thrombocytopenia (23.3% vs. 5.6%), and fatigue (10.9% vs. 5.0%) in the pemetrexed arm and significantly more grades 3 and 4 neutropenia (40.6% vs. 25.8%), febrile neutropenia (4.1% vs. 1.4%), sensory neuropathy (4.1% vs. 0%) and grades 1 and 2 alopecia (36.8% vs. 6.6%) in the sb-paclitaxel arm. Altogether, those findings demonstrate similar activity for pemetrexed and sb-paclitaxel when used in combination with carboplatin–bevacizumab in the first-line treatment of patients with advanced nonsquamous nsclc.

Results from trials of cetuximab (Erbitux: Bristol–Myers Squibb) in combination with taxane–carboplatin have been mixed^38,39. In the BMS099 trial, patients received sb-paclitaxel or docetaxel, both in combination with carboplatin, with or without cetuximab as first-line therapy³⁹. The median pfs (primary endpoint) was similar for treatment with or without cetuximab (4.4 months vs. 4.2 months, p = ns). An improved orr was observed with cetuximab added to chemotherapy (26% vs. 17% with chemotherapy alone, p = 0.007). The median os for cetuximab plus chemotherapy was 9.7 months; it was 8.4 months with chemotherapy alone (p = ns). Treatment-related grades 3 and 4 aes occurred more often with cetuximab. In the swog (formerly the Southwest Oncology Group) S0342 study, in which patients received either first-line sb-paclitaxel–carboplatin with concurrent cetuximab and maintenance cetuximab afterward, or sequential sb-paclitaxel–carboplatin followed by cetuximab, the orrs were similar in the treatment arms (concurrent: 32%; sequential: 30%; p = ns), as were the median oss (concurrent: 10.9 months; sequential: 10.7 months; p = ns)³⁸. Compared with sequential therapy, concurrent therapy was associated with significantly greater rates of grades 3 and 4 toxicities (p = 0.002).

The foregoing studies demonstrated that the taxane–platinum combination plus a targeted agent was efficacious in patients with advanced nonsquamous nsclc; however, the addition of targeted agents was associated with an increased risk of toxicity.

2.4. A New Taxane for the Treatment of NSCLC

The rationale for the development of nab-paclitaxel stemmed from the observation that although sbpaclitaxel is effective, the solvent used in the formulation (Kolliphor el, formerly known as Cremophor el) could lead to severe hypersensitivity reactions and peripheral neuropathy^44–46. In addition, Kolliphor el can reduce the availability of paclitaxel to tumours by entrapping paclitaxel in micelles^46,47. Compared in preclinical models with sb-paclitaxel, nab-paclitaxel reached a mean maximum blood concentration of free paclitaxel that was higher by a factor of 10 and an intratumoural concentration that was 33% higher in patients with advanced or metastatic solid tumours^48,49. Enhanced transport across endothelial cell layers was also demonstrated for nab-paclitaxel compared with sb-paclitaxel⁴⁹. Because of its unique albumin formulation, nab-paclitaxel can be administered safely at doses higher than are possible with sb-paclitaxel^13,47. Compared with sb-paclitaxel, nabpaclitaxel also requires a shorter infusion time^13,23. Furthermore, sb-paclitaxel requires premedication to prevent hypersensitivity reactions; because of its solvent-free formulation, nab-paclitaxel does not^13,23.

In several trials, nab-paclitaxel–carboplatin demonstrated antitumour activity^12,50,51. A phase i/ii study of nab-paclitaxel–carboplatin identified the maximum tolerated dose of single-agent nab-paclitaxel as 125 mg/m² administered in the first 3 weeks of a 4-week cycle⁵¹. The median os was 11 months, the orr was 30%, and the most common treatment-related toxicities were grades 3 and 4 neutropenia and grade 3 leucopenia, sensory neuropathy, fatigue, diarrhea, and anemia. Patients who experienced grade 3 sensory neuropathy generally experienced improvement to grade 2 or less within 60 days. A subsequent dose-finding study revealed that nab-paclitaxel 100 mg/m² weekly, plus every-3-weeks carboplatin, had a favourable efficacy and safety profile in patients with advanced nsclc⁵⁰. The 100 mg/m² 3-of-4-weeks regimen resulted in an orr of 48% and a median os of 11.3 months. Furthermore, compared with an every-3-weeks schedule of nab-paclitaxel, the former regimen was associated with a lower rate of grade 3 or greater aes and with significant reductions in the incidence of peripheral neuropathy, myalgia, arthralgia, and alopecia. Thus, the 100 mg/m² 3-of-4-weeks dose and schedule was chosen for a phase iii trial. In the randomized registered trial comparing that schedule of nab-paclitaxel with an every-3-weeks sb-paclitaxel schedule (both with carboplatin), the nab-paclitaxel combination demonstrated a significantly higher orr (33% vs. 25%, p = 0.005), the primary endpoint of the study; a 0.5-month longer median pfs (6.3 months vs. 5.8 months; hr: 0.902; 95% ci: 0.767 to 1.060; p = 0.214); and a greater than 1-month-longer median os (12.1 months vs. 11.2 months; hr: 0.922; 95% ci: 0.797 to 1.066; p = 0.271) as first-line treatment for patients with advanced nsclc¹². The nab-paclitaxel–carboplatin combination was associated with more thrombocytopenia and anemia, but with significantly less sensory neuropathy, neutropenia, arthralgia, and myalgia. Additionally, patients receiving nab-paclitaxel–carboplatin experienced a faster time to improvement in sensory neuropathy: median time to improvement from grade 3 or greater sensory neuropathy to grade 1 was 38 days for nab-paclitaxel–carboplatin and 104 days for sb-paclitaxel–carboplatin. Compared with sb-paclitaxel–carboplatin, nab-paclitaxel–carboplatin was also associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss assessed using the Functional Assessment of Cancer Therapy–Taxane instrument^12,52.

2.5. Taxanes and Histology

Targeted therapies including bevacizumab, cetuximab, and the thymidylate synthase inhibitor pemetrexed (Alimta: Eli Lilly and Company, Indianapolis, IN, U.S.A.) have demonstrated benefit in some patient populations, but the observed benefit has been mixed and often dictated by histology^37,53–57. Some patients with nonsquamous nsclc derive greater benefit from those agents than from the standard of care, whereas no benefit compared with chemotherapy might be observed for patients with scc^37,53,54. Thus, treatment options for the latter patients are limited. Use of bevacizumab is limited to patients with nonsquamous histology⁴². Pemetrexed is also currently not indicated for scc because of a lack of efficacy^54,58, possibly related to higher expression of thymidylate synthase in scc tumours⁵⁹. Furthermore, some nsclc tumours present with mixed histology (for example, adenosquamous)⁵⁵; other tumours might be poorly differentiated, potentially containing a heterogeneous population of cells^55,60. Until recently, histology was not generally considered when treatment decisions were made⁵. Few phase iii studies have assessed outcome by histology; however, subanalyses of such trials are beginning to surface in light of histology’s growing importance (Table ii)^33,56,61.

TABLE II.

Efficacy outcomes from select histologic analyses of patients with advanced non-small-cell lung cancer treated with taxane-containing regimens

Reference	Histologic subtype	Regimen	os(months)			hr	95% ci	orr (%)	95% ci	or	95% ci
			Pts (n)	Median	95% ci
Scagliotti et al., 200957,a
	Squamous		187	11.9	nr	nr		nr		nr
	Adenocarcinoma		310	8.8	nr
	Large cell		54	9.5	nr
	Other		65	10.6	nr
Tan et al., 200961
	Squamous
		Vinorelbine–cisplatin	65b	8.9	6.4 to 12.8	nr		24.6		nr
		Docetaxel–cisplatin	64b	9.8	8.4 to 12.2			29.1
	Adenocarcinoma
		Vinorelbine–cisplatin	79b	11.7	8.7 to 16.5			28.1
		Docetaxel–cisplatin	75b	11.6	9.7 to 15.7			22.7
Treat et al., 201033
	Squamous
		Gemcitabine–carboplatin	67	6.6	5.1 to 9.5	1.4	0.93 to 1.99	25.4	15.5 to 37.5	0.40c	0.18 to 0.88
		Gemcitabine–paclitaxel	74	10.2	7.7 to 13.7	1.1	0.75 to 1.55	35.1	24.4 to 47.1	0.65	0.31 to 1.33
		Paclitaxel–carboplatin	61	10.3	8.7 to 12.0	Reference		45.9	33.1 to 59.2	Reference
	Nonsquamous
		Gemcitabine–carboplatin	67	8.2	7.3 to 9.5	0.96	0.81 to 1.13	25.3	20.6 to 30.5	0.93	0.65 to 1.34
		Gemcitabine–paclitaxel	74	8.4	7.2 to 9.8	0.97	0.82 to 1.14	31.4	26.2 to 36.9	1.3	0.88 to 1.77
		Paclitaxel–carboplatin	61	8.3	7.3 to 9.8	Reference		26.7	22.0 to 32.0	Reference

^aValues reflect the combined treatment arms (patients received gemcitabine–cisplatin, paclitaxel–carboplatin, or vinorelbine–cisplatin).

^bReflects enrolled patients; number of evaluable patients was not given.

^cp < 0.05.

Pts = patients; os = overall survival; ci = confidence interval; hr = hazard ratio; orr = overall response rate; or = odds ratio; nr = not reported.

Recently, a phase iii trial conducted by Treat and colleagues in patients with advanced nsclc treated with gemcitabine–carboplatin, gemcitabine–sbpaclitaxel, or sb-paclitaxel–carboplatin was retrospectively analyzed^33,34. No difference in orr was noted for patients with nonsquamous histology, but compared with gemcitabine–carboplatin, sb-paclitaxel–carboplatin was associated with a significantly greater orr in patients with scc (46% vs. 25%, p = 0.02)³³. Across treatment groups, no significant differences by histology were noted with regard to os or time to progression. Additionally, no significant differences were noted in grades 3 and 4 aes between scc and nonsquamous histologies.

The role of histology was also assessed in a retrospective analysis of a phase iii trial of first-line vinorelbine–cisplatin compared with sb-paclitaxel–carboplatin and with gemcitabine–cisplatin⁵⁶. No significant difference by histology was observed in the efficacy of these regimens; however, overall, a survival advantage was observed for patients with scc compared with those with adenocarcinoma (p = 0.0021). In the phase iii Global Lung Oncology Branch trial 3, patients with advanced nsclc were treated with first-line vinorelbine–cisplatin or with docetaxel–cisplatin⁶¹. In patients with scc, median os was 9.8 months in the docetaxel arm and 8.9 months in the vinorelbine arm; the respective orrs were 28% and 25%. Median os was similar between the arms for patients with adenocarcinoma (11.6 months vs. 11.7 months); the orr was 23% in the docetaxel arm and 29% in the vinorelbine arm.

In patients with scc, nab-paclitaxel–carboplatin demonstrated an orr of 41% compared with 24% for sb-paclitaxel–carboplatin (p < 0.001, Table iii)^12,62. In patients with nonsquamous histology, nab-paclitaxel–carboplatin was as efficacious as sb-paclitaxel–carboplatin in terms of response (26% vs. 25%, p = ns), and compared with sb-paclitaxel–carboplatin, nab-paclitaxel–carboplatin also demonstrated a nonsignificantly higher orr in patients with large-cell carcinoma (33% vs. 15%, p = ns) and in those with un-differentiated histology (24% vs. 15%, p = ns). In both arms, patients with adenocarcinoma experienced a similar orr (26% vs. 27%, p = ns). The antitumour activity and safety of nab-paclitaxel–carboplatin were also assessed in patients who were ineligible for bevacizumab (scc, history of thrombotic or embolic events or hemoptysis, or cavitary lung lesions)⁶⁴. Results demonstrated an orr of 41% and a median os of 9.7 months in evaluable patients. The most common grades 3 and 4 toxicities were febrile neutropenia, infection, dyspnea, and dehydration.

TABLE III.

Efficacy outcomes from the phase iii trial of paclitaxel formulations with carboplatin in the first-line treatment of advanced non-small-cell lung cancer

Outcome		Regimen
Group	Type	(A) Nab-paclitaxel and carboplatin			(B) Paclitaxel a and carboplatin
		(n)	(%)	95% ci	(n)	(%)	95% ci	hr or rrr	95% ci b	p Valuec
Intention-to-treat12		521			531
Median os (months)		12.1		10.8 to 12.9	11.2		10.3 to 12.6	0.922	0.797 to 1.066	ns
Overall response		170	33	28.6 to 36.7	132	25	21.2 to 28.5	1.313	1.082 to 1.593	0.005
	Complete response	0			1	<1
	Partial response	170	33		131	25
	Stable diseased	104	20		128	24
	Progressive disease	83	16		84	16
Squamous subset62		229			221
	Median os (months)	10.7		9.4 to 12.5	9.5		8.6 to 11.6	0.890	0.719 to 1.101	ns
	Overall response	94	41	34.7 to 47.4	54	24	18.8 to 30.1	1.680	1.271 to 2.221	<0.001
Nonsquamous subset62		292			310
	Median os (months)	13.1		nr	13.0		nr	0.950	nr	nr
	Overall response	76	26	21.0 to 31.1	78	25	20.3 to 30.0	1.034	0.788 to 1.358	ns
Age ≥70 subset63		74			82
	Median os (months)	19.9		12.7 to 22.3	10.4		8.6 to 13.6	0.583	0.388 to 0.875	0.009
	Overall response	25	34	23.0 to 44.6	20	24	15.1 to 33.7	1.385	nr	ns
Age <70 subset63		447			449
	Median os (months)	11.4		10.3 to 12.6	11.3		10.3 to 12.9	0.999	0.855 to 1.167	ns
	Overall response	145	32	28.1 to 36.8	112	25	20.9 to 28.9	1.300	NR	0.013

^aSolvent-based.

^bCalculated for rrrs according to the asymptotic 95% ci of the relative risk of regimen A to regimen B.

^cBy chi-square test.

^dDefined as 16 weeks or more.

ci = confidence interval; hr = hazard ratio; rrr = response rate ratio; os = overall survival; ns = nonsignificant; nr = not reported.

The molecular mechanism or mechanisms explaining the antitumour activity of nab-paclitaxel–carboplatin in patients with scc remain unknown; however, several hypotheses have been put forward. Many are focused on mechanisms that could lead to greater intratumoural paclitaxel accumulation. Compared with other tumour types, scc tumours occur in close proximity to major blood vessels, which might allow for greater access to the bloodstream⁶⁵. Moreover, pharmacokinetic studies have demonstrated a higher systemic exposure to free paclitaxel in patients receiving nab-paclitaxel than in those receiving sb-paclitaxel, and thus more free paclitaxel might be available to scc tumours⁴⁸. Nab-paclitaxel might avoid the limitations of sbpaclitaxel (entrapment of free paclitaxel in Kolliphor el micelles) because it is albumin-bound^46–48. Furthermore, albumin crosses endothelial cells by cell surface receptor–mediated transcytosis⁶⁶. In preclinical studies, nab-paclitaxel crossed endothelial cell layers more efficiently (by a factor of more than 4) than sb-paclitaxel did⁴⁹. Synergy between nab-paclitaxel and other chemotherapy agents has been suggested; thus, it is also possible that nabpaclitaxel acts in synergy with carboplatin^67–69.

First-line nab-paclitaxel–carboplatin in combination with bevacizumab has also been assessed in patients with advanced nonsquamous nsclc⁷⁰. The orr was 31%, and the median os was 16.8 months. The most common grades 3 and 4 aes were neutropenia, fatigue, febrile neutropenia, thrombocytopenia, and neuropathy (with no grade 4 neuropathy being observed). Those results indicate that the nab-paclitaxel–carboplatin combination holds promise for the treatment of patients with advanced nonsquamous nsclc.

Nab-paclitaxel–carboplatin has demonstrated antitumour activity in patients with scc (for whom there is an unmet need) and in patients with nonsquamous histology in combination with bevacizumab. Future trials of nab-paclitaxel–carboplatin in combination with other targeted agents could reveal interesting findings in select patient populations.

2.6. Taxanes in the Elderly

The median age at diagnosis of lung cancer is approximately 70 years¹. Unfortunately, many elderly patients are undertreated because of toxicity concerns, comorbidities, and poor performance status³. Elderly patients are often underrepresented in clinical trials, and their treatment options are limited for the mentioned reasons^3,71. With increasing emphasis on the identification of the appropriate treatment for elderly patients, many subanalyses have been performed. Single-agent and platinum-based therapies have a historical median os of 8–13 months in phase iii studies in elderly patients with nsclc^6,71–75.

In a phase iii trial (ifct-0501), elderly patients (70–89 years of age) with advanced nsclc and a World Health Organization performance status of 0–2 were randomized to sb-paclitaxel–carboplatin or single-agent vinorelbine or gemcitabine⁷¹. The sbpaclitaxel–carboplatin combination demonstrated a median os of 10.3 months compared with 6.2 months for monotherapy (p < 0.0001). Grades 3 and 4 aes occurred more frequently in the platinum doublet arm and included neutropenia, anemia, febrile neutropenia, thrombocytopenia, asthenia, and anorexia. Despite the increased toxicity, the survival benefits lend support for the use of doublet therapy in elderly patients. In a subanalysis of the ecog 4599 trial, the addition of bevacizumab to sb-paclitaxel–carboplatin resulted in a greater orr in patients 70 years of age or older (29% vs. 17% with sb-paclitaxel–carboplatin alone, p = ns), but no improvement in median os (11.3 months vs. 12.1 months, p = ns) and a higher degree of toxicity⁷⁶.

Elderly patients treated with docetaxel–cisplatin in the tax 326 trial had a median os of 12.6 months; the os in the vinorelbine–cisplatin arm was 9.9 months; it was 9.0 months in the docetaxel–carboplatin arm⁷². More elderly patients in the vinorelbine arm than in either docetaxel arm experienced grades 3 and 4 aes, and more grades 3 and 4 aes occurred with docetaxel–carboplatin than with docetaxel–cisplatin. Regardless of treatment, more neurotoxicity, pulmonary events, infection, anorexia, dehydration, and neuromotor issues were experienced by elderly patients in the study than by younger patients. In two phase ii trials of docetaxel–carboplatin in elderly patients (median age: 74–75 years), the median os ranged from 9.9 months to 13.1 months, and the orr was approximately 47% in both trials^77,78. Common grades 3 and 4 toxicities in both trials included neutropenia and anemia. Recent preliminary results from a phase iii trial of gemcitabine compared with docetaxel–gemcitabine in elderly patients revealed no significant differences in survival or response⁷⁹.

Compared with sb-paclitaxel–carboplatin, nab-paclitaxel–carboplatin recently demonstrated improved outcomes in a subgroup of elderly patients (70 years of age and older) enrolled in a phase iii trial (Table iii)^12,63, with a median os of 19.9 months compared with 10.4 months (p = 0.009). A higher orr was also observed in the elderly patients treated with nab-paclitaxel–carboplatin (34% vs. 24% with sb-paclitaxel–carboplatin, p = ns). Toxicities were similar in patients less than 70 and 70 or more years of age, and scores on the Functional Assessment of Cancer Therapy–Taxane instrument revealed significant treatment effects favouring nab-paclitaxel–carboplatin for neuropathy (p < 0.001), pain in hands and feet (p < 0.001), edema (p = 0.004), and hearing loss (p = 0.022).

The underlying mechanisms contributing to the antitumour activity of nab-paclitaxel–carboplatin in those elderly patients remain unknown. It is possible that the improvement in toxicity with nab-paclitaxel compared with sb-paclitaxel, particularly in neuropathy and neutropenia, might allow for higher dose delivery and intensity¹². Treatment-related aes can affect patient quality of life and can lead to dose reductions and delays, which can affect treatment outcomes. In elderly patients with advanced nsclc, greater chemotherapy dose intensity was demonstrated to correlate with better survival outcomes⁸⁰.

Finally, among elderly patients in the aforementioned phase iii trial, a greater percentage receiving nab-paclitaxel–carboplatin than receiving sbpaclitaxel–carboplatin went on to receive second-line therapy, which has been demonstrated to improve survival over best supportive care or placebo^63,81,82. Further studies are warranted to determine the reasons for the improved os demonstrated by nab-paclitaxel–carboplatin in elderly patients.

3. CONCLUSIONS

The efficacy and safety profiles of taxanes have remained consistent over the years since their introduction. In patients with advanced nsclc, sbpaclitaxel–carboplatin has long been considered the cornerstone of first-line therapy. More recently, compared with sb-paclitaxel–carboplatin, nabpaclitaxel–carboplatin has demonstrated improved response rates, manageable toxicity, and statistically and clinically significant reductions in patient-reported taxane-related symptoms. Those clinical benefits have also been observed in elderly patients and in patients with scc histology^62,63. Thus, clinicians now have a new option in this class of drugs that, based on the current evidence, could offer improved benefit to patients with advanced disease, including those who are elderly or who have scc histology.

5. CONFLICT OF INTEREST DISCLOSURES

MAS has received honoraria from Celgene, Genentech, and Eli Lilly. He has received research grants from Celgene, Genentech, Merrimack Pharmaceuticals, Pfizer, Synta Pharmaceuticals, and Eli Lilly.