nab-Paclitaxel as a potential partner with checkpoint inhibitors in solid tumors

Figures & data

Table 1 Checkpoint inhibitors approved for the treatment of solid tumors in the US and Europe

Checkpoint agent	Target	Immunoglobulin subtype	Indication	Country	Manufacturer
Ipilimumab^Citation22,Citation25	CTLA4	IgG1κ	Unresectable/metastatic melanoma	US, Europe	Bristol-Myers Squibb
Pembrolizumab^Citation23,Citation26	PD1	IgG1κ	Unresectable/metastatic melanoma	US, Europe	Merck
			PDL1-positive metastatic NSCLC	US,a Europeb
			Recurrent/metastatic HNSCCc,d	US
Nivolumab^Citation21,Citation33	PD1	IgG4κ	Unresectable/metastatic melanoma	US,e Europef	Bristol-Myers Squibb
			Locally advanced/metastatic NSCLC	US,g Europeh
			Advanced renal cell carcinoma	US,i Europej
Atezolizumab^Citation24	PDL1	IgG1	Locally advanced/metastatic urothelial carcinomac,k	US	Hoffmann-La Roche
			Metastatic NSCLCg

Notes:

a Approved for patients with high PDL1 expression, no EGFR or ALK mutations, and no prior chemotherapy for metastatic disease. Also approved for patients with PDL1-positive tumors who have progressed on or after platinum-containing therapy, and if EGFR- or ALK-mutation-positive, patients must have disease progression on FDA-approved therapy for those mutations before receiving pembrolizumab.

b Locally advanced or metastatic NSCLC. Patients must have received one or more prior chemotherapy regimens, and if EGFR- or ALK-mutation-positive, patients must have received prior treatment with approved therapy for these mutations before receiving pembrolizumab.

c Indication granted under accelerated approval, and continued approval may be contingent upon verification of clinical benefit.

d Patients must have disease progression on or after platinum-containing therapy.

e Approved as a single agent for BRAF^V600 wild type and under accelerated approval, which may be contingent upon verification of clinical benefit for BRAF^V600-mutation-positive melanoma, and for unresectable or metastatic melanoma in combination with ipilimumab.

f As monotherapy or in combination with ipilimumab.

g Metastatic NSCLC with progression on or after platinum-based chemotherapy; patients with EGFR or ALK mutations must have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab or atezolizumab.

h Locally advanced or metastatic NSCLC after prior chemotherapy.

i Patients must have received prior antiangiogenic therapy.

j Patients must have received prior therapy.

k With progression during or after platinum-containing chemotherapy, or progression within 12 months of neoadjuvant/adjuvant treatment with platinum-containing therapy.

Abbreviations: FDA, US Food and Drug Administration; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small-cell lung cancer.

Table 2 Conventional paclitaxel in combination with checkpoint inhibitors

Study	n	Population	Treatment	Efficacy			Grade 3/4 AEs
				ORR	Median PFS, months	Median OS, months
Lynch et al^Citation69	204	First-line, stage IIIB/IV or recurrent NSCLC	A Placebo + Pac 175 mg/m^2 + Carbo AUC 6 q3w ≤6 doses B Concurrent (Ipi 10 mg/kg + Pac/Carbo q3w 4 doses → placebo + Pac/Carbo q3w 2 doses) C Phased (placebo + Pac/Carbo q3w 2 doses → Ipi 10 mg/kg + Pac/Carbo q3w 4 doses)	Best ORR by irRC A 18% B 21% C 32%	irRC A 4.6 B 5.5 C 5.7 Modified WHO A 4.2 B 4.1 C 5.1	A 8.3 B 9.7 C 12.2	(Immune-related) A 6% B 20% C 15%
Reck et al^Citation71	130	First-line, extensive-disease SCLC	A Placebo + Pac 175 mg/m^2 + Carbo AUC 6 q3w ≤6 doses B Concurrent (Ipi 10 mg/kg + Pac/Carbo q3w 4 doses → placebo + Pac/Carbo q3w 2 doses) C Phased (placebo + Pac/Carbo q3w 2 doses → Ipi 10 mg/kg + Pac/Carbo q3w 4 doses)	Best ORR by irRC A 53% B 49% C 71%	irRC A 5.3 B 5.7 C 6.4 Modified WHO A 5.2 B 3.9 C 5.2	A 10.5a B 9.1a C 12.5a	(Immune-related) A 9% B 21% C 17%
Weber et al^Citation72	59	First-line, advanced melanoma	A Ipi 10 mg/kg q3w ≤4 doses B Ipi ≤4 doses + Dac 850 mg/m^2 q3w C Ipi ≤4 doses + Pac 175 mg/m^2 + Carbo AUC 6	Immune-related A 33% B 33% C 28% Modified WHO A 29% B 28% C 11%	NR	NR	(Treatment- related) A 50% B 74% C 75%
Antonia et al^Citation75	56	First-line, advanced NSCLC	A Nivo 10 mg/kg q3w + Gem 1,250 mg/m^2 + Cis 75 mg/m^2 (squamous, n=12) B Nivo 10 mg/kg + Pem 500 mg/m^2 + Cis 75 mg/m^2 (nonsquamous, n=15) C Nivo 10 mg/kg + Pac 200 mg/m^2 + Carbo AUC 6 q3w (squamous and nonsquamous, n=15) D Nivo 5 mg/kg + Pac 200 mg/m^2 + Carbo AUC 6 q3w (squamous and nonsquamous, n=14)	RECIST A 33% B 47% C 47% D 43%	A 5.7 B 6.8 C 4.8 D 7.1	A 11.6 B 19.2 C 14.9 D Not reached	Total ≤7% (Treatment-related) Pneumonitis (n=4), fatigue, and acute renal failure (grade 3 only; n=3 each)
Jamal et al^Citation73,Citation74	30	Unresectable, advanced melanoma	A Ipi 3 mg/kg q3w 4 doses starting at week 4 (concurrent) + Pac 175 mg/m^2 + Carbo AUC 6 q3w 5 doses B Ipi 3 mg/kg q3w 4 doses (1-week delay) + Pac 175 mg/m^2 + Carbo AUC 6 q3w 5 doses	26.7 (by irRC) for all patients	NR	15.9 for all patients	Total 63%
Horinouchi et al^Citation70	15	First-line, stage IIIB/IV or recurrent NSCLC (Japanese)	A Phased Ipi 3 mg/kg + Pac 175 mg/m^2 + Carbo AUC 6 q3w B Phased Ipi 10 mg/kg + Pac 175 mg/m^2 + Carbo AUC 6 q3w	RECIST A 3/6 B 3/7	NR	NR	Neutropenia (100% vs 100%), leukopenia (50% vs 17%), anemia (0% vs 66.7%)
Gadgeel et al^Citation76	74	First-line, advanced NSCLCb	A Pembro 2 or 10 mg/kg + Carbo AUC 6 + Pac 200 mg/m^2 q3w ×4 → Pem maintenance (any histology, n=25) B Pembro 2 or 10 mg/kg + Carbo AUC 6 + Pac 200 mg/m^2 q3w + Bev 15 mg/kg ×4 → Pem + Bev maintenance (nonsquamous, n=25) C Pembro 2 or 10 mg/kg + Carbo AUC 5 + Pem 500 mg/m^2 q3w ×4 → Pembro + Pem maintenance (nonsquamous, n=24)	A 52%c B 48%c C 71%c	10 vs NR vs 10	NR	(Treatment- related) A 36% B 46% C 42%

Notes:

a Data based on a follow-up OS analysis;

b without EGFR-sensitizing mutation or ALK translocation only;

c confirmed.

Abbreviations: AEs, adverse events; AUC, area under the curve; Bev, bevacizumab; Carbo, carboplatin; Cis, cisplatin; Dac, dacarbazine; Gem, gemcitabine; Ipi, ipilimumab; irRC, immune-related response criteria; Nivo, nivolumab; NR, not reported; NSCLC, non-small-cell lung cancer; Pac, paclitaxel; Pem, pemetrexed; Pembro, pembrolizumab; PFS, progression-free survival; q3w, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors; ORR, overall response rate; OS, overall survival; WHO, World Health Organization.

Figure 1 Study schematics of ongoing Phase III trials of atezolizumab in combination with nab-paclitaxel chemotherapy in NSCLC (A, IMpower 130 and B, IMpower 131) and TNBC (C, IMpassion 130).⁸⁶

Note: ^aUsing RECIST criteria.
Abbreviations: AUC, area under the curve; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; IM, intramuscular; IV, intravenous; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; QOL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors; TNBC, triple-negative breast cancer; qw, every week; qw 3/4, first 3 of every 4 weeks; q2w, every 2 weeks.

Table 3 Clinical development of checkpoint inhibitors + nab-paclitaxel-based chemotherapy in solid tumors⁸⁶

	Checkpoint inhibitor	Disease/setting	Phase	ClinicalTrials.gov identifier
PD1	Nivolumab	NSCLC MBC Metastatic PC	I	NCT02309177
		Advanced NSCLC	I/II	NCT02574078
	Pembrolizumab	Neoadjuvant TNBC	I	NCT02622074
		Advanced NSCLC	I	NCT01840579
		Advanced NSCLC	I/II	NCT02382406 NCT02733250
		Metastatic solid tumors	I/II	NCT02331251
		Advanced NSCLC	II	NCT02684461
		HER2^- MBC	II	NCT02752685
		Locally recurrent or metastatic TNBC	III	NCT02819518
		Metastatic squamous NSCLC	III	NCT02775435
PDL1	Atezolizumab	Solid tumors including metastatic PC	I	NCT02715531
		Neoadjuvant NSCLC	II	NCT02716038
		Metastatic nonsquamous NSCLC	III	NCT02367781
		Metastatic squamous NSCLC	III	NCT02367794
		Neoadjuvant TNBC	II	NCT02530489
		Metastatic TNBC	III	NCT02425891
	Durvalumab	Neoadjuvant TNBC	I/II	NCT02489448
			II	NCT02685059
		Advanced solid tumors	I	NCT02658214
CTLA4	Ipilimumab	Metastatic melanoma	II	NCT01827111

Abbreviations: MBC, metastatic breast cancer; NSCLC, non-small-cell lung cancer; PC, pancreatic cancer; TNBC, triple-negative breast cancer.

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