Standard of care in immunotherapy trials: Challenges and considerations

Figures & data

Figure 1. Current standard of care therapy in advanced NSCLC and Melanoma Notes: The current standards of care systemic therapy for metastatic non-small cell lung carcinoma (NSCLC) and melanoma. EGFR = epidermal growth factor receptor; ALK = anaplastic lymphoma kinase rearrangement; TKI = tyrosine kinase inhibitor; PD-1 = programmed cell death protein-1.

Table 1. Pivotal published clinical trials of immunotherapeutics in melanoma and NSCLC.

Immunotherapy	Trial	Phase	Intervention	Population	Recruitment Period	N	SOC	1^st Comparator	2^nd Comparator	Primary Endpoint	Results	p value
Melanoma
Ipilimumab
	Hodi et al.^11	III	Ipilimumab v placebo	Previously treated metastatic melanoma (MM)	09/2004 – 08/2008	676	gp100	Ipilimumab + gp100	Ipilimumab 3 mg/kg	OS	Median OS:	p<0.001
											Ipilimumab + gp100: 10.0 mo
											Ipilimumab: 10.1 mo gp100: 6.4 mo
	Ribas et al.	II	Tremelimumab vs Dacarbazine (DTIC or Temozolomide	Previously untreated MM	03/2006 – 07/2007	655	Dacarbazine or Temozolomide	Tremelimumab	N/A	OS	Median OS:	p = 0.127
											Tremelimumab: 12.7 mo
											Chemotherapy: 10.8 mo
	Robert et al.^30	III	Ipilimumab vs Dacarbazine (DTIC)	Previously untreated MM	08/2006 – 01/2008	502	Dacarbazine	Ipilimumab + Dacarbazine	N/A	OS	Median OS:	p<0.001
											Ipilimumab + DTIC: 11.2 mo
											DTIC: 9.1 mo
Pembrolizumab
	Ribas et al.^31 (KEYNOTE-002)	II	Chemotherapy vs Pembrolizumab	MM after Ipilimumab or BRAF/MEK inhibitor	11/2012 – 11/2013	540	Investigator's choice chemotherapy	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	OS (interim analysis PFS)	6 month PFS:	p<0.001
											Pembrolizumab (2 mg/kg) – 34%
											Pembrolizumab (10 mg/kg) – 38%
											Chemotherapy – 16%
	Robert et al.^35 (KEYNOTE-006)	III	Ipilimumab vs Pembrolizumab	Previously treated MM (2^nd line)	09/2013 – 03/2014	834	Ipilimumab 3 mg/kg	Pembrolizumab 10 mg/kg Q2W	Pembrolizumab 10 mg/kg Q3W	OS and PFS	6 month PFS:
											Pembrolizumab Q2W – 47.3%	p<0.001
											Pembrolizumab Q3W– 46.4%	p<0.001
											Ipilimumab – 26.5%
											1 y OS:
											Pembrolizumab Q2W – 74.1%	p<0.001
											Pembrolizumab Q3W– 68.4%	p = 0.004
											Ipilimumab – 58.2%
Nivolumab
	Weber et al.^32 (CheckMate 037)	III	Nivolumab vs Dacarbazine (DTIC) or Carboplatin-Paclitaxel	Previously treated MM	12/2012 – 01/2014	405	Dacarbazine or Carboplatin/Paclitaxel	Nivolumab 3 mg/kg	N/A	ORR	ORR:
										OS	Nivolumab: 31.7%
											Chemotherapy: 10.6%
											OS not yet reported
	Robert et al.^33 (CheckMate 066)	III	Nivolumab vs Dacarbazine (DTIC)	Previously untreated MM (BRAF WT)	01/2013 – 02/2014	518	Dacarbazine	Nivolumab 3 mg/kg	N/A	OS	1 y OS:	p<0.001
											Nivolumab: 72.9%
											Dacarbazine: 42.1%
Combination
	Postow et al.^58	I	Ipilimumab vs Nivolumab + Ipilimumab	Previously untreated MM	09/2013 – 02/2014	175 (142 BRAF WT)	Ipilimumab 3 mg/kg	Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg Q3W; then Nivolumab 3 mg/kg Q2W	N/A	ORR in BRAF WT only	ORR:	p<0.001
	Hodi et al.^59(CheckMate 069)										Ipilimumab + nivolumab: 61%
											Ipilimumab: 11%
											1 y OS:	p = 0.26
											Ipilimumab + nivolumab: 73%
											Ipilimumab: 65%
	Larkin et al.^54	III	Ipilimumab vs Nivolumab + Ipilimumab OR Nivolumab alone	Previously untreated MM	07/2013 – 03/2014	945	Ipilimumab 3 mg/kg	Nivolumab 3 mg/kg Q2W	Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg Q3W	PFS and OS	Median PFS:	p<0.001
	Wolchok et al.^60(CheckMate 067)										Ipilimumab: 2.9 mo
											Ipilimumab + nivolumab: 11.5 mo
											Nivolumab: 6.9 mo
											OS not yet reported
Talimogene Laherparepvec (T-VEC)
	Antbacka et al.^53	III	T-VEC vs GM-CSF	Previously untreated MM	05/2009 – 07/2011	436	Intralesional T-VEC	Subcutaneous GM-CSF	N/A	DRR	DRR:	p<0.001
											T-VEC: 16.3%
											GM-CSF: 2.1%
NSCLC
Ipilimumab
	Lynch et al.^23	II	Ipilimumab +/− Carboplatin-Paclitaxel	Previously untreated unresectable or metastatic NSCLC (mNSCLC)	02/2008 – 02/2009	204	Carboplatin-Paclitaxel	Concurrent regimen:	Phased regimen:	irPFS	Median irPFS:
								Ipilimumab 10 mg/kg + Carboplatin/Paclitaxel Q3W for 4 doses then 2 doses of chemotherapy	2 doses of Carboplatin/Paclitaxel Q3W then 4 doses of chemotherapy + Ipilimumab 10 mg/kg		Chemotherapy: 4.6 mo	p = 0.13
											Concurrent Rx: 5.5 mo	p = 0.05
											Phased Rx: 5.7 mo
											Median OS:
											Chemotherapy: 8.3 mo	p = 0.48
											Concurrent Rx: 9.7 mo	p = 0.23
											Phased Rx: 12.2 mo
Pembrolizumab
	Herbst et al.^16 (KEYNOTE-010)	II/III	Pembrolizumab vs Docetaxel	Previously treated mNSCLC PD-L1 >1%	08/2013 – 02/2015	1034	Docetaxel	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	PFS and OS	Median PFS
											Chemotherapy: 4.0 mo
											Pembrolizumab (2 mg/kg): 3.9 mo	p = 0.07
											Pembrolizumab (10 mg/kg): 4.0 mo	p = 0.004
											Median OS:
											Chemotherapy: 8.5 mo	p<0.001
											Pembrolizumab (2 mg/kg): 10.4 mo	p<0.001
											Pembrolizumab (10 mg/kg): 12.7 mo
	Reck et al.^24 (KEYNOTE-024)	III	Chemotherapy vs Pembrolizumab	Previously untreated mNSCLC without activating mutation	08/2014	305	Platinum-based chemotherapy	Pembrolizumab 200 mg	N/A	PFS	Median PFS	p<0.001
											Chemotherapy: 6.0 mo
											Pembrolizumab: 10.3 mo
	Langer et al.^56 (KEYNOTE-021)	II	Chemotherapy +/− pembrolizumab	Previously untreated mNSCLC	11/2014 – 01/2016	123	Carboplatin-Pemetrexed	Pembrolizumab 200 mg + Carboplatin-Pemetrexed	N/A	ORR	ORR:	p = 0.002
											Chemotherapy: 29%
											Chemotherapy + pembrolizumab: 55%
Nivolumab
	Brahmer et al.^17 (CheckMate 017)	III	Nivolumab vs Docetaxel	Previously treated SqCC mNSCLC	10/2012 – 12/2013	272	Docetaxel	Nivolumab 3 mg/kg Q2W	N/A	OS	Median OS	p<0.001
											Docetaxel: 6.0 mo
											Nivolumab: 9.2mo
	Borghaei et al.^18 (CheckMate 057)	III	Nivolumab vs Docetaxel	Previously treated Non-SqCC mNSCLC	11/2012 – 12/2013	582	Docetaxel	Nivolumab 3 mg/kg Q2W	N/A	OS	Median OS	p = 0.002
											Docetaxel: 9.4mo
											Nivolumab: 12.2mo
Atezolizumab
	Fehrenbacher et al.^43 (POPLAR II)	II	Atezolizumab vs Docetaxel	Previously treated mNSCLC	08/2013 – 03/2014	287	Docetaxel	Atezolizumab 1200 mg	N/A	OS	Median OS	p = 0.04
											Docetaxel: 9.7 mo
											Atezolizumab: 12.6 mo

Notes: SOC = standard of care; MM = metastatic melanoma; mNSCLC = metastatic NSCLC; BRAF WT = BRAF wild-type; OS = overall survival; PFS = progression-free survival; ORR = overall response rate; SqCC = squamous cell carcinoma; non-SqCC = non squamous cell carcinoma

Table 2. Selected ongoing clinical trials of immunotherapeutics in melanoma and NSCLC.

Immunotherapy	Trial Name	Phase	Population	Start Date	N	SOC	2^nd arm	3^rd arm	4th arm	Primary Endpoint	Clinicaltrials.gov Identifier
Melanoma
Pembrolizumab
	KEYNOTE-054	III	Resected stage III melanoma	07/2015	900	Placebo	Pembrolizumab 200 mg			RFS	NCT02362594
	KEYNOTE-022	I/II	Previously treated MM	05/2014	177	Placebo + Dabrafenib + Trametinib	Pembrolizumab + Dabrafenib + Trametinib	Pembrolizumab + Dabrafenib	Pembrolizumab + Trametinib	DLTs	NCT02130466
										PFS
	MASTERKY-265	Ib/III	Previously untreated MM	12/2014	660	Pembrolizumab + placebo	Pembrolizumab + T-VEC			PFS	NCT02263508
										OS
	NCI/SWOG trial	III	Fully resected stage III/IV melanoma	10/2015	1378	Interferon or Ipilimumab	Pembrolizumab 200 mg			OS	NCT02506153
										RFS
										PD-L1 status
	ECHO-301	III	MM	06/2016	600	Pembrolizumab	Pembrolizumab + epacadostat (IDO-1 inhibitor)			PFS	NCT02752074
										OS
Nivolumab
	CheckMate 064	II	MM	04/2013	177	Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg	Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg			AEs	NCT01783938
	CheckMate 238	III	Fully resected stage III/IV melanoma	03/2015	800	Ipilimumab	Nivolumab			RFS	NCT02388906
Combination
		IIIb/IV	Previously untreated MM	03/2016	340	Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg	Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg			AEs	NCT02714218
	NCI sponsored	III	Previously untreated MM	07/2015	300	Dabrafenib + Trametinib followed by Nivolumab + ipilimumab	Nivolumab + ipilimumab followed by Dabrafenib + Trametinib			OS	NCT02224781
NSCLC
Ipilimumab
		III	Previously untreated SqCC mNSCLC	10/2014	867	Carboplatin-Paclitaxel-placebo	Carboplatin-Paclitaxel-Ipilimumab			OS	NCT02279732
Pembrolizumab
	KEYNOTE-042	III	Previously untreated and PD-L1 positive mNSCLC without activating mutation	10/2014	1240	Platinum-based chemotherapy	Pembrolizumab 200 mg (up to 35 doses)			OS	NCT02220894
	KEYNOTE-091	III	Stage IB/II-IIIA NSCLC post-resection	11/2015	1380	Placebo	Pembrolizumab 200 mg (18 doses)			DFS	NCT02504372
	KEYNOTE-189	III	Previously untreated non-SqCC mNSCLC	10/2015	570	Platinum-Pemetrexed	Pembrolizumab 200 mg + Platinum-Pemetrexed			PFS	NCT02775435
										OS
	KEYNOTE-407	III	Previously untreated SqCC mNSCLC	06/2016	560	Carboplatin-Paclitaxel/nab-paclitaxel	Pembrolizumab 200 mg + Carboplatin-Paclitaxel/nab-paclitaxel			PFS	NCT02775435
										OS
Nivolumab
	CheckMate 026	III	Previously untreated PD-L1 + mNSCLC	03/2014	535	Invetsigator's choice chemotherapy	Nivolumab 3 mg/kg			PFS in strong PD-L1 positive	NCT02041533
	CheckMate 078	III	Previously treated mNSCLC	12/2015	500	Docetaxel	Nivolumab 3 mg/kg			OS	NCT02613507
	CheckMate 227	III	Previously untreated mNSCLC	08/2015	1980	Platinum doublet chemotherapy	Nivolumab	Nivolumab + Ipilimumab	Nivolumab + Platinum doublet chemotherapy	PFS	NCT02477826
										OS
	CheckMate 722	III	Previously treated EGFR mutant/ T790m negative mNSCLC	10/2016	429	Platinum doublet chemotherapy	Nivolumab + Platinum doublet chemotherapy	Nivolumab + Ipilimumab		PFS	NCT02864251
Atezolizumab
	OAK	III	Previously treated mNSCLC	03/2014	1225	Docetaxel	Atezolizumab 1200 mg			OS	NCT02008227
	IMpower150	III	Previously untreated Non-SqCC mNSCLC	03/2015	1200	Carboplatin-Paclitaxel-Bevacizumab	Atezolizumab 1200 mg -Carboplatin-Paclitaxel	Atezolizumab 1200 mg -Carboplatin-Paclitaxel-Bevacizumab		PFS	NCT02366143
	IMpower130	III	Previously untreated Non-SqCC mNSCLC	04/2015	550	Carboplatin + Nab-Paclitaxel	Atezolizumab 1200 mg -Carboplatin-Paclitaxel			PFS	NCT02367781
	IMpower010	III	Resected IB – IIIA NSCLC	10/2015	1127	BSC	Atezolizumab 1200 mg			DFS	NCT02486718
	IMpower110	III	Previously untreated mNSCLC	07/2015	570	Platinum + Pemetrexed/Gemcitabine	Atezolizumab 1200 mg			PFS	NCT02409342
										OS
	IMpower131	III	Previously untreated SqCC mNSCLC	06/2015	1025	Carboplatin-Paclitaxel/nab-paclitaxel	Atezolizumab 1200 mg +Carboplatin-Paclitaxel/nab-paclitaxel			PFS	NCT02367794
										OS
	IMpower132	III	Previously untreated non-SqCC mNSCLC	04/2016	568	Platinum-Pemetrexed	Atezolizumab 1200 mg + Platinum-Pemetrexed			PFS	NCT02657434
	IMpower210	III	Previously treated mNSCLC	07/2016	563	Docetaxel	Atezolizumab 1200 mg			OS	NCT02813785
Durvalumab
	ARCTIC	III	Previously treated mNSCLC	01/2015	730	Vinorelbine	Durvalumab			OS	NCT02352948
	Sub-study 1					Gemcitabine				PFS
						Erlotinib
	ARCTIC	III	Previously treated mNSCLC	01/2015	730	Vinorelbine	Durvalumab	Durvalumab + Tremelimumab	Tremelimumab		NCT02352948
	Sub-study 2					Gemcitabine
						Erlotinib
	PACIFIC	III	Stage III NSCLC following chemoradiation	05/2014	702	Placebo	Durvalumab				NCT02125461
	MYSTIC	III	Previously untreated mNSCLC	07/2015	1092	Platinum based chemo	Durvalumab	Durvalumab + Tremelimumab		PFS	NCT02453282
										OS
	NEPTUNE	III	Previously untreated mNSCLC	11/2015	800	Platinum based chemo	Durvalumab + Tremelimumab			OS	NCT02542293
	abound2L+	II	Previously treated mNSCLC	01/2015	240	nab-Paclitaxel	nab-Paclitaxel + Durvalumab	nab-Paclitaxel + CC-486		PFS	NCT02250326
Combination
	Lung-MAP sub-study	III	Previously treated mNSCLC (without actionable biomarkers)	12–2015	250	Nivolumab	Nivolumab + Ipilimumab			PFS	NCT02785952
										OS

Notes: SOC = standard of care; MM = metastatic melanoma; mNSCLC = metastatic NSCLC; BRAF WT = BRAF wild-type; OS = overall survival; PFS = progression-free survival; ORR = overall response rate; SqCC = squamous cell carcinoma; non-SqCC = non squamous cell carcinoma

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