A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes

Figures & data

Figure 1. Trial schema

Twenty-two stage IV patients with metastatic melanoma were stratified by treatment site of a single index metastasis, which is the irradiated tumor. Two dosing levels for hypofractionated radiation (HFRT) are in each stratum. After enrollment, 2 or 3 fractions of HFRT were given over 3–7 days (red arrows). Ipilimumab (3 mg/kg) was initiated within 7 days of the final HFRT fraction, every 3 weeks x 4 (blue arrows). s.c – subcutaneous

Table 1. Demographics

Stratum	1		2
Dose:	Dose Level 1 8 Gy x 2 (n = 6)	Dose Level 2 8 Gy x 3 (n = 4)	Dose Level 1 6 Gy x 2 (n = 6)	Dose Level 2 6 Gy x 3 (n = 6)
Site of index (irradiated) lesion	Lung	lung	liver/ subcutaneous	liver/ subcutaneous
Prior Therapy*
Treatment-naïve	2 (33%)	3 (75%)	3 (50%)	3 (50%)
Treatment-refractory	4 (67%)	1 (25%)	3 (50%)	3 (50%)
Stage
M1a	0	0	0	2 (33%)
M1b	2 (33%)	2 (50%)	0	2 (33%)
M1c	4 (67%)	2 (50%)	6 (100%)	2 (33%)
LDH
Elevated	4 (67%)	1 (25%)	3 (50%)	2 (50%)
Not elevated	2 (33%)	3 (75%)	3 (50%)	2 (50%)
Gender
Male	5 (83%)	2 (50)	5 (83)	5 (83)
Female	1 (17%)	2 (50)	1 (17%)	1 (17%)
Patient age in years, n (%)
18–44	0	0	0	0
45–64	3 (50)	3 (75)	2 (33)	0
≥65	3 (50)	1 (25%)	4 (67)	6 (100)
Patients with ECOG PS, n (%)
0	4 (67)	3 (75)	3 (50)	2 (33)
1	2 (33)	1 (25%)	3 (50)	4 (67)

*Prior Therapies Detailed in Supplemental Table 1.

Table 2. Summary of Adverse Events

	Any grade	Grades 1–2	Grade 3
Any adverse event	135	120	15
Any treatment-related adverse event	31	28	3
Specific treatment-related adverse event (immune)
Anaphylaxis (with hypotension and angioedema)	1	0	1
Arthralgia (flare of rheumatoid arthritis)	1	1	0
Colitis*	2	1	1
Pruritus	7	7	0
Rash	4	4	0
Uveitis	1	1	0
Specific treatment-related adverse event (nonimmune)
Abdominal Pain	1	1	0
Anorexia	2	2	0
Chills	1	1	0
Dermatitis (radiation)	1	1	0
Diaphoresis	1	1	0
Diarrhea*	1	1	0
Fatigue	3	2	1
Headache	1	1	0
Nausea	4	4	0
Non-treatment related adverse events	104	92	12

There were no grade 4 toxicities.

* Diarrhea was defined as a disorder characterized by frequent and watery bowel movements; colitis was defined as a disorder characterized by inflammation of the colon.

Figure 2. Radiation + ipilimumab is associated with regression of unirradiated tumors in some patients. Waterfall plot of clinical response in unirradiated tumors after radiation treatment (RT) to a single index lesion with ipilimumab. Dashed lines are thresholds for progressive disease (PR; red) and partial response (PR; blue). * Patients with new lesions. ** Clinical progression without imaging

Figure 3. Survival curves

Progression-free survival (PFS) and overall survival (OS) for all patients (dashed line: 95% CI).

Table 3. Patients alive at last follow-up

Study subject #	Radiation site	Stratum	Dose	Best distant response (RECIST)	Time to progression from RT (months)	Therapy at progression	Status at last f/u	Time from RT to last f/u or death (months)
1	Lung	1	8 Gy x 2	SD	9.8	SBRT to new lung lesion; resection of brain met; pembro	Alive; SD on pembro	97.4
8	Lung	1	8 Gy x 2	PD	5.4	pembro	Alive; SD on pembro	36.7
10	Liver	2	6 Gy x 2	PR	N/A	N/A	NED	88.7
16	Lung	1	8 Gy x 3	PR	12.2	Gamma Knife and resection of brain mets; then pembro	Stable disease on pembro	82.6
17	Axillary nodal mass	2	6 Gy x 3	PD	3.3	pembro; then progressed in breast; mastectomy; placed on B-raf inhibitors	Alive; SD on B-Raf inhibitors	82.2
20	Lung	1	8 Gy x 3	SD	7.6	pembro	SD on pembro	24.9
22	Lung	1	8 Gy x 3	PR	12.3	pembro	Stable disease on pembro	57.6