Safety and efficacy of concurrent immune checkpoint inhibitors and hypofractionated body radiotherapy

Figures & data

Table 1. Patient characteristics and treatments.

Characteristic	Total # of patients (%) (n = 59)
Sex
Male	38 (64%)
Female	21 (36%)
Primary diagnoses
Renal cell carcinoma	27 (46%)
Melanoma	18 (31%)
Non-small cell lung cancer	5 (9%)
Bladder carcinoma	7 (12%)
Pancreas adenocarcinoma	1 (1%)
Head and neck squamous cell carcinoma	1 (1%)
Prior treatments for primary tumor
Oncologic surgery	44 (75%)
Chemotherapy	16 (27%)
Targeted therapy	37 (63%)
Immune therapy	6 (10%)
Brain metastasis
Yes	21 (36%)
s/p surgical resection	8
s/p SRS	17
s/p WBRT	7
Observation	1
No	38 (64%)
Metastasis status prior to treatment
Widely metastatic	45 (76%)
Oligo-metastatic	13 (22%)
Non-metastatic	1 (2%)
ECOG PS at the initiation of ICI
0	19 (32%)
1	31 (53%)
2	5 (8%)
≥3	0 (0%)
Unavailable	4 (7%)
ICI type (single vs. multiple)
Nivolumab alone	27 (46%)
Ipilimumab alone	4 (7%)
Pembrolizumab alone	4 (7%)
Atezolumab alone	5 (8%)
>1 ICI	19 (32%)
Any simultaneous combination of ICIs	14 (24%)
Median duration of ICI treatment, in months
All patients	5
Single agent	4
>1 ICI	7.5
ICI status
Ongoing treatment at last follow-up	22 (37%)
Stopped d/t progressive disease	24 (41%)
Stopped d/t toxicity	6 (10%)
Stopped d/t patient's death	5 (8%)
Stopped d/t hospice enrollment	1 (2%)
Stopped because patient finished planned course	1 (2%)
Radiation Characteristic	# of treatments (%)
Total # of concurrent radiation courses	137
# of RT courses before ICI	35 (26%)
# of RT courses simultaneous with ICI	77 (56%)
# of RT courses after ICI	25 (18%)
Treatment sites (out of 137 courses)
Pelvis	24
Head/neck including brain	36
Cervical spine	4
Thoracic spine	10
Lumbar spine	8
Chest wall	13
Lungs/mediastinum	21
Extremities	12
Abdomen	14
Treatment technique
SAbR	77 (56%)
3D-CRT or IMRT	22 (16%)
Conventional 3D	17 (12.5%)
SRS	17 (12.5%)
Superficial	4 (3%)
Number of patients with:
At least one hypofractionated RT (excluding SRS)	59 (100%)
At least one SAbR	49 (83%)
C-RT (3D-CRT or IMRT) but not SAbR	10 (17%)
Did patient receive concurrent RT courses other than hypofractionated body RT
Yes	21 (36%)
No	38 (64%)
Fractionation schemes
SAbR or C-RT
Median dose in Gy (range)	30 (6-54)
Median fraction # (range)	3 (1-5)
Mean target volume (cc)	141
Other concurrent RT (non-SRS)
Median dose (range)	30 (15–60)
Median fraction # (range)	10 (5–20)
SRS
Median dose (range)	24 (13–40)
Median fraction # (range)	1 (1–5)
Did patient receive other non-concurrent RT courses beyond above time limits?
Yes	34 (58%)
No	25 (42%)

Abbreviations: #, number; %, percentage; yrs, years; ICI, immune checkpoint inhibitor; s/p, status post; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; d/t, due to; RT, radiotherapy; SAbR, stereotactic ablative radiotherapy; 3D-CRT, 3-dimensional conformal radiotherapy; IMRT, intensity modulated radiotherapy; C-RT, hypofractionated conformal radiotherapy; Gy, Gray; cc, cubic centimeters.

^a Oligometastatic was defined as ≤5 lesions at the time of initiation of therapy.

^b One Nivolumab alone patient received simultaneous Cabozantinib.

^c This included patients who received sequential or simultaneous ICIs.

^d Some treatments overlap sites.

^e This included conventional RT or SRS.

^f This included all radiation treatments during or ± 8 weeks from ICI start.

^g Two patients received hypofractionated CyberKnife to 40 Gy in 5 fractions.

Table 2. Treatment-related adverse events.

	All patients (n = 59)
	Any Grade	Grade ≥3
All AEs	46 (78%)	12 (20%)
Fatigue	22 (37%)	3 (5%)
Pruritus	3 (5%)	0 (0%)
Fever	4 (7%)	0 (0%)
Nausea	11 (19%)	2 (3%)
Vomiting	5 (8%)	1 (2%)
Anorexia	5 (8%)	0 (0%)
Transaminitis	10 (17%)	2 (3%)
Colitis	2 (3%)	1 (2%)
Diarrhea	4 (7%)	0 (0%)
Rash/dermatitis	10 (17%)	0 (0%)
Cough/SOB	4 (7%)	0 (0%)
Pneumonitis	6 (10%)	3 (5%)
Hypo/hyper-thyroidism	5 (8%)	0 (0%)
Hypophysitis	3 (5%)	0 (0%)
AKI	5 (8%)	1 (2%)
Electrolytes	5 (8%)	2 (3%)
Extremity edema	8 (13%)	0 (0%)
Pancytopenia	1 (2%)	1 (2%)
Anemia	8 (13%)	1 (2%)
Hyperglycemia	1 (2%)	1 (2%)
Adrenal insufficiency	2 (3%)	0 (0%)
Pancreatitis	1 (2%)	0 (0%)
Uveitis	1 (2%)	0 (0%)
Other	18 (31%)	0 (0%)

^a One Nivolumab alone patient received simultaneous Cabozantinib and developed grade 3 pneumonitis, which was considered related to treatment.

^b This category included: shingles (1), headache (1), tinnitus (1), tachycardia (1), arthritis (2), cerebral radiation necrosis (1), paresthesia/neuropathy (2), thrush (1), pain flare after radiation (1), dysgeusia (1), dizziness (1), hearing loss (1), xerostomia (1), thrombocytopenia (1), vertebral fracture (1), and hot flashes (1).

Table 3. Grade 3–4 toxicities in our cohort compared to cohorts from landmark studies.

	H-RT + 1 ICI (this study) (n = 45)	Nivo, melanoma (1) (n = 665)	Nivo, RCC (2) (n = 406)	Nivo, NSCLC (3) (n = 287)	H-RT + Nivo/Ipi (this study) (n = 14)	Nivo + Ipi, melanoma (1) (n = 326)	Nivo 1 mg/kg Ipi 3 mg/kg, rSCLC (4) (n = 61)	Nivo 3 mg/kg Ipi 1 mg/kg, rSCLC (4) (n = 54)
All AEs	6 (13%)	83 (12%)	76 (19%)	30 (10%)	6 (43%)	179 (55%)	18 (30%)	10 (19%)
Fatigue	3 (7%)	4 (0.6%)*	10 (2%)	3 (1%)*	0 (0%)	17 (5%)	0 (0%)	0 (0%)
Pruritus	0 (0%)	1 (0.2%)	0 (0%)		0 (0%)	6 (2%)	1 (2%)	0 (0%)
Fever	0 (0%)	0 (0%)			0 (0%)	4 (1%)
Nausea	1 (2%)	0 (0%)	1 (<1%)	2 (1%)	1 (7%)	7 (2%)	1 (2%)	0 (0%)
Vomiting	1 (2%)	2 (0.3%)			0 (0%)	8 (2%)	1 (2%)	0 (0%)
Anorexia	0 (0%)	0 (0%)	2 (<1%)	0 (0%)	0 (0%)	3 (0.9%)	0 (0%)	0 (0%)
Transaminitis	0 (0%)				2 (14%)		0 (0%)*	1 (2%)
Colitis	0 (0%)	1 (0.2%)			1 (7%)	32 (10%)	1 (2%)	1 (2%)
Diarrhea	0 (0%)	7 (1%)	5 (1%)	2 (1%)	0 (0%)	27 (8%)	3 (5%)	1 (2%)
Rash/dermatitis	0 (0%)	0 (0%)	2 (<1%)		0 (0%)	11 (3%)	2 (3%)	0 (0%)
Cough/SOB	0 (0%)	1 (0.2%)	3 (1%)		0 (0%)	0 (0%)	1 (2%)	2 (4%)
Pneumonitis	2 (4%)	1 (0.2%)*	6 (1%)		1 (7%)	4 (1%)	1 (2%)	1 (2%)
Hypo/hyper-thyroidism	0 (0%)				0 (0%)		1 (2%)	0 (0%)
Hypophysitis	0 (0%)	0 (0%)			0 (0%)	5 (2%)
AKI	1 (2%)				0 (0%)		1 (2%)	0 (0%)
Electrolytes	1 (2%)				1 (7%)
Extremity edema	0 (0%)		0 (0%)	0 (0%)	0 (0%)
Pancytopenia	1 (2%)				0 (0%)
Anemia	1 (2%)	1 (0.2%)	7 (2%)	1 (<1%)	0 (0%)	2 (0.6%)	0 (0%)	1 (2%)
Hyperglycemia	0 (0%)		5 (1%)		1 (7%)		1 (2%)	0 (0%)
Adrenal insufficiency	0 (0%)				0 (0%)		0 (0%)	1 (2%)
Pancreatitis	0 (0%)				0 (0%)
Uveitis	0 (0%)				0 (0%)

Abbreviations: ICI, immune checkpoint inhibitor; H-RT, hypofractionated radiotherapy; RCC, renal cell carcinoma; Nivo, Nivolumab; Ipi, Ipilimumab; NSCLC, non-small cell lung cancer; rSCLC, recurrent small cell lung cancer; SOB, shortness of breath; AKI, acute kidney injury.

*denotes statistical significance with p-value<0.05 using Fisher's exact test. Columns 3, 4 and 5 compared to column 2; and columns 7, 8 and 9 compared to column 6.

(1) D'Angelo, S.P., et al., Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. J Clin Oncol, 2017. 35(2): p. 226–235.

(2) Motzer, R.J., et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma (CheckMate 025). N Engl J Med, 2015. 373(19): p. 1803–13.

(3) Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer (CheckMate 057). N Engl J Med, 2015. 373(17): p. 1627–39.

(4) Antonia, S.J., et al., Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol, 2016. 17(7): 883–95.

Table 4. Relationship of treatment parameters with occurrence of adverse events.

	No AE (n = 13)	Any AE (n = 46)	p	No Grade ≥ 3 AE (n = 47)	Grade ≥ 3 AE (n = 12)	p
Diagnosis
Bladder	3 (42.9%)	4 (57.1%)	0.0659	7 (100%)	0 (0%)	0.4952
Melanoma	3 (16.7%)	15 (83.3%)		14 (77.8%)	4 (22.2%)
NSCLC	0 (0%)	5 (100%)		5 (100%)	0 (0%)
Pancreas	1 (100%)	0 (0%)		1 (100%)	0 (0%)
RCC	5 (18.5%)	22 (81.5%)		19 (70.4%)	8 (29.6%)
SCC HN	1 (100%)	0 (0%)		1 (100%)	0 (0%)
No. of ICI
Single	11 (27.5%)	29 (72.5%)	0.1893	35 (87.5%)	5 (12.5%)	0.0417
>1 ICI	2 (10.5%)	17 (89.5%)		12 (63.2%)	7 (36.8%)
ICI status
Simultaneous	1 (7.1%)	13 (92.9%)	0.1591	8 (57.1%)	6 (42.9%)	0.0260
Other	12 (26.7%)	33 (73.3%)		39 (86.7%)	6 (13.3%)
Treatment order
ICI → RT (ICI first)	3 (27.3%)	8 (72.7%)	0.9153	11 (100%)	0 (0%)	0.1765
RT + ICI (simultaneous)	6 (20.0%)	24 (80.0%)		23 (76.7%)	7 (23.3%)
RT → ICI (RT first)	4 (22.2%)	14 (77.8%)		13 (72.2%)	5 (27.8%)
Single fractions
1 fraction	1 (16.7%)	5 (83.3%)	1.0000	5 (83.3%)	1 (16.7%)	1.0000
>1 fraction	8 (25.8%)	23 (74.2%)		26 (83.9%)	5 (16.1%)
1-3 fractions
1–3 fractions	3 (16.7%)	15 (83.3%)	1.0000	13 (72.2%)	5 (27.8%)	0.2320
>3 fractions	4 (21.1%)	15 (78.9%)		17 (89.5%)	2 (10.5%)
Other concurrent RT
Yes	6 (28.6%)	15 (71.4%)	0.5131	16 (76.2%)	5 (23.8%)	0.7386
No	7 (18.4%)	31 (81.6%)		31 (81.6%)	7 (18.4%)
Head and Neck RT
No	9 (25.0%)	27 (75.0%)	0.4916	29 (80.6%)	7 (19.4%)	0.8309
Yes	4 (17.4%)	19 (82.6%)		18 (78.3%)	5 (21.7%)
Bone RT
No	8 (19.0%)	34 (81.0%)	0.3844	32 (76.2%)	10 (23.8%)	0.2979
Yes	5 (29.4%)	12 (70.6%)		15 (88.2%)	2 (11.8%)
Lung and Chest RT
No	8 (25.8%)	23 (74.2%)	0.4620	23 (74.2%)	8 (25.8%)	0.2723
Yes	5 (17.9%)	23 (82.1%)		24 (85.7%)	4 (14.3%)
Below Diaphragm RT
No	6 (18.2%)	27 (81.8%)	0.4213	27 (81.8%)	6 (18.2%)	0.6428
Yes	7 (26.9%)	19 (73.1%)		20 (76.9%)	6 (23.1%)
Median BED (Gy), total (IQR)	127.3 (83.5-160.0)	131.8 (77.5-206.5)	0.5043	127.3 (75.4-201.0)	146.0 (97.3-185.4)	0.5157
Median infusions (IQR)	4 (2-8)	8 (4-15)	0.1020	8 (4-15)	4 (3.5-7.5)	0.0632
Median ICI duration (mos), months (IQR)	2.7 (1.0-4.5)	3.8 (2.1-8.3)	0.1798	3.8 (2.1-8.3)	3.2 (1.7-4.1)	0.2247

Abbreviations: AE, adverse events; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; SCC HN, head and neck squamous cell carcinoma; ICI, immune checkpoint inhibitor; RT, radiotherapy; BED, biologically equivalent dose; IQR, inter-quartile range.

^a Other included those who received single or >1 sequential but no concurrent ICIs.

^b Patients who only received 1 fraction versus patients who only received more than 1 fraction to all treated sites.

^c Patients who only received 1–3 fractions versus patients who only received more than 3 fractions to all treated sites.

^d This included conventional RT or brain SRS.

Table 5. Relationship of radiotherapy treatment site to occurrence of adverse events.

	Any Grade AE			Grade ≥3 AE
	No RT to/near organ	RT to/near organ	p	No RT to/near organ	RT to/near organ	p
Lung	n = 22	n = 37		n = 22	n = 37
Pneumonitis	2 (9.1%)	4 (10.8%)	1.0000	1 (4.5%)	2 (5.4%)	1.0000
Abdomen	n = 26	n = 33		n = 26	n = 33
Transaminitis	5 (19.2%)	5 (15.2%)	0.7365	1 (3.8%)	1 (3.0%)	1.0000
AKI	3 (11.5%)	2 (6.1%)	0.6458	1 (3.8%)	0 (0%)	0.4407
Adrenal insufficiency	1 (3.8%)	1 (3.0%)	1.0000	—	—	—
Pancreatitis	0 (0%)	1 (3.0%)	1.0000	—	—	—
Colon	n = 17	n = 42		n = 17	n = 42
Colitis	2 (11.8%)	0 (0%)	0.0795	1 (5.9%)	0 (0%)	0.2881
Thyroid	n = 22	n = 37
Hypo/hyper-thyroidism	3 (13.6%)	2 (5.4%)	0.3513	—	—	—
Head	n = 35	n = 24
Hypophysitis	1 (2.9%)	2 (8.3%)	0.5607	—	—	—
Uveitis	1 (2.9%)	0 (0%)	1.0000	—	—	—

Abbreviations: AE, adverse events; RT, radiotherapy.

Table 6. Relationship of treatment parameters with treatment response.

	CR versus PR, SD, and PD			CR and PR versus SD and PD
	CR (n = 4)	PR+SD+PD (n = 35)	p	CR+PR (n = 10)	SD+PD (n = 29)	p
Diagnosis
Bladder	0 (0%)	3 (100%)	0.0449	0 (0%)	3 (100%)	0.4186
Melanoma	3 (30.0%)	7 (70.0%)		4 (40.0%)	6 (60.0%)
NSCLC	1 (25.0%)	3 (75.0%)		2 (50.0%)	2 (50.0%)
Pancreas	0 (0%)	1 (100%)		0 (0%)	1 (100%)
RCC	0 (0%)	21 (100%)		4 (19.0%)	17 (81%)
No. of ICI
Single	2 (8.0%)	23 (92.0%)	0.6085	7 (28.0%)	18 (72.0%)	0.7212
>1 ICI	2 (14.3%)	12 (85.7%)		3 (21.4%)	11 (78.6%)
ICI status
Simultaneous	2 (18.2%)	9 (81.8%)	0.5619	2 (18.2%)	9 (81.8%)	0.6927
Other	2 (7.1%)	26 (92.9%)		8 (28.6%)	20 (71.4%)
Treatment order
ICI → RT (ICI first)	0 (0%)	6 (100%)	0.2555	1 (16.7%)	5 (83.3%)	0.1658
RT + ICI (simultaneous)	4 (19.0%)	17 (81.0%)		8 (38.1%)	13 (61.9%)
RT → ICI (RT first)	0 (0%)	12 (100%)		1 (8.3%)	11 (91.7%)
Single fractions
1 fraction	1 (50.0%)	1 (50.0%)	0.3377	1 (50.0%)	1 (50.0%)	1.0000
>1 fraction	3 (15.0%)	17 (85.0%)		7 (35.0%)	13 (65.0%)
1-3 fractions
1–3 fractions	3 (25.0%)	9 (75.0%)	0.2174	5 (41.7%)	7 (58.3%)	1.0000
>3 fractions	0 (0%)	12 (100%)		4 (33.3%)	8 (66.7%)
Other concurrent RT
Yes	1 (7.1%)	13 (92.9%)	1.0000	2 (14.3%)	12 (85.7%)	0.2786
No	3 (12.0%)	22 (88.0%)		8 (32.0%)	17 (68.0%)
Bone RT
No	4 (20.0%)	16 (80.0%)	0.1060	8 (40.0%)	12 (60.0%)	0.0648
Yes	0 (0%)	19 (100%)		2 (10.5%)	17 (89.5%)
Lung RT
No	0 (0%)	24 (100%)	0.0166	4 (16.7%)	20 (83.3%)	0.1411
Yes	4 (26.7%)	11 (73.3%)		6 (40.0%)	11 (60.0%)
Brain RT
No	4 (13.8%)	25 (86.2%)	0.5558	9 (31.0%)	20 (69.0%)	0.4016
Yes	0 (0%)	10 (100%)		1 (10.0%)	9 (90.0%)
Head & Neck RT
No	4 (12.1%)	29 (87.9%)	1.0000	9 (27.3%)	24 (72.7%)	1.0000
Yes	0 (0%)	6 (100%)		1 (16.7%)	5 (83.3%)
Soft Tissue RT
No	4 (11.8%)	30 (88.2%)	1.0000	8 (23.5%)	26 (76.5%)	0.5875
Yes	0 (0%)	5 (100%)		2 (40.0%)	3 (60.0%)
Adrenal RT
No	4 (10.5%)	34 (89.5%)	1.0000	9 (23.7%)	29 (76.3%)	0.2564
Yes	0 (0%)	1 (100%)		1 (100%)	0 (0%)
Median (IQR)
BED, total (Gy)	149 (132-186)	134 (84-206)	0.5785	132 (99-161)	136 (90-272)	0.5200
ICI infusions	7.5 (4.0-22.5)	8.0 (4.0-15.0)	0.9815	9.5 (4-21)	8 (6-15)	0.7468
Time on ICI (mos)	4.2 (3.5-10.5)	4.0 (3.0-8.5)	0.6513	6.8 (3.1-10.3)	3.7 (3.1-10.3)	0.3532

Abbreviations: AE, adverse events; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; ICI, immune checkpoint inhibitor; RT, radiotherapy; BED, biologically equivalent dose; IQR, inter-quartile range; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

^a Other included those who received single or >1 sequential but no concurrent ICIs.

^b Patients who only received 1 fraction versus patients who only received more than 1 fraction to all treated sites.

^c Patients who only received 1–3 fractions versus patients who only received more than 3 fractions to all treated sites.

^d This included conventional RT or brain SRS.