Table 2.
Incidence of adverse events in combination studies with ant-PD-1/PD-L1 antibodies and other therapies, across multiple solid tumors
| Agent | Author(s) | Phase | Tumor type | Total patients (N) | Treatment schedule | Treatment-related toxicities (grade 1–5) | Grade 3–4 treatment-related toxicities |
|---|---|---|---|---|---|---|---|
| Immune checkpoint antibodies | |||||||
| Nivolumab + ipilimumab | Wolchok et al. [34] | I | Melanoma | 86 (n = 53 concurrent, n = 33 sequenced) | Concurrent (N: 0.3–10 mg/kg every 3 weeks) + I (1–10 mg/kg every 3 weeks) then N + I every 3 months × 8 | Total = 93% (n = 49)a Rash (55%, n = 29) Pruritus (47%, n = 25) Fatigue (38%, n = 20) Diarrhea (34%, n = 18) Colitis (9%, n = 5) AST elevation (23%, n = 12) ALT elevation (21%, n = 11) |
Total = 53%a (n = 28)b Elevated lipase (13%, n = 7) AST elevation (13%, n = 7) ALT elevation (11%, n = 6) Diarrhea (6%, n = 3) Colitis (4%, n = 2) Rash (4%, n = 2) |
| Postow et al. [35] | II | Melanoma | 142 (n = 95 combination arm, n = 47 I-alone arm) | N (1 mg/kg every 3 weeks × 4, followed by 3 mg/kg every 2 weeks till progression/toxicity) + I (3 mg/kg every 3 weeks × 4) | Total = 91% (n = 86) Diarrhea (45%, n = 42) Rash (41%, n = 39) Colitis (23%, n = 22) AST elevation (22%, n = 21) ALT elevation (21%, n = 20) Hypothyroidism (16%, n = 15) Hypophysitis (12%, n = 11) |
Total = 54% (n = 51)b Colitis (17%, n = ) Diarrhea (11%, n = ) AST elevation (11%, n = 10) ALT elevation (7%, n = 7) Hypophysitis (7%, n = 3) Pneumonitis (2%, n = 2) |
|
| Larkin et al. [36] | III | Melanoma | 945 (N only = 316, N + I = 314, I alone = 315) | N (3 mg/kg every 3 weeks) versus I (3 mg/kg every 3 weeks × 4) versus N + I (N: 1 mg/kg × 4 doses + I then N: 3 mg/kg every 3 weeks × 4, or 3 mg/kg from cycle 3 on every 2 weeks) | Total = 96% (n = 299) Diarrhea (44%, n = 138) Fatigue (35%, n = 110) Pruritus (33%, n = 104) Rash (40%, n = 126) AST elevation (15%, n = 45) ALT elevation (18%, n = 55) Hypothyroidism (15%, n = 47) Colitis (12%, n = 37) |
Total = 55% (n = 172) Diarrhea (9%, n = 29) Fatigue (4%, n = 13) Pruritus (2%, n = 6) Rash (5%, n = 15) AST elevation (6%, n = 19) ALT elevation (8%, n = 26) Hypothyroidism (<1%, n = 1) Colitis (8%, n = 24) |
|
| Sampson et al. [23] | I | Glioblastoma multiforme | 20 (n = 10 combination arm) | Combination arm: N (1 mg/kg) + I (3 mg/kg every 3 weeks) followed by N (3 mg/kg every 2 weeks) | Total = 100% Fatigue (40%, n = 8) Diarrhea (35%, n = 7) AST elevation (25%, n = 5) High lipase (25%, n = 5) Vomiting (20%, n = 4) ALT elevation (20%, n = 4) |
Total = 70% (n = 7) Colitis (10%, n = 2) Hypothyroidism (10%, n = 2) Diarrhea (10%, n = 2) ALT elevation (10%, n = 2) Cholecystitis (5%, n = 1) Diabetic ketoacidosis (5%, n = 1) Elevated lipase (5%, n = 1) |
|
| Pembrolizumab + ipilimumab | Patnaik et al. [37] | I | NSCLC | 18 | P (2 or 10 mg/kg every 3 weeks) + I (1 or 3 mg/kg every 3 weeks × 4) + maintenance P | Total = 83% (n = 15) Fatigue (33%, n = 4) Low appetite (17%, n = 2) Pruritus (17%, n = 2) Rash (17%, n = 2) Myasthenia gravis (6%, n = 1) Myocarditis (6%, n = 1) Pneumonitis (6%, n = 1) Uveitis (6%, n = 1) |
Total = 17% (n = 3) Rash (17%, n = 2) Adrenal insufficiency (6%, n = 1) |
| MEDI4736 + tremelimumab | Antonia et al. [38] | Ib | NSCLC | 102 | M (3–20 mg/kg every 4 weeks or 10 mg/kg every 2 weeks) + T (1–3 mg/kg every 2 or 4 weeks × 6 doses) for 1 year | Total = 93% (n = 95) Diarrhea (27%, n = 28) Fatigue (26%, n = 27) Colitis (12%, n = 12) ALT elevation (10%, n = 10) AST elevation (6%, n = 6) Hypothyroidism (6%, n = 6) Pneumonitis (5%, n = 5) |
Total = 61% (n = 60) Diarrhea (8%, n = 8) Colitis = (9%, n = 9) ALT elevation (3%, n = 3) AST elevation (4%, n = 4) Myasthenia gravis (n = 1) Polymyositis (n = 1) Pneumonitis (4%, n = 4) Hypothyroidism (1%, n = 1) |
| Chemotherapy | |||||||
| Nivolumab + platinum-doublet chemotherapy | Antonia et al. [39] | I | NSCLC | 56 | N (10 mg/kg every 3 weeks or 5 mg/kg every 3 weeks) + chemotherapy × 4) + N alone (10 mg/kg every 3 weeks or 5 mg/kg every 3 weeks) | Total = 93% (n = 52) Fatigue (71%, n = 40) Nausea (46%, n = 26) Low appetite (36%, n = 20) Alopecia (30%, n = 17) Pneumonitis (13%, n = 7) |
Total = 45% (n = 25) Fatigue (5%, n = 3) Anemia (4%, n = 2) Rash (4%, n = 2) Acute renal failure (5%, n = 3) Pneumonitis (7%, n = 4) |
| Targeted therapy | |||||||
| Durvalumab + AZD9291 | Oxnard et al. [40] | Ib | EGFR-mutant T790M-positive NSCLC | 14 | M (3 or 10 mg/kg every 2 weeks) + A (80 mg daily) | Total: not reportedb Diarrhea (50%, n = 7) Vomiting (50%, n = 7) Anemia (45%, n = 6) Pneumonitis (21%, n = 3) |
Total: 1% (n = 2)b Neutropenia = 2 |
| Durvalumab + gefitinib | Creelan et al. [41] | Ib | NSCLC | 10 | M (3 or 10 mg/kg every 4 weeks) + G (250 mg daily) × 1 year | Total = 100% (n = 10) ALT elevation (50%, n = 5) AST elevation (50%, n = 5) Diarrhea (50%, n = 5) |
Total = 30% (n = 3) Dyspnea (1%, n = 1) Fatigue (1%, n = 1) ALT elevation (1%, n = 1) |
| Durvalumab + dabrafenib + trametinib | Ribas et al. [42] | Ib | BRAF-mutant and wild-type melanoma | 65 | M (3 or 10 mg/kg every 2 weeks) + D (150 mg b.i.d.) + T (2 mg q.d.) or M (10) + T or M (10) + T (× 6 weeks only) | Total = 98% (n = 64) Pyrexia (37%, n = 24) Chills (24%, n = 16) Arthralgia (17%, n = 11) Peripheral edema (17%, n = 11) Folliculitis (18%, n = 12) Pneumonitis (1%, n = 1) AST elevation (12%, n = 8) ALT elevation (10%, n = 7) Low ejection fraction (2%, n = 2) |
Total = 46% (n = 30) Pyrexia (2%, n = 2) Chills (3%, n = 1) Peripheral edema (5%, n = 3) AST elevation (8%, n = 2) ALT elevation (4%, n = 1) Low ejection fraction (9%, n = 2) Pneumonitis (0%, n = 0) |
| Pidilizumab + rituximab | Westin et al. [43] | II | Follicular lymphoma | 32 | P (3 mg/kg every 4 weeks × 4–12) + R (375 mg/m2 weekly × 4) | Total = 94% (n = 30) Anemia (47%, n = 14) Fatigue (43%, n = 13) Leucopenia (37%, n = 11) |
Total: 0% (n = 0) |
| Antiangiogenic therapy | |||||||
| Atezolizumab + bevacizumab | Sznol et al. [44] | Ib | RCC | 10 | B (15 mg/kg every 3 weeks) + A (20 mg/kg every 3 weeks) | Total: 80% (n = 8) Fatigue (40%, n = 4) Low appetite (30%, n = 3) Diarrhea (30%, n = 3) Arthalgia (20%, n = 2) |
Total: 0% (n = 0) |
| Atezolizumab + bevacizumab | Bendell et al. [45] | Ib | CRC | 14 (A + B) | A (20 mg/kg every 3 weeks) + B (15 mg/kg every 3 weeks) | Total = 79% (n = 11) Fatigue (21%, n = 3) Nausea (29% n = 4) Pyrexia (21%, n = 3) Decreased appetite (7%, n = 1) |
Total = 7% (n = 1) Neutropenia (7%, n = 1) |
| Nivolumab + sunitinib or pazopanib | Amin et al. [46] | Ib | RCC | 53 (N + S, n = 33, N + P, n = 20) | N (2–5 mg/kg every 3 weeks) + S (50 mg 4 weeks on, 2 weeks off) or P (800 mg daily) | Total: 100% (n = 53) Sunitinib: Fatigue (n = 27) Diarrhea (n = 20) ALT elevation (n = 13) AST elevation (n = 12) Acute renal failure (n = 4) Pneumonitis (n = 2) Pazopanib: Fatigue (n = 12) AST elevation (n = 6) ALT elevation (n = 5) |
Total: 77% (n = 41) Sunitinib: ALT elevation (18%, n = 6), AST elevation (9%, n = 3) Autoimmune nephritis (3%, n = 1) Pneumonitis (3%, n = 1) Pazopanib: AST elevation (20%, n = 4) ALT elevation (20%, n = 4) Fatigue (15%, n = 3) Diarrhea (20%, n = 4) |
| Antiangiogenic therapy + chemotherapy | |||||||
| Atezolizumab + bevacizumab + FOLFOX | Bendell et al. [45] | Ib | CRC | 30 (A + B + F) | A (14 mg/kg every 2 weeks) + B (10 mg/kg every 2 weeks) + F (standard doses, every 2 weeks) | Total = 100% (n = 30) Fatigue (47%, n = 14) Nausea (27% n = 8) Pyrexia (20%, n = 6) Decreased appetite (20%, n = 6) |
Total = 20% (n = 6) Neutropenia (7%, n = 2) AST elevation (7%, n = 2) ALT elevation (3%, n = 1) Diarrhea (3%, n = 1) |
aResults from concurrent arm only.
bAll case adverse events.
GBM, glioblastoma multiforme; HNSCC, head and neck squamous cell carcinoma; CRC, colorectal carcinoma; RCC, renal cell carcinoma; EGFR, epidermal growth factor receptor; N, nivolumab, I, ipilimumab; P, pembrolizumab; A, atezolizumab; B, bevacizumab; F, FOLFOX chemotherapy (5-flurouracil bolus and continuous infusion, leucovorin, oxaliplatin).