Table 1.
General characteristics of the studies and participants.
| Characteristics | 1st Line Treatment | 2nd Line Treatment | Next generation | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Title | PROFILE 1014 | Cui et al | Lu et al | Zhou et al | ASCEND-4 | PROFILE 1007 | ASCEND-5 | ALUR | Tan et al | ALEX | J-ALEX | ALTA-1L |
| Year | 2013 | 2016 | 2016 | 2018 | 2017 | 2014 | 2017 | 2017 | 2016 | 2017 | 2017 | 2018 |
| Design | Phase III | Retrospective | Phase III | Retrospective | Phase III | Phase III | Phase III | Phase III | Retrospective | Phase III | Phase III | Phase III |
| No. of Patients | 343:172/171 | 80:30/50 | 207:104/103 | 73:32/28/13 | 376:189/187 | 347:173/174 | 231:115/116 | 109:72/35 | 709:189/557 | 303:152/151 | 207:103/104 | 275:137/138 |
| Age: Exp Con | 52(22–76) 54(19–78) | 58(37–83) 52(26–72) | NA | 55(22–81) 54(22–80) | 51(22–81) 49(24–85) | 54(44–63) 54(47–64) | 55.5(21, 82) 59.0(37, 80) | 52 52 | 54(18–91) 58(25–88) | 61(27–85) 59(25–84) | 58(27–86) 60(29–89) | |
| Male Female | 131:68/63 | 38:15/23 42:15/27 | NA | 36:19/11/6 37:13/17/7 | 160:87/73 216:102/114 | 153:75/78 | 102:47/55 129:68/61 | 58:41/17 49:31/18 | 378:77/301 | 132:64/68 171:87/84 | 82:41/41 125:62/63 | 125:68/57 150:69/81 |
| No of BM | 45/47 | NA | 21/32 | NA | 59/62 | 60/60 | 65/69 | 47/26 | NA | 58/64 | 16/31 | 40/41 |
| Experimental agent | Crizotinib 250 mg PO BID | Crizotinib 250 mg PO BID | Crizotinib 250 mg PO BID | Crizotinib 250 mg PO BID | Ceritinib 750 mg PO QD q3w | Crizotinib 250 mg PO BID | Ceritinib 750 mg PO QD q3w | Alectinib 600 mg PO BID | Ceritinib 750 mg PO QD q3w | Alectinib 600 mg PO BID | Alectinib 600 mg PO BID | Brigatinib 180 mg once daily with a 7-day lead-in at 90 mg |
| Control | Chemo: Pemetrexed 500 mg/m2 with either cisplatin 75 mg/m2 or carboplatin AUC 5–6, IV q3w for ≤ 6 cycles | Chemo: Pemetrexed 500 mg/m2, docetaxel 75 mg/m2, or gemcitabine 1,250 mg/m2 on days 1 and 8 with either cisplatin 75 mg/m2 or carboplatin AUC 5–6, IV q3w | Chemo: Pemetrexed 500 mg/m2 with either cisplatin 75 mg/m2 or carboplatin AUC 5–6, IV q3w for ≤ 6 cycles | Chemo: Platinum based Pemetrexed /Platinum based non-pemetrexed | Chemo: Pemetrexed 500 mg/m2 with either cisplatin 75 mg/m2 or carboplatin AUC 5–6 for 4 cycles followed by maintenance pemetrexed | Chemo: Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 q3w | Chemo: Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 q3w | Chemo Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 q3w | Crizotinib 250 mg PO BID | Crizotinib 250 mg PO BID | Crizotinib 250 mg PO BID | Crizotinib 250 mg PO BID |
| PFS Exp vs. Con | MPFS: 10.9 m vs. 7.0 m HR: 0.45(0.35–0.6) p < 0.001 | MPFS: 13.3 m vs. 5.4 m HR: 0.20(0.11–0.36) p < 0.001 | MPFS: 11.1 m vs. 6.8 m HR: 0.40(0.29–0.57) p < 0.0001 | MPFS: 16.1 m vs. 6 m HR: 0.37(0.28–0.43) p < 0.001 *MPFS: 16.1 m vs. 2.9 m HR: 0.18(0.12–0.21) p < 0.001 | MPFS: 16.6 m vs. 8.1 m HR: 0.55(0.42–0.73) p < 0.00001 | MPFS: 7.7 m vs. 3.0 m HR: 0.49(0.37–0.64) p < 0.001 | MPFS: 5.4 m vs. 1.6 m HR: 0.49(0.36–0.67) p < 0.0001 | MPFS: 7.1 m vs. 1.6 m HR: 0.32(0.17–0.59) p < 0.001 | MPFS: 13.8 vs. 8.3 m HR: 0.52(0.44–0.62) p < 0.001 | MPFS: not reached vs. 11.1 m HR: 0.47(0.34–0.65) p < 0.001 | MPFS: not reached vs. 10.2 m HR: 0.34(0.17–0.71) p < 0.0001 | MPFS: not reached vs. 9.8 m HR: 0.49(0.33–0.74) p < 0.001 |
| ORR | Exp: 128/172, 74% (67–81) Con: 77/171, 45% (37–53) | Exp: 22/30, 73.3% (57–89) Con: 18/50, 36% (23–49) | Exp: 91/104, 87.5% Con: 47/103, 45.6% | Exp: 32/32, 100% Con: 1-PP:5/28, 17.9% N1-PP:2/13, 15.4% | Exp: 137/189, 72.5% (65–79) Con: 50/187, 27% (20–34) | Exp: 113/173, 65% (58–72) Con: 34/174, 20% (14–26) | Exp: 45/115, 39% (30–49) Con: 8/116, 6.9% (3–13) | Exp: 27/72, 37.5% Con: 1/35, 2.9% | Exp: 126/152, 83% (76–88) Con: 114/151, 75.5% (68–82) | Exp: 76/83, 92% (86–97) Con: 71/90, 79% (70–87) | Exp: 97/137, 71% (62–78) Con: 83/138, 60% (51–68) | |
| IC RR | IC progression/New IC lesions Exp: 25/172, 15% Con: 26/171, 15% | NA | NA | NA | ICRR BBM = Exp: 25/54, 46.3% (33–60) Con: 11/52, 21.2% (11–35) mBBM = Exp: 16/22, 72.7% (50–89) Con: 6/22, 27.3% (11–50) | NA | NA | ICRR BBM = Exp: 18/50, 36% Con: 0/26, 0% mBBM = Exp: 13/24, 54.2% Con: 0/16, 0% | ICRR BBM = Exp: 38/64, 59% (46–71) Con: 15/58, 26% (15–39) mBBM = Exp: 17/21, 81% (58–95) Con: 11/22, 50% (28–72) | ICRR BBM = Exp: 29/43, 67% (51–81) Con: 8/47, 17% (8–31) mBBM = Exp: 14/18, 78% (52–94) Con: 6/21, 29% (11–52) | ||
| OS | HR: 0.82(0.54–1.26) p = 0.36 | NA | HR: 0.90(0.56–1.45) p = 0.33 | NA | HR: 0.73(0.50–1.08) p = 0.056 | HR: 1.02(0.68–1.54) p = 0.54 | HR: 0.89(0.35–2.24) p = NS | HR: 0.59(0.46–0.75) p < 0.001 | HR: 0.76(0.48–1.20) p = 0.24 | |||
| Adverse events | NA | Overall AEs: l 75/80, 93.6% | NA | NA | All grades: Exp:189/189, 100% Con: 170/175, 97% Grade 3 or 4: Exp:148/189, 78% Con:108/175, 62% | NA | All grades: Exp:49/115, 43% Con: 36/113, 32% | All grades: Exp:54/70, 77% Con: 29/34, 85% Grade 3–5: Exp:19/70, 27% Con:14/34, 41% | All grades: Exp:147/152, 97% Con: 146/151, 97% Grade 3–5: Exp:63/152, 41% Con:76/151, 50% | All grades: Exp:132/136, 97% Con: 137/137, 100% Grade 3–5: Exp:83/136, 61% Con:76/137, 55% | ||
| Cross over | 70% | 82(80%) | NA | 72% | 112 (64%) | 70.6% | 25% | |||||
BM, brain metastases; NA, not available; Exp, experimental group; Con, control group; Chemo, chemotherapy; PFS, progression free survival;
*
MPFS, median progression free survival for crizotinib versus platinum based non-pemetrexed; HR, hazards ratio; ORR, objective response rate; m, months; IC, intracranial; ICRR, intracranial response rate; BBM, baseline brain metastases; mBBM, measurable baseline brain metastases; OS, overall survival; AEs, adverse events.