TABLE 3.
Main characteristics of Phase 3 clinical trials selected for the analysis.
| Trial registration number (first posted date) | Intervention model/masking | Tumor type | Treatment arm(s) | Number of patients | Primary endpoint | Cycle length | Timing of scans | Time frame (primary endpoint) | DI ORR | DI PFS | Reference | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | NCT00069108 (September 18, 2003) | Parallel assignment/none (open label) | Colorectal cancer | E: XELOX | E (ITT): 313 | PFS per LI | E: 3 weeks up to eight cycles | Every 6 weeks (+ within 2 weeks of study completion, withdrawal or treatment discontinuation) | Up to 3 years | E (ITT): 1.50 | E (PP): 0.92 | Rothenberg et al. (2008) |
| AC: FOLFOX-4 | AC (ITT): 314 | |||||||||||
| E (PP): 251 | AC: 2 weeks up to 12 cycles | AC (ITT): 1.33 | AC (PP): 1.04 | |||||||||
| AC (PP): 314 | ||||||||||||
| 2 | NCT02370498 (25 Feb 2015) | Parallel assignment/none (open label) | Gastric adenocarcinoma | E: pembrolizumab | E (all): 296AC (all: 296 | PFS (and OS) per BICR in PD-L1+ patients | E: 21 days | Every 6 weeks | Up to 30 months | E (all): 1.10 | E (all): 1.07 | Shitara et al. (2018) |
| Gastroesophageal junction adenocarcinoma | AC: paclitaxel | E (PD-L1+): | AC (all): 1.22 | AC (all): 0.78 | ||||||||
| 196 | AC: 28 days | E (PD-L1+): 1.09 a | E (PD-L1+): 1.07 a | |||||||||
| AC (PD-L1+): 199 | AC (PD-L1+: 1.15 a | AC (PD-L1+: 0.76 a | ||||||||||
| 3 | NCT00075270 (9 Jan 2004) | Parallel assignment/ | Metastatic breast cancer | E: lapatinib (+ paclitaxel) | E: 291 | TTP per LI and BICR | E: 3 weeks | For efficacy 9 weeks after study entry, at 12-week intervals, and at treatment end. For survival at 12-week intervals | Average 26 weeks | E: 1.31 | E: 0.86 b | Di Leo et al. (2008) |
| double (participant, investigator) | AC: placebo (+ paclitaxel) | AC: 288 | AC: 3 weeks | AC: 1.35 | AC: 0.88 b | |||||||
| 4 | NCT01120184 (10 May 2010) | Parallel assignment/ | Breast cancer | AC: trastuzumab + taxane | PFS | PFS per BICR | 3 weeks (except paclitaxel every 1 week) | Every 9 weeks for 81 weeks, then every 12 weeks thereafter, and/or up to 42 days after last dose | Up to 48 months | AC: 1.02 | AC: 0.91 | Perez et al. (2017) |
| triple (participant, investigator, and outcomes assessor) | E1: trastuzumab emtansine + placebo | AC: 365 | E1: 1.08 | E1: 1 | ||||||||
| E2: trastuzumab emtansine + pertuzumab | E1: 367 | E2: 1.05 | E2:0.97 | |||||||||
| E2: 363 | ||||||||||||
| ORR | ||||||||||||
| AC: 287 | ||||||||||||
| E1: 303 | ||||||||||||
| E2: 299 | ||||||||||||
| 5 | NCT00689936 (4 Jun 2008) | Parallel assignment/ | Multiple myeloma (previously untreated; stem cell transplant ineligible) | Arm 1: lenalidomide + low-dose DEX (until disease progression) | Arm 1: 535 | PFS per BICR and LI | 4 weeks | After each treatment cycle and every | PFS by BICR: median follow-up time of 17.1 months | Arm 1: 1.07 | Arm 1: 1.02 | Benboubker et al. (2014) |
| none (open label) | Arm 2: lenalidomide + low-dose DEX (18 cycles) | Arm 2: 541 | 28 days during the follow-up phase | PFS by BICR: median follow-up time of 17.7 months | Arm 2: 1.07 | Arm 2: 1.01 | ||||||
| Arm 3/AC: melphalan + prednisone + thalidomide | Arm 3/AC: 547 | Arm 3/AC: 1.08 | Arm 3/AC: 1.03 | |||||||||
| 6 | NCT01360554 (25 May 2011) | Parallel assignment/ | Non-small-cell lung cancer | E: dacomitinib (PF-00299804) + placebo (erlotinib) | All population | PFS per BICR and | 28 days (continuous oral daily dosing) | At the end of cycles 2, 3, and 4, then every other cycle | Median follow-up of 7.1 months, until disease progression | E: 1.13 | E: 0.73 | Ramalingam et al. (2014) |
| quadruple (participant, care provider, investigator, and outcomes assessor) | AC: erlotinib + placebo (PF-00299804) | E: 439 | PFS in KRAS wild-type patients | AC: 1.29 | AC: 0.76 | |||||||
| AC: 439 | ||||||||||||
| 7 | NCT01774721 (24 Jan 2013)/EudraCT | Parallel assignment/ | Non-small-cell lung cancer with EGFR-activating mutations | E: dacomitinib (PF-00299804) | E: 227 | PFS per BICR | 28 days (continuous oral daily dosing) | At the end of cycles 1–2, then at | Up to 48 months | E: 1.01 | E: 1.13 | Wu et al. (2017) |
| 2012-004977-23 (25 Oct 2018) | none (open label) | AC: gefitinib | AC: 225 | every other cycle | AC: 0.98 | AC: 1.20 | ||||||
| 8 | NCT02604342 (13 Nov 2015)/EudraCT | Parallel assignment/ | Non-small-cell lung cancer | E: alectinib | E: 79 | PFS per LI | 3 weeks (alectinib: continuous oral twice daily dosing) | Every 6 weeks | Up to 33 months | E: 1.40 | E: 1.35 | Novello et al. (2018) |
| 2015-000634-29 | none (open label) | AC: premetrexed/ | AC: 40 | AC: 0.22 | AC: 0.875 | |||||||
| docetaxel | ||||||||||||
| 9 | NCT01245062 (22 Nov 2010) | Crossover assignment/ | Melanoma | E: trametinib (GSK1120212) | BRAF V600E + w/o brain metastasis | PFS in BRAF V600E+ w/o brain metastasis per BICR and LI | 3 weeks (trametinib: continuous dosing) | At weeks 6, 12 | Average of 20.3 months | BRAF V600E+ w/o brain metastasis | BRAF V600E+ w/o brain metastasis | Flaherty et al. (2012) |
| none (open label) | AC: dacarbazine or paclitaxel | E: 178 | 21, and 30; then, every 12 weeks | E: 1.30 | E: 0.92 | |||||||
| AC: 75 | AC: 2.33 | AC: 0.88 | ||||||||||
| 10 | NCT02718417 (24 Mar 2016) EudraCT | Parallel assignment/ | Ovarian cancer | AC: chemotherapy then observation | AC: 335 | PFS per BICR | Chemotherapy: 3 weeks | After three cycles and at completion of chemotherapy; then, every 12 weeks during maintenance | Maximum duration of 27 months | AC: 0.914 a | AC: NA a | Monk et al. (2021) |
| 2015-003239-36 | none (open label) | E1: chemotherapy then avelumab in maintenance | E1: 332 | Avelumab: 2 weeks | E1: 0.852 | E1: 0.821 | ||||||
| E2: chemotherapy in combination with avelumab then avelumab in maintenance | E2: 331 | E2: 0.864 | E2: 0.890 | |||||||||
| 11 | NCT00083889 (4 Jun 2004) | Parallel assignment/ | Renal cell carcinoma | AC: IFNα | AC: 375 | PFS per BICR and LI | AC: 3 weeks | At day 28 of cycles 1 through 4, and every two cycles thereafter until the end of treatment | Duration of treatment phase | AC: 1.50 | AC: 1.00 | Motzer et al. (2007) |
| none (open label) | E: sunitinib (SU011248) | E: 375 | E: 6 weeks | E: 1.19 | E: 0.99 | |||||||
| 12 | NCT02421588 (April 20, 2015) EudraCT | Parallel assignment/ | Ovarian cancer (platinum resistant) | E (Arm A): lurbinectedin (PM01183) | E: 221 | PFS per BICR | E: 3 weeks | Every 8 weeks | Up to 3 years | E: 1.09 | E: 1.10 | Gaillard et al. (2021) |
| 2014–005251-39 (17 Oct 2019) | none (open label) | AC (Arm B): pegylated liposomal doxorubicin or topotecan | AC: 221 | AC: pegylated liposomal doxorubicin (4 weeks) | AC: 1.31 | AC: 1.00 | ||||||
| topotecan (3 weeks) | ||||||||||||
| 13 | NCT03052608 (14 Feb 2017) | Parallel assignment/ | Non-small-cell lung cancer | E: lorlatinib | E: 149 | PFS per BICR | 28 days | Every 8 weeks (±1 week) | Up to 33 months | E: 1.06 a | E: NA a | Shaw et al. (2020) |
| none (open label) | AC: crizotinib | AC: 147 | AC: 1.07 | AC: 0.98 | ||||||||
| 14 | NCT01102426 (13 Apr 2010) | Parallel assignment/ | Relapsed/refractory multiple myeloma | E: plitidepsin + dexamethasone | E: 171 | PFS per BICR | 4 weeks | NA | Up to 5 years | E: 1.31 | E: 1.12 | Spicka et al. (2019) |
| none (open label) | AC: dexamethasone | AC: 84 | AC: 0.33 | AC: 0.65 | ||||||||
| 15 | NCT01287741 c | Parallel assignment/ | Diffuse large B-cell lymphoma | E: obinutuzumab + chemotherapy | E: 712 | PFS per LI | 21 days | 4–8 weeks (CT) or 6–8 weeks (FDG-PET) after the last treatment or sooner in the case of early discontinuation | LE up to approximately 6.5 years | E: 0.999 a | NA a | Vitolo et al. (2017) |
| (1 Feb 2011) EudraCT 2010-024194-39 | none (open label) | AC: rituximab + chemotherapy | AC: 706 | BICR: up to approximately 4 years and 9 months | AC: 0.992 a | |||||||
| (23 Apr 2017) | ||||||||||||
| 16 | NCT02580058 d | Parallel assignment/ | Ovarian cancer | E1: avelumab | E1: 188 | PFS per | Avelumab: 2 weeks; doxorubicin: 4 weeks | MRI or CT scans every 8 weeks | Up to 30 months | E1: 1.43 | E1: 1.00 | Pujade-Lauraine et al. (2021) |
| (20 Oct 2015) | none (open label) | E2: avelumab plus pegylated liposomal doxorubicin (PLD) | E2: 188 | BICR and OS | E2: 1.40 | E2: 1.27 | ||||||
| AC: PLD alone | AC: 190 | AC: 2.26 | AC: 1.06 | |||||||||
| 17 | NCT02603432 d | parallel assignment/ | Urothelial cancer | E (Arm A): avelumab plus best supportive care (BSC) | E (Arm A): 350 | OS | 4 weeks | Every 8 weeks for 12 months and then every 12 weeks | Up to 41 months at the time of final analysis | E (Arm A): 1.27 | E (Arm A): 1.5 | Powles et al. (2020) |
| (11 Nov 2015) | none (open label) | Arm B: best supportive care (BSC) alone | Arm B: 350 | Arm B: 2.43 | Arm B: 1.05 | |||||||
| 18 | EudraCT | Parallel assignment/ | Untreated advanced renal cell carcinoma | AC: sunitinib | ITT: | PFS per LI in PD-L1 selected population | AC: 4 weeks on, 2 weeks off | At week 12, then every 6 weeks up to week 78, and then every 12 weeks | Up to approximately 24 months | ITT | ITT | Rini et al. (2019) |
| 2014-004684-20 NCT02420821 (20 Apr 2015) | none (open label) | E: atezolizumab + bevacizumab | AC: 461 | E: 3 weeks | AC: 1.064 | AC: 1.012 | ||||||
| E: 454 | E: 1.099 | E: 1.167 | ||||||||||
| 19 | EudraCT 2010-024132-41 | Parallel assignment/ | Non-Hodgkin’s lymphoma | E: obinutuzumab + chemotherapy | Follicular lymphoma population | PFS per LI in the follicular lymphoma population | 21 or 28 days | After three cycles (bendamustine treated) or four cycles (CHOP or CVP) and on the completion of induction therapy; every 2 months for 2 years; then, every 3–6 months, with CT performed every 6–12 months, until progression or withdrawal from the trial | Up to ∼4 years and 7 months | E: 0.957 | E: 1.15 | Hiddemann et al. (2018); Marcus et al. (2017) |
| (16 Mar 2017) | none (open label) | AC: rituximab + chemotherapy | E: 601 | AC: 0.970 | AC: 1.08 | |||||||
| NCT01332968 (11 Apr 2011) | AC: 601 | |||||||||||
| 20 | EudraCT | Parallel assignment/ | Advanced BRAFV600 wild-type melanoma | E: cobimetinib + atezolizumab | E: 222 | PFS per BICR | Every 8 weeks through 80 weeks; then, every 12 weeks until progression | 3 weeks | For approximately 16 months | E: 1.07 | E: 1.02 | Gogas et al. (2021) |
| 2016-004387-18 d (01 May 2020) NCT03273153 (6 Sep 2017) | none (open label) | AC: pembrolizumab | AC: 224 | AC: 1.16 | AC: 1.26 | |||||||
| 21 | NCT00789373 (First posted: 11 Nov 2008) | Parallel assignment/ | Non-small-cell lung cancer | E: pemetrexed (maintenance) | E: 316/359 | PFS per LI | Every other cycle (6 weeks [±1]) | 21 days | (Up to 19.3 months) | E: 1 | E: 1.043 | Paz-Ares et al. (2012) |
| quadruple (participant, care provider, investigator, and outcomes assessor) | AC: placebo | AC: 156/180 | AC: 1 | AC: 1.088 |
Trials that were included in our initial analysis (Dello Russo et al., 2021) are highlighted in gray. ITT, intention to treat population; ORR, objective response rate; PFS, progression-free survival; PD-L1, programmed cell death ligand 1; PP, per protocol; TTP, time to progression.
a
Not included in the analysis because the subgroup of the whole population or the specific arm/group was missing the DI for one of the outcomes (either ORR or PFS).
b
Time to progression was used for comparative analysis.
c
Trial NCT01287741 is included in the table because HR values for PFS per LI and BICR were available for comparison. DI was calculated and included in a pooled analysis (see text).
d
For these trials, DI based of the HR values for PFS was not available.