|
| Type of cancer | Drug | Target | Clinical trial, Phase | Outcome | Ref |
|
| Malignant melanoma | Ipilimumab (FDA approved in 2011) | CTLA-4 | NCT00094653, III | 676 unresectable stage III or IV melanoma treated with Ipilimumab vs gp100 vaccine. Improved survival with Ipilimumab, with median OS 10 months. Grades 3-4 AEs seen only in 10–15% patients. | [38] |
| Ipilimumab | CTLA-4 | I/II | Among 88 patients with unresectable stage III/IV melanoma treated with Ipilimumab at different dose levels, 7 had stable disease and 2 had response. Grades 3-4 AEs were only seen in 14% patients. | [50] |
| Ipilimumab + Dacarbazine vs Dacarbazine | CTLA-4 | NCT00324155, III | 502 patients with untreated metastatic melanoma were given Ipilimumab + Dacarbazine vs Dacarbazine alone. Median OS was 11 months in combination arm vs 9 months with Dacarbazine only arm. | [51] |
| Ipilimumab + Dacarbazine vs Ipilimumab | CTLA-4 | NCT00050102, II | 72 patients with unresectable, metastatic melanoma received Ipilimumab with Dacarbazine or Ipilimumab alone. ORR was 14.3% with median OS 14.3 months in first arm vs ORR of 5.4% with median OS 11.4 months in second arm. | [52] |
| Tremelimumab | CTLA-4 | NCT00086489, I/II | 28 patients with metastatic melanoma received escalating (3, 6, and 10 mg/kg) doses of Tremelimumab. Durable antitumor responses were seen and drug was well tolerable. | [53] |
| Tremelimumab | CTLA-4 | NCT00257205, III | In 534 patients with treatment naïve, unresectable stage III or IV melanoma, median OS was 12.6 months in Tremelimumab arm vs 10.7 months in Temozolamide or Dacarbazine arm. ORR was similar in both arms but response duration was 35.8 months vs 13.7 months. No significant survival advantage was seen. | [54] |
| Nivolumab | PD-1 | NCT00441337, I | 10 patients with advanced metastatic melanoma showed evidence of antitumor activity with Nivolumab and drug was well tolerated. | [55] |
| Nivolumab | PD-1 | NCT00730639, I | Among 107 advanced melanoma patients treated with Nivolumab, 33 had objective tumor regression, with a response duration of 2 years, and median OS was 16.8 months. | [56] |
| Pembrolizumab (MK-3475) | PD-1 | NCT01295827, I | MK-3475 was used in 173 patients with advanced melanoma who progressed after Ipilimumab. ORR was 26% and treatment was well tolerated. | [57–59] |
| MPDL3280A | PD-L1 | NCT01375842, I | In 45 melanoma patients, MPDL3280A was well tolerated and an ORR of 26% was observed. 24-week PFS was 25%. | [60] |
| BMS-936559 | PD-L1 | NCT00729664, I | Among 55 melanoma patients, durable tumor responses and prolonged stable disease were seen. | [61] |
|
| Lung | Ipilimumab | CTLA-4 | II | An objective response rate of 19% for NSCLC patients with squamous histology and 15% with nonsquamous histology. Patients who received phased Ipilimumab and Carboplatin and Paclitaxel showed improved PFS as compared to Carboplatin/Paclitaxel alone. | [62] |
| Nivolumab | PD-1 | I | Among 6 heavily pretreated patients with NSCLC, one had partial remission for over 14 months and other 5 had stable disease. | [55] |
| Nivolumab | PD-1 | I | Among 129 NSCLC patients, 17% had objective responses. Best response of 24% was seen at 3 mg/kg dose and median OS was 14.9 months. Durable and rapid responses, with OS 42% at 1 year and 24% at 2 years, across all histological subtypes. Median OS was 9.2 m in squamous and 10.1 m in nonsquamous. | [63–65] |
| Pembrolizumab (MK-3475) | PD-1 | I | Among 38 patients with advanced NSCLC who received >2 prior therapies, responses as early as 9 weeks were seen in 24% patients, both in squamous and non-squamous histologies. Median OS was 51 weeks. | [66] |
| BMS-936559 | PD-L1 | I | Among 49 patients with advanced NSCLC, objective responses were seen in 6 patients and another 6 with stable disease (both squamous and nonsquamous subtypes). | [61] |
| MPDL-3280A | PD-L1 | NCT01375842, I | 85 patients with NSCLC were evaluated for safety and 53 for efficacy. ORR was 21% with higher rates in PD-L1 positive tumors. Responses were sustained and dramatic response was seen in the smoking cohort. | [67, 68] |
| MEDI-4736 | PD-L1 | NCT01693562, I | In 13 heavily retreated NSCLC patients (median 4 lines of prior treatment), 3 patients achieved PR and 2 with response not reaching PR as early as 6 weeks. Response was durable. Acceptable safety profile at all doses. | [69] |
| Tremelimumab vs best supportive care | CTLA-4 | NCT00312975, II | Among 87 patients with locally advanced or metastatic NSCLC, no superiority in PFS was seen in study arm over BSC. 4.8% ORR was seen. | [70] |
|
| Metastatic CRPC | Ipilimumab | CTLA-4 | NCT00323882, I/II | 50 CRPC patients received Ipilimumab 10 mg/kg and RT and had manageable AEs. Eight patients had PSA decline >50%, 1 had CR and 6 had stable disease. | [71] |
| Ipilimumab | CTLA-4 | III | No difference in OS with Ipilimumab vs placebo in post-Docetaxel CRPC and bone metastasis following radiation therapy. PFS advantage was seen with Ipilimumab. | [72] |
| Nivolumab (BMS-936558) | PD-1 | NCT00730639, I | No objective responses were seen in 17 CRPC enrolled. | [63] |
|
| Metastatic RCC | Nivolumab | PD-1 | NCT01354431, II | 168 patients with metastatic clear cell RCC, median duration of response was 15.7 months and median OS was 18.2 months. 54% of responses lasted >12–20+ months. | [44] |
| Nivolumab | PD-1 | NCT01358721, I | 91 patients with metastatic RCC, Nivolumab showed clinical activity in previously treated and untreated metastatic RCC [ORR 16%]. Median duration of response was 15 months. Responses were higher in PD-L1+ patients (ORR 22%) but also seen in PD-L1 patients (ORR 8%). | [73] |
| Nivolumab + Sunitinib or Pazopanib | PD-1 | NCT01472081, I | Seven patients with metastatic RCC received Nivolumab in combination with Sunitinib (S) (33 patients) or Pazopanib (P) (20 patients). 41% had responses as early as 6 weeks, with ORR 52% in (S) arm; 56% has responses as early as 6 weeks, with ORR 45% in (P) arm PFS at 24 weeks was 78% for S arm and 55% for (P) arm. | [74] |
| MPDL3280A | PD-L1 | NCT01375842, I | 53 patients with metastatic RCC were evaluated for efficacy and safety. RECIST responses were observed across all doses and some has prolonged stable disease prior to RECIST response. 24-month PFS was 50%. | [75] |
| Nivolumab + Ipilimumab | CTLA-4 | NCT01472081, I | ORR was 29% in Nivolumab (N) and Ipilimumab (I) (N-3 mg/kg and I-1 mg/kg) arm. ORR was 39% in N-1 mg/kg and I-3 mg/kg arm. Stable disease was seen in 33% in N3 + I1 arm and 39% in N1 + I3 arm. | [76] |
|
| Urothelial bladder | MPDL3280A | PD-L1 | NCT01375842, I | ORR was 50% with a median time to response of 43 days, among 31 metastatic urothelial bladder cancer patients, including visceral metastases. | [71] |
|
| Ovarian | Ipilimumab | CTLA-4 | I | Among 2 pretreated advanced ovarian cancer patients, CA-125 level stabilization was seen in one and reduction in the other. | [77] |
| Ipilimumab | CTLA-4 | I | Among 11 patients with FIGO stage IV ovarian cancer, who previously received GVAX-antitumor activity was seen in one with dramatic fall in CA-125 and regression of metastatic lesions. Another 5 patients had stable disease per CA-125 and imaging. | [78] |
| MDX-1105 (BMS-936559) | PD-L1 | NCT00729664, I | Among 17 patients with ovarian cancer, 1 has partial response and 3 had stable disease lasting at least 24 weeks, all at 10 mg/kg dose. | [61] |
|
| SCC head and neck | MPDL3280A | PD-L1 | NCT01375842, I/II | One patient with metastatic head and neck cancer had response by second cycle of therapy. | [79] |
| MK3475 | PD-1 | NCT01848834, IB | On interim analysis of 60 patients with metastatic or recurrent head and neck cancer, drug was well tolerated. Tumor shrinkage was seen in many patients, but protocol specific analysis is pending. | [80] |
| MEDI4736 | PD-L1 | NCT01693562, I | Preliminary data suggests that even in heavily pretreated patients of head and neck cancer, tumor shrinkage was detectable as early as 6 weeks. | [81] |
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