The 2016 ASCO Annual Meeting was held in Chicago, IL from June 3 to 7 and attracted more than 30,000 attendees. As the largest international oncology conference, ASCO 2016 meeting content reflects the exponential growth of immuno-oncology (I-O) in recent years. There were 216 abstracts on checkpoint inhibition alone at this year’s meeting, a dramatic increase from less than 80 at ASCO 2015 (Figure 1). This article highlights results from key clinical studies on checkpoint inhibitors and CAR-T (chimeric antigen receptor T cell) therapy presented at ASCO 2016.
Checkpoint Inhibitors as Monotherapy
This year’s ASCO meeting continued pushing the frontier of checkpoint inhibition in solid tumors. Clinical data presented on single agent therapy in head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma, and renal cell carcinoma (RCC) generated high interest as they offered new hope to patients with poor prognosis.
Nivolumab and Pembrolizumab in HNSCC
As presented in four oral abstract sessions, both nivolumab and pembrolizumab demonstrated strong results in heavily pretreated HNSCC, supporting their use as new standards of care. CheckMate-141 is a randomized phase III study in 361 patients with recurrent or metastatic HNSCC.1 Patients were randomized to either nivolumab or investigator’s choice of therapy (mitoxantrone, docetaxel, or cetuximab).
Nivolumab improved median overall survival (mOS) compared with control 7.5 m vs 5.1 m; HR = 0.70; [97.73% CI 0.51–0.96; P=0.010]. The benefit of nivolumab was higher among the PD-L1 ≥1% subgroup, in which the objective response rate (ORR) with nivolumab and control was 17.0% and 1.6%, respectively, while mOS was 8.7 and 4.6 months; HR = 0.56; [95% CI 0.36–0.83].
Among the PD-L1 <1% subgroup, ORR with nivolumab and control was 12.3% and 10.5%, while mOS was 5.7 vs 5.8 m; HR = 0.89; [95% CI 0.54-1.45]. Median progression-free survival (mPFS) was similar with nivolumab (2.0 months) and control (2.3 months). Grade 3/4 treatment-related adverse events (TRAE) was lower for nivolumab (13.1%) than control (35.1%).
Pembrolizumab as a single agent demonstrated remarkably similar efficacy and safety as nivolumab for recurrent and metastatic HNSCC in phase I (KEYNOTE-012)2,3 and phase II (KEYNOTE-055)4 clinical trials, with ORR of 18%, mPFS of 2.1 to 2.2 months, and mOS of 8.0 months. Grade 3/4 TRAE was also similar to that of nivolumab (12%-13%).
With positive results presented at ASCO (Table 1), HNSCC has become the new racing ground for nivolumab and pembrolizumab. The FDA granted pembrolizumab Priority Review and a PDUFA date of August 9, 2016, for recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Nivolumab has received Breakthrough Therapy designation for previously treated recurrent or metastatic HNSCC.
Multiple PD-L1 Inhibitors in Urothelial Carcinoma
Results of 3 checkpoint inhibitors in urothelial carcinoma were presented at ASCO this year (Table 2). Atezolizumab, an anti-PD-L1 antibody, demonstrated efficacy in both the first- and second-line setting. IMvigor210 was a phase II study of atezolizumab in patients with inoperable locally advanced or metastatic urothelial carcinoma. In cohort 1 of the study, 119 patients who are cisplatin-ineligible received atezolizumab as first-line therapy.5 ORR was 19% in the overall group and 22% in the PD-L1 ≥5% group. The mOS for both the overall group and PD-L1 ≥5% group was 10.6 months. Grade 3/4 TRAE was recorded in 12% patients.
Results of cohort 2, which recruited 310 patients with platinum-treated metastatic urothelial carcinoma, was reported in a separate session.6 Unlike cohort 1 where the PD-L1 expression did not seem to significantly impact ORR and mOS, atezolizumab as second-line therapy was more efficacious with higher PD-L1 expression. ORR in the overall, PD-L1 ≥5%, and PD-L1 negative groups was 15%, 26%, and 8%, respectively. Among the responders, 71% have ongoing responses. mOS was 7.9 months overall and 11.4 months in the PD-L1 ≥5% group. Grade 3/4 TRAE was observed in 16% of patients.
Atezolizumab is the latest checkpoint inhibitor to receive FDA approval ( May 18, 2016). It is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.7
Two other anti-PD-L1 agents demonstrated activity in urothelial carcinoma in the second-line setting. In a phase I/II study of 42 patients with bladder cancer (51% with ≥2 prior systemic treatments), durvalumab achieved an ORR of 38% overall, 54% in the PD-L1 positive group, and 7% in the PD-L1 negative group.8 Grade 3/4 TRAE totaled 4.9%. A phase Ib study of avelumab as second-line therapy demonstrated an ORR of 18% in patients with metastatic urothelial carcinoma (median number of prior therapies = 2).9
ORR was higher in ≥1% PD-L1 patients (50%) and low in PD-L1 negative patients (4.5%). Median PFS was 11.7 weeks and mOS was 12.9 months. Grade 3/4 TRAE occurred in 9.1% of patients. Durvalumab was granted Breakthrough Therapy designation by the FDA for treatment of patients with PD-L1 positive urothelial bladder cancer. Avelumab has received FDA Breakthrough Therapy designation for metastatic Merkel Cell Carcinoma.
Nivolumab Continuation Beyond Progression of Advanced Renal Cell Carcinoma (RCC)
An analysis presented at the ASCO annual meeting shed light on the value of checkpoint inhibition after initial disease progression. CheckMate-025 is a randomized phase III study in patients with advanced clear-cell RCC after previous treatment with 1 or 2 antiangiogenic therapy.10 Of 406 patients treated with nivolumab, 153 continued treatment after first RECIST progression. Of these, 14% experienced ≥30% tumor reduction. Patients who received continued nivolumab had improved survival compared with those who did not (28.1 m vs 15.0 m; P<0.001). These results demonstrate that patients on nivolumab may experience delayed but beneficial immune responses after progression.
Checkpoint Inhibitors in Combination Therapy
Research on checkpoint inhibition has advanced beyond single agents to combination strategies. Results of dual checkpoint inhibition and checkpoint inhibitor plus chemotherapy were featured in this year’s ASCO annual meeting.
Nivolumab or Pembrolizumab in Combination with Ipilimumab in Melanoma
The combination of anti-PD-1 therapy with anti-CTLA-4 therapy is being tested in a number of tumor types. CheckMate-067 is a randomized phase III study that evaluated the combination of nivolumab and ipilimumab in treatment-naïve advanced melanoma.11 Updated results were presented at the meeting. A total of 945 patients were randomized 1:1:1 to nivolumab 1 mg/kg Q3W + ipilimumab 3 mg/kg Q3W for 4 doses followed by nivolumab 3 mg/kg Q2W, nivolumab 3 mg/kg Q2W + placebo, or ipilimumab 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity.
Patients who received nivolumab plus ipilimumab had significantly improved mPFS compared with nivolumab alone 11.5 vs 6.9 m; HR = 0.75; [95% CI 0.60-0.92] or ipilimumab alone 11.5 vs 2.9 m; HR = 0.42; [95% CI 0.31-0.57]. Combination therapy showed greater efficacy than either agent alone regardless of PD-L1 expression and BRAF status. ORR was also significantly higher with combination therapy than with ipilimumab alone (57.6% vs 19%; P<0.001). Median duration of response was not reached for the combination arm. Combination therapy was associated with higher grade 3/4 TRAE (56.5%) than nivolumab alone (19.8%) or ipilimumab alone (27.0%).
Another session reported results on KEYNOTE-029, a phase I expansion cohort study of pembrolizumab plus ipilimumab that enrolled 153 patients with advanced melanoma without prior checkpoint inhibition.12 Similar to nivolumab plus ipilimumab, pembrolizumab plus ipilimumab resulted in 51% ORR. Grade 3/4 TRAE was observed in 38% of patients.
Nivolumab Plus Ipilimumab in Lung Cancer
Combination of nivolumab and ipilimumab also produced encouraging results in lung cancer. In CheckMate-012, a phase Ib study of 148 patients with advanced non-small cell lung cancer (NSCLC) without prior chemotherapy, overall ORR was higher with front-line nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q12W (A, 47%) and nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W (B, 39%) than nivolumab alone (23%).13
The ORR for the PD-L1 ≥1% subgroup was 57%, 57%, and 28%. Combination therapy in the first-line setting was also associated with extended mPFS compared with nivolumab alone, especially in PD-L1 positive patients. In the PD-L1 ≥1% subgroup, mPFS for A, B, and nivolumab alone was 8.1, 10.6, and 3.5 months, and mOS was 90, 83, and 69 months. As in CheckMate-067, grade 3/4 TRAE was higher for the combination (33%-37%) than for nivolumab alone (19%), although the discontinuation rate was similar across the groups (10%-13%).
Nivolumab plus ipilimumab was also evaluated in small cell lung cancer (SCLC) that progressed after platinum-based chemotherapy in the phase I/II CheckMate-032 study.14 Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (A) and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (B) produced higher ORR than nivolumab 3mg/kg alone (23%, 19%, and 10%). Median OS was also higher for combination therapy than nivolumab alone (7.7, 6.0, and 4.4 mo). Grade 3/4 TRAE for A, B, and nivolumab alone was 30%, 19%, and 13%, while the discontinuation rate was 11%, 7%, and 6%.
Other Combination Strategies
One study presented at ASCO assessed the strategy combining anti-PD-L1 therapy and chemotherapy in metastatic triple-negative breast cancer (mTNBC).15 In a phase Ib study of 32 patients with mTNBC treated with ≤3 prior lines of therapy, atezolizumab plus nab-paclitaxel produced an ORR of 38%. However, the combination was associated with substantial toxicity, including 47% serious neutropenia. Half of responders discontinued therapy.
Another phase Ib study combined pembrolizumab with utomilumab, an agonist of the co-stimulatory protein 4-1BB (CD137) found on T cells and natural killer cells.16 This combination resulted in objective responses in 26% of a small group of patients with solid tumors (n=23). The regimen seemed well-tolerated and there was no treatment discontinuation.
CAR-T Therapy in B-Cell Malignancies
Adoptive cell transfer (ACT), in which autologous immune cells collected from patient blood are engineered to recognize tumor antigens, expanded in culture, and reinfused back into the patient, is a novel immunotherapeutic approach gaining substantial interest in recent years. In particular, ACT involving CAR-T has become a field of intense competition.
JCAR 014, a CD19 CAR-T therapy comprised of a defined ratio of CD8+ and CD4+ CAR-T cells, was evaluated in a phase I/II study of 90 patients with relapsed or refractory CD19+ B-cell malignancies.17 All 34 patients with acute lymphoblastic leukemia (ALL) who completed response assessment achieved morphologic bone marrow complete remission (CR). Addition of fludarabine to cyclophosphamide lymphodepletion dramatically increased CAR-T cell expansion and persistence. Among 41 non-Hodgkin’s lymphoma (NHL) patients receiving JCAR 014, 50% of those who had lymphodepletion without fludarabine achieved ORR and 8% achieved CR.
Addition of fludarabine improved the ORR and CR to 74% and 44%. Similarly, ORR and CR were higher among 13 patients with chronic lymphocytic leukemia (CLL) when fludarabine was added (ORR: 91%; CR: 45%) compared with no fludarabine (ORR: 50%; CR: 0%). Serious neurotoxicity was observed in 39% of patients with ALL, 20% of patients with NHL, and 23% of patients with CLL. There were 5 patient deaths in the trial.
Another session focused on JCAR015, a 19-28z CAR-T therapy, in 51 adult patients with relapsed, refractory B-cell ALL.18 CR was achieved in 77% of patients who had morphologic disease and 90% of patients who had minimal disease. Overall, 27% of patients remained disease-free for more than 1 year. Severe cytokine release syndrome (CRS) or neurological toxicities occurred in 55% of patients who had morphologic disease and 20% of those who had minimal disease. Three patients died of treatment toxicity.
In spite of the high response rates, these CAR-T therapies were associated with potentially fatal toxicities that may be attributed to addition of fludarabine to cyclophosphamide in the lymphodepletion regimen.17,18 The JCAR 015 study was briefly halted by the FDA after 3 patient deaths. It was allowed to resume with a modified pre-conditioning protocol excluding fludarabine.19
Other CAR-T therapies are also showing encouraging results. A study conducted at the National Institutes of Health (NIH) reported using low-dose conditioning chemotherapy of cyclophosphamide plus fludarabine followed by infusion of CD19 CAR-T in patients with diffuse large B-cell lymphoma.20 Of the 22 patients treated, 73% obtained an objective response, including 55% CR. Among the complete responders, 10 have ongoing remission. Again, neurological toxicities were the most prominent toxicities.
Another study (ZUMA-1) utilizes KTE-C19,21 which has the same CAR construct as the NIH trial. Seven patients with chemotherapy-refractory aggressive B-cell NHL received KTE-C19 with a fixed dose of cyclophosphamide/fludarabine preconditioning regimen. Of these, 71% achieved an objective response, with 57% achieving CR. Three of the remissions are ongoing at 9 months of follow-up. One subject experienced a dose-limiting toxicity of grade 4 CRS and neurotoxicity.
Table 3. Summary of Key Findings on Immunotherapy at ASCO 2016
- Nivolumab improved OS compared with chemotherapy in recurrent/metastatic HNSCC in a phase III randomized study.
- Pembrolizumab also demonstrated similar efficacy and safety.
- PD-L1 inhibitors demonstrated activity in advanced urothelial carcinoma.
- Atezolizumab received FDA approval for urothelial carcinoma that progressed after platinum-based chemotherapy.
- Patients with RCC who continued nivolumab beyond progression had improved survival compared with those who discontinued.
- Nivolumab plus ipilimumab showed higher efficacy than monotherapy in melanoma, NSCLC, and SCLC.
- Atezolizumab plus nab-paclitaxel showed activity in TNBC.
- Utomilumab (anti-4-1BB) is a promising new immunotherapeutic agent for solid tumors.
- CAR-T demonstrated high response rates in B-cell malignancies.
- Ferris RL, et al. J Clin Oncol. 2016;34 (suppl); Abstract 6009.
- Mehra R, et al. J Clin Oncol. 2016;34 (suppl); Abstract 6012.
- Chow LQM, et al. J Clin Oncol. 2016;34 (suppl); Abstract 6010.
- Bauml J, et al. J Clin Oncol. 2016;34 (suppl); Abstract 6011.
- Balar AV, et al. J Clin Oncol. 2016;34 (suppl); Abstract 4500.
- Dreicer R, et al. J Clin Oncol. 2016;34 (suppl); Abstract 4515.
- Atezolizumab [package insert]. Genentech. 2016.
- Massard C, et al. J Clin Oncol. 2016;34 (suppl); Abstract 4502.
- Apolo AB, et al. J Clin Oncol. 2016;34 (suppl); Abstract 4514.
- Escudier BJ, et al. J Clin Oncol. 2016;34 (suppl); Abstract 4509.
- Wolchok JD, et al. J Clin Oncol. 2016;34 (suppl); Abstract 9505.
- Long GV, et al. J Clin Oncol. 2016;34 (suppl); Abstract 9506.
- Hellmann MD, et al. J Clin Oncol. 2016;34 (suppl); Abstract 3001.
- Antonia SJ, et al. J Clin Oncol. 2016;34 (suppl); Abstract 100.
- Adams S, et al. J Clin Oncol. 2016;34 (suppl); Abstract 1009.
- Tolcher AW, et al. J Clin Oncol. 2016;34 (suppl); Abstract 3002.
- Turtle CJ, et al. J Clin Oncol. 2016;34 (suppl); Abstract 102.
- Park JH, et al. J Clin Oncol. 2016;34 (suppl); Abstract 7003.
- Juno Therapeutics. News release. July 12, 2016. http://ir.junotherapeutics.com/phoenix.zhtml?c=253828&p=irol-newsArticle&ID=2184987.
- Kochenderfer J, et al. J Clin Oncol. 2016;34 (suppl); Abstract LBA3010.
- Neelapu SS, et al. J Clin Oncol. 2016;34 (suppl); Abstract 7559.