November 2014, Part 4

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Immunotherapeutic Strategies for Improving Patient Outcomes: Presentations From the European Society for Medical Oncology

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Immunotherapy is the hot topic on everyone’s mind in the oncology community, and there are numerous research studies focusing on how to optimally provide immunotherapeutic strategies to ultimately improve patient outcomes. At the European Society for Medical Oncology (ESMO) 2014 Congress, many exciting presentations outlined the work being done to provide immunotherapeutic approaches in many different cancers. Here we present a summary of that work in progress by disease state.

MelanomaRenal Cell CarcinomaSoild TumorsProstate CancerLung CancerGenitourinary Cancer

MELANOMA

Use of Nivolumab Plus Ipilimumab Immunotherapy in Patients With Advanced Melanoma

The most recent advancement in the treatment of advanced melanoma is the development of immunotherapies targeting immune checkpoint molecules that are implicated in cancer evasion, such as the programmed death-1 receptor (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Blocking these pathways represents an immunotherapy strategy in cancer therapy that can restore tumor-specific T-cell–mediated immunity. Ipilimumab, a fully human anti–CTLA-4 monoclonal antibody, and nivolumab, a fully human anti–PD-1 antibody, have improved clinical outcomes as single agents in patients with advanced melanoma. Kluger and colleagues presented updated data for survival, efficacy, and clinical activity by BRAF mutation status from a phase 1 clinical trial that evaluated concurrent or sequential therapy with nivolumab plus ipi­limumab in several cohorts of patients with advanced melanoma (Kluger H, et al. ESMO 2014. Abstract 1085O).

In the initial 1-3 concurrent cohorts, 53 patients received nivolumab (0.3, 1.0, or 3.0 mg/kg) every 3 weeks for 8 cycles plus ipilimumab (1 or 3.0 mg/kg) every 3 weeks for 4 cycles as induction; maintenance therapy was then administered with both agents every 12 weeks for 8 doses if patients had no progression by immune-related criteria and no dose-limiting toxicities. An additional 41 patients (cohort 8) received nivolu­mab 1 mg/kg plus ipilimumab 3 mg/kg at the same induction schedule, then nivolumab 3 mg/kg every 2 weeks for up to 48 doses as maintenance treatment. The 2 sequential cohorts (n=33) included patients who had received previous standard ipilimumab therapy and who then received maintenance nivolumab 1 or 3 mg/kg every 2 weeks for up to 48 doses (4-12 weeks after last ipilimumab dose).

In the initial concurrent cohort (n=53), 40% of patients achieved an objective response rate (ORR) by RECIST criteria and 42% demonstrated tumor reduction of ?80% by week 36; the equivalent rates were 43% and 28%, respectively, in cohort 8. Patients in the sequenced cohort also achieved similar responses, with an ORR of 41% by RECIST criteria, including complete response in 6 patients. In the concurrent cohorts 1-3, the 1-year and 2-year overall survival (OS) rates were 85% and 79%, respectively; these OS rates were even higher in cohort 2 (94% and 88%, respectively). By contrast, the 1-year OS rate was lower (70%) in the sequential cohorts; this was hypothesized to be the results of residual levels of plasma ipilimumab.

Retrospective analysis of the clinical responses by BRAF mutation status showed that clinical activity was independent of BRAF mutation status. Safety analysis across all cohorts (n=94) showed that grade 3/4 treatment-related adverse events (AEs) were reported in 64% of patients; notably, biochemical laboratory abnormalities, including elevations in lipase (15%), ALT (12%), and AST (11%) accounted for the majority of the reported incidence rate.

Kluger and colleagues concluded that the concurrent treatment with nivolumab plus ipilimumab was associated with unprecedented OS rates, which was accompanied by a manageable safety profile in patients with advanced melanoma. Moreover, treatment responses were independent of BRAF mutation status and were durable in many patients.

The EORTC 18071 Trial: Comparing Adjuvant Ipilimumab Treatment and Placebo in Patients With Stage III Melanoma


The adjuvant treatment options for patients with locally advanced melanoma that are at high risk for relapse are limited, underscoring the need for effective agents in this setting. The monoclonal antibody ipilimumab that is directed against the immune checkpoint molecule CTLA-4 to augment antitumor immune responses is currently approved for patients with advanced melanoma. Eggermont and colleagues presented results from the large, randomized, double-blind ECOG 18071 clinical trial that sought to test ipilimumab in the adjuvant setting (Eggermont A, et al. ESMO 2014. Abstract 1087O).

In this trial, 951 patients who had undergone complete resection of stage III cutaneous melanoma were randomized to receive ipilimumab 10 mg/kg (n=475) or placebo (n=476) every 3 weeks for 4 doses (ie, induction therapy), then every 3 months for up to 3 years until completion, disease recurrence, or unacceptable toxicity (ie, maintenance therapy). The primary end point was recurrence-free survival (RFS); secondary end points included OS and distant metastasis-free survival.

At a median follow-up of 2.7 years, ipilimumab therapy resulted in a significant prolongation of RFS compared with placebo (26.1 vs 17.1 months), with a 25% reduction in risk of recurrence (hazard ratio [HR] 0.75; P=.0013). The 3-year RFS rates were 46.5% and 34.8%, respectively, for the ipilimumab and the placebo cohorts. The RFS benefit extended to all patient subgroups assessed, including stage IIIA, IIIB, and IIIC, microscopic or macroscopic lymph nodes, and with or without an ulcerated primary lesion. In particular, post hoc analysis showed that the RFS benefit was higher for patients with microscopic disease and for those with ulceration of the primary disease.

A higher incidence of grade 3/4 immune-related AEs was reported in the ipilimumab-treated group compared with the placebo group (42% vs 2.5%, respectively). Common immune-related AEs were gastrointestinal (16% vs 0.8%), hepatic (10.7% vs 0.2%), and endocrine (8.5% vs 0%) in nature. There were 5 treatment-related deaths (1.1%). Treatment discontinuation because of AEs was 52%, of which 38.6% discontinued within 12 weeks.

Health-related quality-of-life assessment showed no clinically significant differences between treatment arms in mean scores for global health status at any time. The researchers concluded that ipilimumab as adjuvant therapy provided a significant improvement in RFS compared with placebo for patients with stage III melanoma at high risk for recurrence. Although the safety profile was consistent with that observed with ipilimumab therapy in advanced disease, the investigators pointed out that its use in the adjuvant setting was associated with a higher incidence of endocrinopathies.

Nivolumab Versus Investigator’s Choice Chemotherapy in Patients With Advanced Melanoma

The treatment options for patients with advanced melanoma that have progressed on approved agents is limited. Nivolumab is a fully human monoclonal antibody that is directed toward the immune checkpoint receptor PD-1, which has demonstrated durable antimelanoma activity in early clinical trials in pretreated patients with advanced disease. CA209-037 is a randomized, open-label, phase 3 clinical trial that is evaluating nivolumab versus investigator’s choice of chemotherapy (ICC) in 405 patients with advanced melanoma who have progressed with previous CTLA-4 therapy and a BRAF inhibitor (Weber J, et al. ESMO 2014. Abstract LBA3_PR).

In this trial, eligible patients were randomized to receive nivolumab 3 mg/kg IV every 2 weeks or ICC (dacarbazine 1000 mg/m2 every 3 weeks, or carboplatin AUC 6 plus paclitaxel 175 mg/m2 every 3 weeks) until disease progression or unacceptable toxicity. To be eligible for inclusion, patients with BRAF wild-type must have progressed after ipilimumab, whereas patients with BRAF V600 mutation must have progressed while receiving ipilimumab and a BRAF inhibitor. Patients were stratified by PD-1 ligand (PD-L1) expression, BRAF mutation status, and best overall response to previous ipilimumab. Coprimary end points were ORR and OS. A planned efficacy analysis of ORR was assessed as planned in the first 120 patients receiving nivolumab and 47 patients receiving ICC, with a follow-up of ?6 months.

The interim efficacy analysis by central review showed that patients who received nivolumab therapy achieved a higher ORR compared with those who received ICC (32% vs 11%), including 3 complete responses. The median time to response was 2.1 and 3.5 months in the nivolumab and ICC groups, respectively, and the median duration of response was not reached (range, ?1.4 to ?10 months) and 3.6 months, respectively. Of the 38 responses achieved with nivolumab therapy, 36 are ongoing, with a minimum follow-up of 24 weeks.

Reduction of ?50% in target lesion burden occurred in 82% (31/38) of nivolumab responders and 60% (3/5) of ICC responders. Among the 120 patients who received nivolumab, an additional 10 patients (8.3%) had immune-related response patterns and experienced a ?30% reduction in target lesion tumor burden. Including the patients with immune-related responses, a total of 37 patients continued treatment beyond RECIST 1.1–defined disease progression.

Grade 3/4 treatment-related AEs were reported in 9% and 31% of patients treated with nivolumab and ICC, respectively. Treatment discontinuations as a result of any grade treatment-related AEs occurred in 2.2% and 7.8% of patients, respectively. The safety profile of nivolumab was consistent with that described previously. Common AEs (any grade) included skin (29%), gastrointestinal (12%), endocrine (8%), and hepatic (5%); grade 3/4 toxicities occurred in <1% of patients in each of these categories.

These results indicate that nivolumab monotherapy was associated with a higher response rate compared with control and was well tolerated in patients with advanced melanoma who had failed previous therapy with ipilimumab and BRAF inhibitors.

Nivolumab Improves Survival in Ipilimumab-Naive Patients With Advanced Melanoma


Nivolumab is a fully human monoclonal antibody that is directed toward the immune checkpoint receptor PD-1. A phase 1 dose-escalation/cohort expansion study demonstrated encouraging antitumor activity and tolerability in 107 ipilimumab-naive, previously treated patients with advanced melanoma; patients received nivolumab 0.1, 0.3, 1, 3, or 10 mg/kg IV every 2 weeks for up to 96 weeks. McDermott and colleagues reported the long-term clinical activity, response duration off therapy, and correlative studies with tumor PD-L1 expression from this trial (McDermott D, et al. ESMO 2014. Abstract 1088PD).

Objective responses by RECIST criteria were achieved by 34 of 107 patients (32%); the median duration of response was 99.4 weeks. The responses are ongoing in 19 of 34 patients (56%). The ORR in the 3 mg/kg dose cohort was 41% (7/17) and was chosen as the dose for future phase 3 clinical trials. Responses were rapid, with 44% of responders achieving responses at first tumor assessment (6 weeks). Of the 21 responding patients who discontinued nivolumab for reasons other than disease progression, 11 (52%) maintained responses for ?24 weeks off the drug.

Updated analysis showed that nivolumab therapy was associated with OS rates of 63%, 48%, and 41%, at year 1, year 2, and year 3, respectively. Median OS was 17.3 months across doses, and the median progression-free survival (PFS) was 3.7 months across dose cohorts. Based on PD-L1 expression status using a 5% tumor cell surface–staining cutoff in a subset of 41 patients with available tumor samples, median OS was not reached for the 18 patients (44%) who had PD-L1–positive tumors and was 12.5 months for the 23 patients (52%) who had PD-L1–negative tumors, with a median PFS of 9.1 and 1.9 months, respectively.

No new treatment-related toxicities emerged in this study; common AEs with nivolumab therapy included skin, gastrointestinal, hepatic, and endocrine toxicities as previously described.

McDermott and colleagues concluded that nivolu­mab therapy in patients with advanced melanoma demonstrated promising 2-year and 3-year OS rates, durable responses, and an acceptable safety profile, with greater benefit seen in patients with PD-L1–positive disease.

Two Dosing Schedules of Pembrolizumab for Patients With Advanced Melanoma

Pembrolizumab is a humanized high-affinity antibody that exerts dual ligand blockade of the immune checkpoint receptor PD-1. The KEYNOTE-001 trial is a phase 1 nonrandomized dose-escalation trial that tested pembrolizumab in 5 dose/schedule cohorts that included 135 ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) patients. A pooled analysis of the 5 cohorts showed an overall response rate of 34%, with higher responses achieved in the IPI-N subgroup versus the IPI-T subgroup (40% vs 28%, respectively). Based on no unfavorable safety signals, the treatment cohort was then expanded to include 276 patients with IPI-N and IPI-refractory disease who were randomized to receive MK-3475 10 mg/kg or 2 mg/kg every 3 weeks. The efficacy and safety of pembrolizumab 10 mg/kg every 3 weeks and 10 mg/kg every 2 weeks in patients enrolled in a randomized expansion cohort of the KEYNOTE-001 trial were reported (Robert C, et al. KEYNOTE-001 Trial. ESMO 2014. Abstract LBA34).

A total of 244 patients were enrolled in the 2 dose-expansion cohorts of 10 mg/kg every 3 weeks (n=121; IPI-T group) and 10 mg/kg every 2 weeks (n=123; IPI-N group). The safety analysis showed that treatment-related AEs were similar between the 2 dose cohorts; common toxicities included fatigue (38%), pruritus (23%), and diarrhea (18%). At a median follow-up of 42.3 weeks, 70% of patients in the every-3-weeks cohort and 57% in the every-2-weeks cohort achieved a decrease in target lesion size compared with baseline. In the total population, the overall response rate by RECIST criteria was 33%, including a 5% complete response rate. There were no significant differ­ences in the overall response rates between the 2 dose schedules (P=.5052) or based on previous ipilimumab use. Median PFS was 13.1 weeks and 22.6 weeks in the every-3-weeks and every-2-weeks cohorts, respectively.

Robert and colleagues concluded that the response rates, PFS, and safety were comparable between the 2 pembrolizumab cohorts and support the use of the recently approved dose and schedule of pembrolizu­mab 2 mg/kg every 3 weeks in patients with advanced melanoma.

RENAL CELL CARCINOMA

Immunotherapy With Nivolumab Plus Ipilimumab for Patients With Metastatic Renal Cell Carcinoma

Despite the advancements in targeted therapies for the management of patients with metastatic renal cell carcinoma (mRCC), their prognosis remains poor, underscoring the need for novel treatment strategies. Combination therapy with the 2 immune checkpoint inhibitors, nivolumab and ipilimumab, was shown to be effective in patients with advanced melanoma. Taken together with evidence of encouraging antitumor activity in mRCC, the combination of nivolumab and ipi­limumab was evaluated in patients with mRCC.

Hammers and colleagues presented data from a trial of patients with mRCC who were randomized to receive either nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3 + I1; 21 patients), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1 + I3; 23 patients) every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity (Hammers H, et al. ESMO 2014. Abstract 1050O). The primary objective was safety assessment; the secondary objective was efficacy analysis by RECIST 1.1 criteria.

ORRs were similar in the 2 treatment arms (N3 + I1, 43%; N1 + I3, 48%).

The median duration of response was 31.1 weeks in the N3 + I1 cohort and was not yet reached in the N1 + I3 cohort. Median PFS was similar between the 2 patient cohorts (36.6 vs 38.3 weeks, respectively). Responses occurred by first tumor assessment (6 weeks) in 44.4% and in 54.5%, respectively. The majority of the patients showed ongoing response to therapy at the time of this analysis (77.8% vs 81.8%, respectively) and continued to respond even after treatment discontinuation that was not related to disease progression (33.3% vs 45.5%,
respectively).

The AE profile was as previously described with this combination strategy in patients with melanoma; common toxicities were gastrointestinal disorders, hepatic toxicities, and endocrinopathies. Hammers and colleagues concluded that the grade 3/4 events, including diarrhea, and elevations in ALT or AST were largely manageable by using recommended treatment algorithms.

Overall, nivolumab plus ipilimumab combination therapy was associated with an acceptable toxicity and an encouraging antitumor activity in patients with mRCC. This strategy is the rationale for a planned phase 3 clinical trial for first-line treatment of patients with mRCC.

Biomarker Analysis of Nivolumab in Previously Treated and Untreated Patients With mRCC

Nivolumab is a fully human monoclonal antibody that inhibits the PD-1 immune checkpoint receptor to restore T-cell antitumor immune responses. Nivolumab demonstrated clinical activity in previously treated patients with mRCC, with an overall response rate of 29% and a 1-year OS rate of 70%. To establish the optimal dose of nivolumab in patients with mRCC to achieve the best clinical activity, a prospective, open-label, parallel-group, randomized phase 1 trial was conducted in previously treated, as well as treatment-naive, patients with mRCC (Choueiri T, et al. ESMO 2014. Abstract 1051PD).

In addition to assessments of antitumor response and safety, this prospective study was specifically focused on biomarker analysis, with the primary objective of investigating the immunomodulatory activity of tumor-infiltrating T cells from baseline to posttreatment and serum chemokines in patients with mRCC.

In this study, 91 previously treated patients (1-3 previous therapies; ?1 antiangiogenic agent) were randomized to receive nivolumab 0.3, 2, or 10 mg/kg IV every 3 weeks, whereas the 24 previously untreated patients received nivolumab 10 mg/kg. Across all dose groups, T-cell infiltrates increased from baseline to C2D8 by a median of 78% for CD3+ and by a median of 88% for CD8+. The mean increase from baseline to C4D1 was 180% and 79% for the chemokines CXCL9 and CXCL10, respectively. Tumor-infiltrating lymphocytes increased in the previously treated and the treatment-naive patients, and this was independent of dose.

Among the 90 evaluable patients included in the overall population, the overall response rate was 17% and included 12 of 67 (18%) previously treated patients and 3 of 23 (13%) treatment-naive patients; 6 (43%) of these responses are ongoing. The median duration of response was 64 weeks. The PFS rate was 18% at 48 weeks. Based on an analysis of PD-L1 expression (n=56), the overall response rate was 22% for PD-L1–positive patients and 8% for PD-L1–negative patients.

Grade 3/4 AEs occurred in 15% (n=14) of the patients, including 2 cases of colitis, 2 cases of elevated AST, 1 case of diarrhea, 1 case of elevated ALT, and 1 case of pneumonitis.

Choueiri and colleagues concluded that nivolumab demonstrated antitumor activity and a manageable safety level in patients with previously treated or untreated mRCC; no dose-response relationship was observed. The biomarker analysis was consistent with downstream immunomodulatory effects of nivolumab, resulting from PD-1 inhibition.

Nivolumab Plus Sunitinib or Pazopanib in Patients With mRCC


Targeting the vascular endothelial growth factor (VEGF) axis is an established antitumor strategy in the management of mRCC. The VEGF receptor inhibitors sunitinib and pazopanib are standard of care in the treatment of patients with mRCC; however, their antitumor effects are not durable, underscoring the need for novel therapeutic strategies in this setting. It was hypothesized that anti-VEGF strategies suppress Tregs to attenuate tumor-induced immunosuppression and might sensitize tumors to immunotherapy when used in combination. Nivolumab inhibits the PD-1 immune checkpoint receptor to restore T-cell antitumor immune responses and has shown clinical activity in mRCC. Amin and colleagues reported preliminary results from a phase 1 trial of nivolumab plus either sunitinib (S+N) or pazopanib (P+N) in patients with mRCC (Amin A, et al. ESMO 2014. Abstract 1052PD).

In this pilot study, sunitinib 50 mg, 4 weeks on and 2 weeks off, or pazopanib 800 mg daily was administered until disease progression or unacceptable toxicity, whereas previously treated patients received nivolumab 2 mg/kg IV and titrated up to 5 mg/kg IV every 3 weeks; nivolumab 5 mg/kg was expanded to treatment-naive patients based on tolerability.

Overall, 7 patients were each initially treated with sunitinib plus nivolumab 2 and 5 mg/kg, and this cohort was then expanded to an additional 19 treatment-naive patients (total, n=33) based on no reports of dose-limiting toxicities.

In the P+N arm, 4 dose-limiting toxicities, including elevations of ALT/AST in 3 patients and fatigue in 1 patient, were observed, leading to closure of this arm. Grade 3/4 treatment-related AEs were reported in 27 of 33 patients (82%) and in 14 of 20 patients (70%) in the S+N and P+N groups, respectively. Common treatment-related grade 3/4 AEs in the S+N group included elevated ALT (18%), hypertension (18%), hyponatremia (15%), and reduced lymphocyte count (15%); among the patients in the P+N group, events included elevated ALT (20%), AST (20%), diarrhea (20%), and fatigue (15%). Grade 3 pneumonitis was reported in 1 patient in the S+N arm. Grade 3/4 treatment-related AEs led to treatment discontinuations in 12 of 33 patients (36.4%) in the S+N cohort and 5 of 20 patients (25%) in the P+N cohort.

The ORRs were 52% in the S+N arm and 45% in the P+N arm, with median duration of response of 54.0 and 30.1 months, respectively. Many of the responses occurred by the time of first assessment at 6 weeks: in 41% of patients in the S+N cohort and in 56% of patients in the P+N cohort. At the time of the analysis, the authors reported that many of the responses were still ongoing: 10 in the S+N group and 3 in the P+N group, with 4 patients in the S+N group continuing to respond after treatment discontinuation that was not related to disease progression.

The median PFS was 48.9 and 31.4 weeks for the S+N and P+N arms, respectively. Amin and colleagues concluded that combination therapy with sunitinib plus nivolumab showed encouraging antitumor activity and was associated with a manageable safety profile in patients with mRCC. They also noted that the combination therapy resulted in responses that were higher than previously reported for monotherapy with either agent. However, the combination of pazopanib plus nivolumab is not a feasible treatment option at the dose and schedule studied here because of dose-limiting toxicities.

Long-term Follow-up Results of MPDL3280A in mRCC

The human monoclonal antibody MPDL3280A is directed against PD-L1, disrupting its binding to receptors PD-1 and B7.1. A phase 1 study evaluated the safety and efficacy of MPDL3280A in several cancer types, including melanoma and mRCC. McDermott and colleagues reported the long-term follow-up and immune correlative data for the cohort of patients with mRCC who were treated with MPDL3280A IV every 3 weeks at doses of 3 to 20 mg/kg for ?1 year (McDermott D, et al. ESMO 2014. Abstract 809O).

The 69 enrolled patients received MPDL3280A for a median duration of 239 days (range, 21-834 days). Of the 62 patients evaluable for efficacy, the overall response rate was 15%; the median duration of response was 54 weeks. The 24-week PFS rate was 51% (95% CI, 38-63). Responses to MPDL3280A correlated with the intensity of PD-L1 expression, with PD-L1–positive patients (defined by immunohistochemistry [IHC] 1/2/3 level staining) achieving a 20% overall response rate, whereas patients with PD-L1–negative disease achieved an overall response rate of 10%.

Of the 69 enrolled patients in this study, 80% had a treatment-related AE, the majority of which were grade 1 or 2. The incidence of grade 3 treatment-related AEs was 16%, including anemia (4%), dehydration (3%), fatigue (3%), and hypophosphatemia (3%); there were no reports of grade 4 treatment-related AEs or deaths.

The results from a cohort with 10 patients with mRCC from another phase 1 study of MPDL3280A, in combination with bevacizumab, were also presented. In this study, 1 MPDL3280A-related grade 3 AE of neutropenia was reported; no grade 4 AEs or deaths were attributed to MPDL3280A. Objective responses were achieved by 4 patients, and 5 patients achieved disease stabilization. Of the 10 patients in this cohort, 9 are still receiving the study treatment.

Taken together, the results from these 2 studies suggest that MPDL3280A is well tolerated and demonstrate antitumor activity alone as well as in combination with bevacizumab. These results also provide preliminary indications that responses to MPDL3280A may correlate with PD-L1 positivity.

Dose-Ranging Phase 2 Results of Nivolumab in mRCC

Nivolumab inhibits the PD-1 immune checkpoint receptor to restore T-cell antitumor immune responses and has shown clinical activity in mRCC. Motzer and colleagues presented updated OS and duration of response from a blinded, dose-ranging, phase 2 trial that evaluated 3 nivolumab doses in patients with mRCC whose disease had progressed while receiving inhibitors of the VEGF pathway (Motzer R, et al. ESMO 2014. Abstract 810O).

In this trial, eligible patients with clear cell mRCC (?1 agent targeting the VEGF pathway; ?3 prior systemic therapies) were randomized to receive nivolumab 0.3, 2, or 10 mg/kg IV every 3 weeks until progression or toxicity. The majority of the 168 patients in this trial had received ?2 prior systemic therapies, including VEGF receptor tyrosine kinase inhibitors (TKIs) (98%), mTOR inhibitors (38%), and immunotherapy (24%).

Across the doses tested, overall response rates were similar at about 20%; the median duration of response was not reached for 0.3- and 2-mg/kg doses, and was 22.3 months for the 10-mg/kg dose. Median PFS was 2.7, 4.0, and 4.2 months for the 0.3-, 2-, and 10-mg/kg cohorts, respectively. The median OS was 18.2 months for the 0.3-mg/kg cohort and approximately 25 months for the 2- and 10-mg/kg cohorts.

By PD-L1 expression, there was preliminary evidence of improvement in PFS, OS, and overall response rate in patients with PD-L1–positive disease, but this needs further validation.

The incidence of grade 3/4 treatment-related AEs was ?17% across doses and was consistent with previously described events, including skin, gastrointestinal, endocrine, and hepatic toxicities. There was no grade 3/4 pneumonitis.

These results suggest that nivolumab monotherapy is well tolerated in the treatment of patients with mRCC and is associated with encouraging efficacy, with no evidence of a clear dose-response relationship.

SOLID TUMORS

MPDL3280A Plus Bevacizumab, With or Without Chemotherapy, in Advanced Solid Tumors

Inhibition of the PD-1/PD-L1 immune checkpoint pathway is a novel immunotherapeutic approach that is showing considerable promise in different tumor types. MPDL3280A is an anti–PD-L1 human monoclonal antibody that specifically prevents binding to its receptor PD-1 on activated T cells. Based on the hypothesis that VEGF blockade may synergize with immunotherapy, and that chemotherapy may potentiate immune responses, a recent phase 1b study evaluated the safety and antitumor activity of MPDL3280A in combination with bevacizumab, with or without chemotherapy, in patients with locally advanced or metastatic solid tumors (Lieu C, et al. ESMO 2014. Abstract A1049O).

In this open-label study, patients were enrolled in 1 of 2 treatment arms – MPDL3280A 20 mg/kg every 3 weeks plus bevacizumab 15 mg/kg every 3 weeks in patients with refractory tumors or with 1L renal cell carcinoma (RCC; arm A), or MPDL3280A 15 mg/kg every 2 weeks plus bevacizumab 10 mg/kg every 2 weeks plus FOLFOX at standard doses in patients with oxaliplatin-naive tumors (arm B).

A total of 35 patients in arm A and 36 patients in arm B received treatment, with the majority having a colorectal cancer (CRC) diagnosis (40% and 83%, respectively). The incidence of grade 3/4 AEs was 49% in arm A and 67% in arm B, and those attributable to MPDL3280A were 3% and 17%, respectively. In arm A, grade 3/4 AEs regardless of attribution included abdominal pain (9%), hypertension (9%), hyperbilirubinemia (6%), pneumonia (9%), and tumor pain (6%); in arm B, grade 3/4 AEs included neutropenia (39%), diarrhea (11%), and an increase in AST (8%). In arm A, RECIST responses were observed in 40% of patients with 1L RCC and in 8% of patients with CRC; in arm B, responses were reported in 36% of patients with CRC and 44% of patients with 1L CRC.

These preliminary results demonstrated that MPDL-3280A combination therapy with bevacizumab plus chemotherapy confers antitumor activity and is well tolerated without exacerbation of known toxicities of bevacizumab and FOLFOX, and this may be a promising treatment in patients with advanced or metastatic solid tumors.

PROSTATE CANCER

Sequential Sipuleucel-T Immunotherapy and Androgen Deprivation in Men With Metastatic Prostate Cancer

Sipuleucel-T is an autologous cellular immunotherapy directed against prostatic acid phosphatase (PAP) that is currently approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Two studies are currently evaluating the optimal sequencing of sipuleucel-T in the context of androgen-deprivation therapy (ADT) in patients with mCRPC. Enzalutamide is an androgen receptor inhibitor that is also approved for the treatment of patients with mCRPC.

In the ongoing, randomized, open-label, phase 2 STRIDE clinical trial, Petrylak and colleagues assessed the safety and efficacy of sipuleucel-T plus enzalutamide, administered either concurrently or sequentially in patients with asymptomatic or minimally symptomatic mCRPC (Petrylak DP, et al. ESMO 2014. Abstract 774P). In the concurrent arm, eligible patients have received sipuleucel-T infusions (3 infusions at 2-week intervals) starting 2 weeks after enzalutamide (160 mg daily for 52 weeks); in the sequential arm, patients are administered sipuleucel-T infusions 10 weeks before initiation of enzalutamide therapy. The primary end point is T-cell immune response to the sipuleucel-T immunizing antigen, PA2024. A secondary end point is time to recurrence of elevated serum prostate-specific antigen (PSA) level.

Overall, 52 patients had completed sipuleucel-T infusions and were available for safety and efficacy assessments. No significant differences were found between the treatment arms in sipuleucel-T product parameters, including antigen-presenting cell (APC) activation, APC count, and total nucleated cell (TNC) count. The safety profiles were similar between the treatment arms and are consistent with those previously reported with sipuleucel-T and enzalutamide.

The incidence of AEs (all grades) was similar between the concurrent and the sequential arms (80% vs 96%, respectively), with treatment-related grade 3/4 events reported in 4 and in 7 patients, respectively.

In the second trial, known as STAND, Drake and colleagues also evaluated the optimal sequencing of sipuleucel-T and ADT in 65 men with biochemically recurrent prostate cancer who are at high risk for metastases (Drake C, et al. ESMO 2014. Abstract 775P). The patients were randomized to receive sipuleucel-T followed by ADT 2 weeks after the third infusion, or ADT 3 months before sipuleucel-T therapy.

The primary end point is cellular immune response; secondary end points are humoral/cytokine responses, drug parameters, and safety. Preliminary analysis of this trial indicates that sipuleucel-T induces robust immune responses to PA2024 and PAP in both arms, correlating with cumulative TNC count and maximum eosinophil count after sipuleucel-T treatment.

Taken together, the findings from these 2 clinical trials indicate that sipuleucel-T induces potent immune responses in patients with mCRPC, regardless of the ADT sequencing.

Androgen Deprivation Plus Ipilimumab Immunotherapy in Hormone-Naive Patients With Metastatic Prostate Cancer

ADT is an integral component of the management of patients with hormone-naive metastatic prostate cancer (HN-mPCa). There is some evidence implicating ADT in immune regulation by increasing the thymic output of T cells, antigen-specific T-cell responses, and infiltration of T cells into the prostate. Ipilimumab is an approved immunotherapy that blocks the function of CTLA-4 to restore T-cell antitumor immune responses. Thus, it was hypothesized that the combination of ipilimumab plus ADT might have synergistic interactions in men with HN-mPCa and would thus achieve undetectable PSA levels (?0.2 ng/mL); this PSA level is a strong predictor of survival. To test this hypothesis, Subudhi and colleagues conducted a single-arm observational study to evaluate the safety and antitumor efficacy of ADT, administered for 8 months, plus ipilimumab 10 mg/kg for up to 4 doses at 4-week intervals in 50 men with HN-mPCa (Subudhi SK, et al. ESMO 2014. Abstract 1053PD). The primary end point was the rate of undetectable PSA at 7 months after treatment initiation.

Subudhi and colleagues reported that 10 of the 25 evaluable patients (40%) achieved a PSA level of ?0.2 ng/mL 7 months after ADT initiation, and 1 patient had a sustained response 1 year after ADT completion. A total of 17 patients recovered their testosterone levels (?50 ng/dL). The median time to PSA progression was 330 days from the PSA nadir. Two of 25 patients (8%) achieved complete radiographic response, with PSA responses ongoing for 944 and 364 days, respectively. Immunologic changes, including increased rate of CD4+ T cells, CD4+ central memory, and ICOS+CD4+ T-cell changes were also reported with this combination.

However, after a predetermined criterion based on the incidence of unacceptable toxicities, the trial was closed when 12 of the 27 evaluable patients (44%) developed grade 3/4 toxicity. These immune-related AEs included hepatic (15%), gastrointestinal (11%), endocrine (11%), and dermatologic (4%) toxicities, which were reversible using standard ipilimumab management algorithms.

The results from this pilot study suggest that the combination of finite ADT plus ipilimumab has promising antitumor activity in patients with HN-mPCa. Subudhi and colleagues suggested that conducting future trials with a lower dose of ipilimumab would be considered because of the concern about the incidence of immune-related AEs in this trial.

Updated OS Data for the CA184-043 Trial: Immunotherapy With Ipilimumab Does Not Improve Survival in Patients With Metastatic Prostate Cancer

Ipilimumab is an approved immunotherapy that blocks the function of CTLA-4 to augment T-cell antitumor immune responses. The multicenter, randomized, double-blind, phase 3 clinical trial CA184-043 evaluated the efficacy of radiotherapy followed by ipi­limumab or placebo in 799 men with advanced mCRPC who had at least 1 bone metastasis and had progressed with previous docetaxel therapy. It was previously reported that the primary end point of improvement in OS in patients with mCRPC was not met (HR 0.85; P=.053). Fizazi and colleagues reported updated OS data for the CA184-043 trial with an additional 1 year of follow-up, which was conducted with the intent-to-treat population of patients with mCRPC (Fizazi K, et al. ESMO 2014. Abstract 763PD).

Consistent with the previous published report, the updated OS analysis showed no significant improvement (HR 0.84; P=.268) with ipilimumab plus radiotherapy compared with control with an additional year of follow-up. The 2-year and 3-year OS rates for ipilimumab plus radiotherapy were 25% and 12%, respectively, compared with 17% and 6%, respectively, for radiotherapy alone. A post hoc subgroup analysis showed that ipilimumab might benefit patients with favorable prognostic features, such as alkaline phosphatase <1.5 upper limit of normal, hemoglobin 0.11 g/dL, and no visceral metastasis (median OS, 22.1% vs 16.1%; HR, 0.70).

As previously reported, immune-related AEs included gastrointestinal, dermatologic, endocrine, and hepatic toxicities; however, the majority of the immune-related AEs were manageable with established ipilimumab treatment algorithms.

With an additional 1 year of follow-up, ipilimumab plus radiotherapy did not improve survival outcomes in patients with advanced mCRPC, with some preliminary evidence suggesting that specific subgroups might derive some benefit.

LUNG CANCER

MAGRIT Trial: recMAGE-A3 + AS15 as Adjuvant Therapy in Resected MAGE-A3–Positive Patients With Lung Cancer

Adjuvant chemotherapy is the standard of care for patients with stage II/IIIA non–small cell lung cancer (NSCLC), as well as for patients with high-risk stage IB NSCLC; however, this is not applicable to all patients, and the 5-year disease-free survival (DFS) has been suboptimal, underscoring the need for novel therapeutic approaches. The randomized, double-blind, placebo-controlled phase 3 MAGRIT trial evaluated the recMAGE-A3 + AS15 immunotherapy regimen as adjuvant therapy in patients with resected MAGE-A3–positive NSCLC, regardless of previous adjuvant chemotherapy (Vansteenkiste JF, et al. ESMO 2014. Abstract 1173O). The 3 coprimary end points were DFS in the overall patient population, DFS in the patients with no adjuvant chemotherapy, and DFS in patients with a potentially predictive gene signature.

Of the 13,849 patients screened for the trial, MAGE-A3 was detected in the tumor samples of 4210 patients. Of these, 2272 were randomized to receive MAGE-A3 cancer immunotherapy (MAGE-A3 CI) or placebo (13 injections) over a 27-month treatment period. At a median follow-up of 38.8 months, no differences were seen in median DFS between the MAGE-A3 CI and the placebo cohorts (60.5 vs 57.9 months, respectively; HR 1.024; P=.7379) in the overall population. Similarly, patients who did not receive previous adjuvant chemotherapy did not benefit from the investigational treatment compared with placebo, resulting in a median DFS of 58 and 56.9 months, respectively (HR 0.970; P=.7572).

Consistently, no improvement was seen in OS between the 2 treatment arms. Subset analysis also did not reveal any survival benefit for any patient subgroups analyzed, including by age, disease stage, histopathology, chemotherapy, tumor region, and MAGE-A3 quantitative expression. The rate of grade 3/4 AEs was similar (16%) between the treatment groups. Common AEs included pyrexia, injection-site pain, injection-site reaction, fatigue, pain, influenza-like illness, and myalgia, >95% of which were grade 1/2 in severity.

These results indicate that immunotherapy with MAGE-A3 in the adjuvant setting did not provide a DFS advantage in the overall patient population or in patients who did not receive previous chemotherapy. Vansteenkiste and colleagues concluded that therapeutic vaccination with MAGE-A3 CI represents a promising strategy that was tested in the appropriate setting, with proper study design and statistical power; however, it is not yet feasible to be used in the setting of NSCLC with the current technology.

Nivolumab Plus Platinum-Based Doublet Chemotherapy or Erlotinib in Patients With Advanced Lung Cancer

Despite major treatment advances in advanced NSCLC, the prognosis remains poor. The 1-year OS rate with standard first-line therapy of platinum-based doublet chemotherapy (PT-DC) is 30% to 40% for patients with advanced NSCLC, with response rates of 20% to 30%. Although higher response rates and improvement in PFS may be achieved with first-line epidermal growth factor receptor (EGFR) TKI therapy compared with PT-DC, acquired resistance to these therapies inevitably occurs. Nivolumab is a fully human immune checkpoint inhibitor antibody directed toward the PD-1 receptor, which is implicated in immune escape mediated by the constitutive activation of EGFR signaling. Gettinger and colleagues reported interim data from a phase 1 study evaluating the safety and antitumor activity of nivolumab in combination with 3 standard PT-DC regimens or erlotinib in patients with advanced chemotherapy-naive NSCLC (Gettinger S, et al. ESMO 2014. Abstract 1054PD).

Based on NSCLC histology, 56 eligible patients were assigned to receive nivolumab 10 mg/kg IV every 3 weeks concurrently with 3 different standard PT-DC regimens: cisplatin 75 mg/m2 + gemcitabine 1250 mg/m2 IV (squamous) or pemetrexed 500 mg/m2 (nonsquamous), or nivolumab 5 or 10 mg/kg IV every 3 weeks + paclitaxel 200 mg/m2 IV + carboplatin AUC 6 (any histology), or nivolumab 3 mg/kg IV every 2 weeks + erlotinib 150 mg po daily (EGFR mutation positive).

At the time of analysis, 66% and 57% of patients in the nivolumab plus PT-DC and nivolumab plus erlotinib arms had discontinued treatment because of disease progression. In the nivolumab plus PT-DC subgroup (n=56) at a median follow-up of 75 weeks, grade 3/4 treatment-related AEs occurred in 45% of patients, with nivolumab plus paclitaxel/carboplatin showing the highest frequency (73%), but many of which were laboratory abnormalities. Treatment discontinuations because of AEs were reported in 11 patients (20%) across the arms. Four patients had grade 3/4 pneumonitis, with any grade pneumonitis occurring in 7% of patients. In terms of antitumor activity, patients achieved an overall response rate ranging from 33% to 47%, a PFS rate at week 24 ranging from 38% to 71%, and a 1-year OS rate ranging from 50% to 87%.

In the nivolumab plus erlotinib subgroup (n=21) at a median follow-up of 72 weeks, grade 3 AEs were reported in 24% of patients; no pneumonitis occurred in this cohort. Treatment discontinuation due to treatment-related AEs were reported in 4 patients because of grade 3 elevations in AST, grade 3 diarrhea, grade 2 nephritis, and grade 2 flushing. In the efficacy cohort (n=20), the overall response rate was 15%, with an additional 9 patients achieving disease stabilization as best response.

The estimated median duration of response was not reached (range, 60.1 at ?70 weeks), 24-week PFS rate was 51% (median PFS, 29.4 months), and 1-year OS was 73% (median OS not reported).

Gettinger and colleagues concluded that concurrent use of nivolumab and platinum-based chemotherapy demonstrated promising antitumor activity in chemotherapy-naive patients with advanced NSCLC that was associated with some additive effects of each agent or regimen on toxicity. Nivolumab plus erlotinib showed durable clinical benefit and an acceptable safety profile in EGFR mutation–positive patients with advanced NSCLC. These data support further evaluation of nivolumab combination regimens in patients with advanced NSCLC.

GENITOURINARY CANCER

Anti–PD-L1 Monoclonal Antibody MPDL3280A in Metastatic Urothelial Bladder Cancer

Treatments are limited for patients with metastatic urothelial bladder cancer (mUBC). MPDL3280A is a human monoclonal antibody that is directed against PD-L1, disrupting its binding to receptors PD-1 and B7.1. Results from a phase 1a study that evaluated
MPDL3280A 15 mg/kg IV every 3 weeks for up to 16 cycles in 74 patients with mUBC were reported (Bellmunt J, et al. ESMO 2014. Abstract 808O).

Analysis showed that PD-L1 IHC 2/3 expression level was observed in 33 patients and IHC 0/1 in 36 patients. In the IHC 2/3 cohort, the overall response rate was 52%, including 2 complete responses, and the median PFS was 24 weeks. For patients with IHC 0/1, the overall response rate was 14%, and all were partial responses; the median PFS was 8 weeks. Overall, 19 of the 22 responders continued to respond at the time of the analysis. The median time to first response was 42 days for the 17 responders. The median duration of response was not reached in either the PD-L1–positive patients (range, 0.1+ to 42+ weeks) and the PD-L1–negative patients (range, 6+ to 19+ weeks).

All grade treatment-related AEs occurred in 65% of patients. Common AEs included fatigue (15%), decreased appetite (12%), and nausea (11%). Treatment-related grade 3 AEs were experienced by 5% of patients and included asthenia, thrombocytopenia, and decreased blood phosphorus; no treatment-related grade 4 AEs or deaths were observed. There were no discontinuations resulting from treatment-related AEs.

Overall, these preliminary results for MPDL3280A monotherapy in patients with heavily pretreated UBC indicate that this monoclonal antibody is well tolerated in this patient population and leads to antitumor responses that correlate with PD-L1 status.

Pembrolizumab in Advanced Urothelial Tract Cancer

Pembrolizumab is a humanized antibody that exerts dual blockade of the PD-1 receptor. It has demonstrated robust antitumor activity and acceptable tolerability in several tumors, including melanoma and lung cancer. The KEYNOTE-012 trial is an ongoing multicohort, open-label, phase 1b study that is evaluating the safety, tolerability, and antitumor activity of pembroliz­umab in patients with PD-L1–positive advanced solid tumors, including recurrent or metastatic urothelial cancer (Pilmack A, et al. ESMO 2014. Abstract LBA23).

Prior to study entry, tumor samples were screened for PD-L1 expression using a prototype IHC assay, with positivity defined by PD-L1 expression staining in stroma or ?1% of tumor cells. Eligible patients received pembrolizumab 10 mg/kg every 2 weeks until complete response, progression, or unacceptable toxicity. Any patients deriving benefit could remain on pembrolizu­mab beyond the initial progression. The primary efficacy end point was overall response rate.

A total of 33 patients were enrolled in the trial; 22 patients (67%) received ?3 doses of pembrolizumab. Of the 33 patients evaluable for safety, 61% reported treatment-related AEs of any grade; common AEs included fatigue, peripheral edema, and nausea. Grade 3/4 treatment-related AEs were reported in 4 patients (12%)and included 1 case each of dehydration, neuromyopathy, maculopapular rash, pruritic rash, rhabdomyolysis, and thrombocytopenia. By central review of the 29 evaluable patients using RECIST 1.1 criteria, the overall response rate was 24%, including a complete response in 3 patients (10%). Overall, 64% of patients experienced a decrease in target lesions.

At a median follow-up of 11 months, the median time to response was 8 weeks, response duration was 16 to 40+ weeks (median not reached), with 6 of 7 responses ongoing. The median PFS was 8.6 weeks (6-month OS rate, 23.1%), and the median OS was 9.3 months (6-month OS rate, 58%).

The results indicate that pembrolizumab is associated with an acceptable safety and tolerability profile and produces durable responses in patients with advanced urothelial cancer.

Uncategorized - November 26, 2014

New Drugs and Clinical Trial Data: Updates in Cutaneous Malignancies

Immune-targeted therapies and inhibitors of Hedgehog pathway signaling dot the landscape in recent investigations in the treatment of melanoma, BCC, and MCC. A rundown of findings with newly approved therapies and investigational therapies was presented at the Third Annual World Cutaneous Malignancies Congress. Immune Therapies in Melanoma In the treatment [ Read More ]

Letter to Our Readers - November 26, 2014

Immunotherapy: Early Success in Melanoma Provides Hope for Success in Other Cancers

Dear Colleague, Immunotherapy is a term we have heard for years, if not decades, but the fruits of researchers’ labor have just recently begun to be realized, most notably in the field of melanoma. As a result, so many of us associate immunotherapy with melanoma. True, we have seen great [ Read More ]