Once again, immunotherapy is set to be a very hot topic at the American Society of Clinical Oncology annual meeting, held this year from May 30 to June 3 in Chicago.

More mature data from the emerging class of anti-PD-1/PD-L1 cancer checkpoint inhibitors in a range of tumor types will be presented, building on the enormous momentum at the 2013 meeting, which was mainly centered on results in the flagship melanoma indication, but also highlighted promising efficacy in non-small cell lung cancer Also see "Melanoma Success Paves Way For Path Of Gold In Cancer Immunotherapy" - Pink Sheet, 10 June, 2013..

Abstracts for the 2014 meeting were released on May 14. An ASCO planning report by lead author Robert Jeng and a team of analysts at Sagient Research Systems’ BioMedTracker identifies the most important immunotherapy abstracts as part of a comprehensive analysis of the meeting, which includes over 1,000 oral presentations and 2,500 posters.

[Editor’s note: For a free copy of the pre-ASCO report from our colleagues at BioMedTracker, see http://www.biomedtracker.com/ReportDetail.cfm?ReportID=469. Free registration is required.]

Leaders in cancer checkpoint inhibitor development –Bristol-Myers Squibb Co., Roche/Genentech Inc. and Merck & Co. Inc. – have been touting their aggressive approaches to development in recent earnings calls ([A#00140505007]). Meanwhile, AstraZeneca PLCis advancing as a fourth major player – on May 14, the company inked a deal to study its PD-L1 inhibitor MEDI4736 in combination with Incyte Corp.’s oral immunotherapeutic candidate INCB24360, which targets the emerging indoleamine 2,3 dioxygenase (IDO) checkpoint target ([A#14140514004]).

Aside from checkpoint inhibitors, other ASCO immunotherapy highlights include data from a potentially registrational single-arm trial of Amgen Inc.’s pioneering bispecific antibody blinatumomab in acute lymphoblastic leukemia ([A#14140422002]).

Commentary on the top immunotherapy candidates and related abstracts by Jeng and colleagues appears below (excerpted and adapted from the analysts’ Pre-ASCO report):

Bristol’s Anti-PD1 Antibody Nivolumab

Abstract #LBA9003: Survival, response duration, and activity by BRAF mutation status of nivolumab and ipilimumab concurrent therapy in advanced melanoma

Fewer major presentations for nivolumab are being featured at ASCO this year, but the first survival data from the Phase Ib Study 004 of the combination with Yervoy in melanoma will be shared in a Late Breaking Abstract. Data are not set to be released until June 2.

In renal cell carcinoma, notable results include the first Phase II data from a study in patients with clear cell RCC (Abstract #5009) as well as top-line data from the Phase I CheckMate 016 combination study (Abstract #5010). In line with performance to date for immunotherapies, the Phase II data illustrate the lack of a strong dose response for progression-free survival and objective response rate (ORR). Median overall survival was only reached in the lowest 0.3 mg/kg dose group (18.2 months). The higher dosing groups (2 and 10 mg/kg) will likely have slightly higher, but roughly similar, OS numbers, based on performance so far for checkpoint inhibitors. Ultimately, if duration of response is as good or better than it has been in other indications, median survival will probably become a secondary consideration. So far, PD-1 inhibitors have resulted in modest median OS numbers, but have resulted in remarkably long survival for a fraction of patients. Thus, the shape of the actual survival curves (and a trend towards a long survival “tail”) will be key if presented at the ASCO meeting.

The CheckMate 016 study (Abstract #5010) evaluated a combination of nivolumab with Pfizer Inc.’s Sutent (sunitinib), GlaxoSmithKline PLC s Votrient (pazopanib), or Bristol’s Yervoy in metastatic RCC. The abstract shows early signs of activity with ORRs of 52% in combination with Sutent and 45% with Votrient. The PFS rate of 24 weeks was encouraging at 78% and 55% with Sutent or Votrient, respectively. Some dose-limiting toxicities were observed, notably in four of 20 patients in an expanded pazopanib arm. Nevertheless, most adverse events appeared manageable.

In lung cancer, top-line data are available from the Phase I CheckMate 012 study evaluating nivolumab in chemotherapy-naïve patients either as a single agent or combination therapy with other agents, including Yervoy. Abstract #8024 indicates an overall ORR of 30% which is impressive, especially considering many immunotherapies from outside the checkpoint inhibitor classes have not fared well in NSCLC. These results are also in line with the early data from the Phase Ib 003 study across tumor types that generated so much excitement at the 2012 and 2013 ASCO meetings. Abstract #8023 focuses on the CheckMate 012 patients from the Yervoy combination arm of the study, revealing a 22% ORR, which is derived from a smaller sample size and is thus generally in line with the overall results. Other details from the study are also described in Abstracts #8113 and #8022.

Other notable nivolumab abstracts include #5012, #5511, #4504, 8112 and #9002.

Along with the abstract releases, Bristol announced a collaboration with Celldex Therapeutics Inc. to evaluate a combination of nivolumab with the anti-CD27 antibody varlilumab in multiple tumor types and that nivolumab gained “breakthrough therapy” designation with FDA for Hodgkin’s lymphoma.

Merck’s Anti-PD-1 Antibody MK-3475

Abstract #LBA9000: Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients with melanoma

Although a number of minor updates have been released, the primary abstract of interest for Merck’s drug is the late-breaking LBA9000, the presentation of the first large dataset of 411 patients from either the Phase II Study 002 evaluating the drug against chemotherapy or the Phase III Study 006 that has BMS’ Yervoy as an active comparator. Data will not be available until June 2.

Roche’s anti-PD-L1 Antibody RG7446 (MPDL3280A).

Abstract #5011: Inhibition of PD-L1 by MPDL3280A and clinical activity in patients with metastatic urothelial bladder cancer

RG7446 is already in Phase III trials NSCLC, but the primary presentation of interest at this year’s ASCO meeting reports new data in 31 bladder cancer patients who had taken part in a Phase I study of solid tumors. Previous releases from the study showed early efficacy signals in melanoma and NSCLC. Abstract #5011 now reveals an impressive 50% ORR (1 CR and 9 PRs) in 10 out of 20 of the urothelial bladder cancer patients who over-expressed the PD-L1 biomarker. Updated data will be presented at the ASCO meeting, including results for more patients and results for those who were PD-L1 negative.

AstraZeneca’s Anti-PD-L1 Antibody MEDI-4736

Abstract #3001: A Phase I study of MEDI4736 in patients with advanced solid tumors. Abstract #3002: Preliminary data from a multi-arm expansion study of MEDI4736

MEDI-4736 is a relative newcomer to the anti-PD-1 crowd with its first Phase III study initiated in May for NSCLC and little public data released. ASCO abstracts feature updated data for a Phase I study, providing the first quantitative response data, albeit from only 26 patients (13 NSCLC, 8 melanoma, and 5 other). Abstract #3001 reveals 4 PRs, and a 46% disease control rate. These data are too early to extrapolate too much, but updated data from more patients could be available at the actual meeting presentation. Additionally, safety data from 105 patients are presented in Abstract #3002. Importantly, no discontinuations were reported, even though 33% of patients experienced a treatment-related adverse event (7% Grade 3 or above), suggesting an acceptable safety profile.

CureTech Ltd.’s Anti-PD1 Antibody Pidilizumab (CT-011)

Abstract #9001: Phase II, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma

Little information had been released for pidilizumab, which is unique among the PD-1 therapies in its development for diffuse large B-cell lymphoma. At ASCO, updated data will be presented from a Phase II study in melanoma patients. The abstract presents similar response (10%) and survival data (64.5% at 12 months) as a previous disclosure, but also provides new details on various subgroups including BRAF V600 wild-type patients (69.3% survival at 12 months). The abstract also includes the first safety details.

It will be interesting to learn about pidilizumab in general and why it appears to be faring worse than other PD-1 antibodies. The low 10% response rate is concerning, and it should be noted that development was suspended in colorectal cancer last year, a development that is difficult to explain because clinical data were never released.

Amgen’s Bispecific Antibody Blinatumomab

Abstract #7005: Confirmatory open-label, single-arm, multicenter Phase II study of the BiTE antibody blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia

Of the 189 patients enrolled in a confirmatory trial of blinatumomab in relapsed/refractory LL, 43% (82 patients) had a complete response or complete response with partial blood count recovery (CR/CRh), the primary endpoint of the study. CR/CRh rates of at least 30% were observed in all groups when patients were analyzed by number of prior salvage regimens, including the difficult subgroup of patients who had two or more prior salvage therapies or were primary refractory. This response rate compares favorably to late-line cytotoxic agents available for ALL, including Spectrum Pharmaceuticals Inc.’s Marqibo (vincristine sulfate), which demonstrated a ~15% CR/CRh in patients failing 2+ lines of treatment or 1+ lines of salvage.

Given the lack of treatment options for relapsed/refractory ALL patients, the new data slightly increase BioMedTracker’s estimation of the likelihood of approval to 74%. In April, Amgen said it was discussing the potential for accelerated approval based on the study results with FDA.

Incyte’s IDO Inhibitor INCB24360

Abstract #3010: Preliminary results from a phase I/II study of INCB024360 combined with Yervoy in patients with melanoma

Combination therapies are generating huge interest – especially immunotherapies, which may complement each other through multiple pathways of T-cell activation. This abstract features top-line data from a study evaluating the Incyte’s INCB24360 with Bristol’s Yervoy. IDO catalyzes the rate-limiting step in tryptophan degradation and is proposed to inhibit T-cell activation in the tumor microenvironment, while Yervoy inhibits the well-characterized CTLA-4 immune checkpoint. These are limited data from a very small sample size, but do show promising activity with tumor reduction by the first evaluation in six of eight patients. This is especially promising considering that immunotherapies typically have a long lag time for efficacy.

Other IDO inhibitors in development include NewLink Genetics Corp.’s NLG-919 and indoximod. Little new information for these two drugs is expected at the meeting, but ASCO may nevertheless help gauge sentiment on IDO inhibitors in general as well, as their suitability in combination therapies.

ASCO Immunotherapy Alert: BioMedTracker’s Top Abstract Picks

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