Late-Stage Failures of Monoclonal Antibody Biotherapeutics

Clinical assessment of biotherapeutics continues to be the biggest assessment to development costs of biotherapeutic products. Phase III clinical trials are particularly designed by carefully selecting the patient population to confirm the safety and efficacy. However, despite the significant developments that have happened in clinical trial design and the considerable experience that the biopharma industry has gained in the past three decades, therapeutic products continue to fail in late stage clinical trials. In this article, the authors showcase some of the monoclonal antibody (mAb) candidates that reached Phase III clinical trials but were discontinued at later stages.

Background

The increasing importance of biotherapeutics drugs is evident as mAbs have become the predominant treatment modality for various autoimmune and cancerous diseases over the past 25 years. Major advancements in technologies have made the discovery and development of mAb therapies quicker and more efficient during these years. New drug development and approval is highly time-consuming and resource-intensive and takes an average of a decade or more to bring to market. The approximate cost of bringing a new biotherapeutic to market is an estimated $2.6 billion (including the cost of a failed mAb candidate) (1). More time and resources would have been spent into the development of a mAb candidate that later fails in late-stage trials (2). Because of this, most biopharmaceutical companies seek to identify and terminate poor drug candidates early in their development, in particular, prior to expensive, years-long Phase III clinical trials by using the “fail early, fail fast” strategy (3,4). More than half of all drug candidates will ultimately fail in Phase III trials, which are meant to be confirmatory trials (5).

Anticancer drugs are approved by the regulatory agencies on the basis of safety and efficacy, which usually needs to be demonstrated in Phase III clinical trials (6). A failure rate of 97%in oncology clinical trials is typically due to issues with drug efficacy or toxicity. Failing to understand the mechanism of action (MOA) of such cancerous drugs can lead to the mischaracterization of target-specific inhibitors, misidentification of biomarkers, and may cause interlaboratory variability between cell lines without reasonable cause (7,8).Typically, Phase III clinical trials for oncology drugs involve a large number of patients and require a substantial investment on the part of participants, investigators, and sponsors (6). Clinical data are often not reported publicly and it is very difficult to derive the reason behind unsuccessful clinical trials. Therefore, a comprehensive understanding is required to improve the knowledge that can be used to guide further drug development in late stage. To elucidate that understanding, three cancer immunotherapy case studies are discussed here.

Case study 1: Rova-T

Rovalpituzumab tesirine (Rova-T) is a novel biomarker-specific antibody-drug conjugate (ADC) that offers a targeted therapy for approximately 85% of small cell lung cancer (SCLC) patients whose tumors express delta-like canonical notch ligand 3 (DLL3), but the clinical dosing is limited due to off-target toxicities (9). This novel drug is being developed by StemcentRx, a division of AbbVie.

Akamatsu et al. reported a Phase I study to evaluate tolerability, pharmacokinetic (PK), preliminary anti-tumor activity, and expression of DLL3 in 29 Japanese patients. Similar PK and adverse events (AEs) were seen compared to studies in non-Japanese patients, demonstrating a manageable safety profile with promising preliminary efficacy (10). In another study, Rova-T exhibited an overall response of 44% in SCLC patients with high expression of DLL3 and who had relapsed. These patients had previously failed one or more standard therapies in Phase I/II studies (11,12). Rudin et al. performed a Phase I trial in 82 patients to assess the safety, including the maximum-dose tolerance and toxic effects. The primary activity endpoint was an objective response by intention-to-treat analysis. The trial showed a single-agent anti-tumor activity with a manageable safety profile. Significant toxicities with high DLL3 expression were reported in 10 patients out of 60 with a fixed objective response (13). Morgensztern et al. studied 339 patients in a Phase II study to assess safety and efficacy/objective response rate (ORR). The overall survival (OS) results in ORR were 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. Toxicity issues were observed in 63% of the patients with previously treated SCLC (14). Carbone et al. demonstrated anti-tumor activity and a favorable risk benefit in 199 Patients (14). In another comparability study of 20 patients to evaluateprogrammed cell death ligand 1 (PD-L1), DLL3, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) expression in SCLC patients to find a candidate responder, the clinicopathological characteristics and immunohistochemical (IHC) staining intensity were compared. Saito et al. demonstrated that one out of 20 patients (5%) exhibited positive PD-L1 expression in the metastatic lesions, as well as in the primary lung tumor. DLL3 was highly expressed in 14/20 patients (70%) and EZH2 was positive in 17/20 patients (85%) (15).

Rova-T surprisingly fell short of the mark with respect to Phase II results, which were announced in March 2018. The drug also failed to improve overall survival compared with standard chemotherapy in a Phase III trial (TAHOE) in second-line disease in December 2018 (16).

There are multiple reasons why late-stage failures occur in mAb development. These include strategic and commercial factors, lack of rigorous trial design, incomplete understanding of mode-of-action of the disease, dosing criteria, and proceeding to Phase III on the basis of poor-quality Phase II data (17,18). A well-designed PK/pharmacodynamic (PD) study with relevant biomarker and endpoint analysis can justify Phase III studies that can facilitate the drug development process (19). In many cases, public disclosures are limited for many late-stage failures, and this limits how much the industry learns from late-stage failures (17,20).

Case study 2: Depatux-M

Depatuxizumab mafodotin (Depatux-M) is an ADC that specifically targets tumor cells expressing epidermal growth factor receptor (EGFR) and has demonstrated efficacy in recurrent glioblastoma multiforme (rGBM). rGBM is the most aggressive type of brain tumor that carries an extremely poor prognosis. Approximately 50% of patients exhibit tumors with EGFR amplification, thereby presenting an attractive therapeutic target (21,22).

Lassman et al. studied an international Phase I multicenter trial for safety and efficacy of Depatux-M plus temozolomide in patients with EGFR-amplified and rGBM (22). Van den Bent et al. reported on the dose response of Depatux-M in combination with temozolomide in a randomized controlled Phase II trial in recurrent EGFR-amplified rGBM (23). In Lassman et al.'s multicenter Phase I study, patients received Depatux-M (0.5–1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every two weeks by intravenous infusion. Depatux-M alone or in combination with temozolomide demonstrated an acceptable safety and PK profile in rGBM (24). In van den Bent et al.’s study, patients with EGFR-amplified rGBM developed ocular toxicity when treated with Depatux-M monotherapy (25).

Due to the lack of survival benefit for patients receiving Depatux-M compared with placebo when combined with temozolomide, an independent data monitoring committee recommended that the study be stopped. The randomized, placebo-controlled Phase III study was designed to evaluate the efficacy and safety. The drug had also been tested in gliosarcoma and non-small cell lung cancer (NSCLC) as well as other solid tumors, but it no longer appears in AbbVie’s pipeline (26).

Case study 3: Opdivo

Opdivo (nivolumab) is the blockbuster cancer immunotherapy drug from Bristol Myers Squibb that failed to meet the primary goal of a late-stage trial of patients with a rare type of brain cancer. The drug, when used along with the current standard of care for GBM, did not prevent the cancer from spreading when compared with the standard of care alone, concluded the Phase III "CheckMate 548" trial (27,28). Opdivo in combination with ipilimumab and chemotherapy is used to treat advanced lung cancer in adults (29). Selby et al. reported that ipilimumab and nivolumab show significant anti-tumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CheckMate-067). A synergistic anti-tumor activity was observed in mouse MC38 and CT26 colorectal tumor models with concurrent, but not sequential CTLA-4 and PD-1 blockade (30). Osa et al. suggested that the PD-1–blocking antibody nivolumab persists in patients twenty weeks after the last infusion. After systematic evaluation, the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events is 20 weeks (31). The original data were from a Phase I/II trial that showed a 12% response rate for the PD-1 inhibitor, with the effect lasting a median 17.9 months. But merely two months after that regulatory win, the Phase III CheckMate-331 study found that Opdivo was no better than chemotherapy at extending patients’ lives in those who had failed one round of platinum chemo (32).

Conclusion

Many drug products fail in late-stage development because of inadequate efficacy or safety. Though numerous drugs enter clinical trials every year, rigorous preclinical and clinical studies are required for successful drug development. The rationale behind late-stage failures could be lack of information about the MOA or wrong choice of the patient population and dosage. The later in the clinical timeline a drug candidate fails, the more time and resources have been spent towards its development. These failures and the costs associated can be prevented to some extent by adhering to the guidelines and recommendations provided by the regulatory authorities. By considering the previous mistakes and avoiding the common problems of the trials, the prospects of a drug succeeding and being approved can be magnified. With an improved understanding of the molecular mechanisms of the disease, one would assume that Phase III failures would be a rare occurrence. However, caveats remain in the industry’s ability to use in-vitro and preclinical models for accurately predicting toxicity.

One of the most common inadequacies that resulted in the failure of late-stage trials, particularly of cancer drugs, was that the MOA of the product candidate was not completely understood prior to entering clinical trials. This could have been avoided by planning more accurate and stringent protein interaction studies. Also, drug targets, which were previously thought to be essential for cancer, have now been shown to be less relevant. Thus, it is quite challenging to remain abreast of the latest developments. By adhering to the principles and recommendations from the previous mistakes, it is possible to avoid these common pitfalls to increase the success in Phase III clinical trials and ultimately gain regulatory approval.

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About the authors

Anurag S. Rathore*, asrathore@biotechcmz.com, is professor and coordinator of the DBT Center of Excellence for Biopharmaceutical Technology, and Rozaleen Dash, PhD, is a postdoctoral fellow at the Center of Excellence, Biopharmaceutical Technology; both are at the Department of Chemical Engineering, Indian Institute of Technology Delhi, India.

*To whom all correspondence should be addressed.