The Conduct of a Cooperative Clinical Trial (Recent Results in Cancer Research)

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In small—cell lung cancer, alternative dosing and schedules also demonstrated activity and tolerability Table 2 ; ref.

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The varied dosing of ICI agents creates difficulty in clinical use and future development. Currently existing PK and clinical trial data better support weight-based dosing than flat dosing; however, the optimal dose has not been fully determined for many of the ICI antibodies.

As there is no clear dose—response or dose—toxicity relationship with ICI antibodies, there likely will not be substantial changes in efficacy or toxicity with small changes in dosing. Therefore, flat dosing may be more attractive than weight-based dosing, as it appears to result in similar anti-tumor activity in the majority of population weights and body surface areas while providing ease of administration and less drug wastage.

However, further cost-effectiveness data are needed to define the more efficient dosing strategy that optimizes efficacy as well as cost-effectiveness. IgG1 and IgG3 may elicit more natural killer cell antibody-dependent cell-mediated cytotoxicity while IgG4 may demonstrate more complement pathway activation Table 1 ; ref. Anti-drug antibodies ADA have been detected but the actual presence of neutralizing ADAs is low and do not significantly impact the clearance, safety, PK, PD, or efficacy of pembrolizumab, pidilizumab, atezolizumab, or nivolumab 37, 38, 51, Head-to-head comparative studies should be considered to clarify these issues.

A DLT period of at least 6 to 8 weeks could be considered before escalating to higher doses and both the early and late toxicity data should be considered to make recommendations regarding the RP2D. The effect of steroids and immunosuppressive therapy to treat irAEs on continued efficacy should be captured in clinical trials, as well as the incidence of irAE recurrence with continued therapy.

Additionally, as the immunologic effects of these agents persist, there are many anecdotal reports of patients experiencing improved responses or enhanced immune-related toxicities with subsequent therapies 55 months to years post therapy. This requires trials designs to incorporate longer follow-ups in order to better characterize the late toxicities and effects on subsequent therapies.

For example, at least a day follow-up could be considered for evaluation of immune-related toxicities and long-term follow-up of up to 1-year could be incorporated into studies so that long-term toxicities, including effects on subsequent therapies, could be evaluated. In most clinical trials, initial response assessments generally occur at 8 to 12 weeks; however, immunologic responses can be delayed and pseudoprogression has been described The onset of response and the incidence of pseudoprogression may vary across tumor types and should be noted in addition to standardized immune-response criteria.

Although pseudoprogression has been notable in malignancies where immune modulation has a substantial role i. Moreover, the benefit of treatment after a true progression is unclear. This suggests that continuing therapy beyond progression is unlikely to be beneficial in the majority of patients; however, clinicians often do so as there are no clear clinical characteristics or highly predictive biomarkers across the various malignancies that can identify patients who are more likely to have delayed response.

Predictive biomarkers of response to ICIs need to be further studied and incorporated into trials and are discussed in the series see accompanying article by Mehnert and colleagues, ref. The mechanism and risk factors for identification of such phenomenon have not been clearly defined. Ongoing and future trials should take into consideration the atypical outcomes such as pseudo- or hyper-progression as efficacy endpoints, in addition to the traditional RECIST response assessments, so that these can be better defined and understood.

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Although the use of anti-CTLA4 antibodies i. The initial phase I trials 60, 61 established a 2-year limit to therapy; however, subsequent studies allowed ongoing therapy as long as there is clinical benefit Clinical trial protocols vary from 6 months to 1. Unlike vaccines, ICIs are passively administered antibodies with uncertainty and variability in their ability to engage the adaptive immune system.

It is unknown whether ongoing therapy is truly superior to limited treatment of a defined duration or to the use of a maintenance regimen with less frequent administration. Moreover, there may be long-term toxicities that emerge after years of treatment that may not occur with limited therapy. An ongoing study of nivolumab in advanced NSCLC 63 randomizing patients at 1 year to treatment continuation versus discontinuing therapy with the option of re-treatment at progression may help address this question but clearly, additional studies are needed.

In the melanoma data, the majority of patients with complete responses who stopped therapy appeared to remain in remission with a median duration of response ranging from 17 to 43 months However, for other malignancies, especially in patients who have stable disease or partial response as best response, discontinuation of therapy poses potential risk due to the inability to consistently re-induce responses at the time of progression. Without guidance from the literature, many clinicians and patients have opted to continue therapy indefinitely in the absence of a complete response, especially in situations where there is a lack of effective therapeutic options at progression, but this comes at a substantial cost.

This area has implications not only in disease outcomes but also in financial costs to the individual and society at large; thus, there is an urgent need to address this issue in clinical trials. ICIs have been predominantly approved in advanced disease and there are ongoing studies to explore these agents in earlier settings Table 3. In addition, there are an expanding number of clinical trials of immuno-oncology combination therapy in which multiple immune pathways are concurrently targeted see accompanying article by Day and colleagues. One of the important areas in the next phase of development is to understand the mechanisms of primary and acquired resistance to ICI therapy.

Despite the reported efficacy of ICIs in a number of solid tumors, the response rates are often modest and patients who achieve complete response are rare. Therefore, studies of pre- and posttreatment correlative samples will be paramount in understanding the mechanism of resistance, development of predictive biomarkers, and rational design of the next generation of clinical trials.

Immuno-oncology is undergoing rapid development with initial trials resulting in meaningful improvements in patient outcomes. The next generation of clinical trials has the opportunity to address areas of need such as the inclusion of inadequately represented patient populations, optimization of drug dosing and duration, better characterization of long-term toxicities and design of rational drug combinations in patients with primary and acquired resistance.

Until such studies are conducted, use of these agents in the clinic should be carefully selected to ensure safety. For example, treatment in patients with autoimmune disease should be limited to those with limited organ involvement and perhaps to later lines of therapy, and off-label combination therapies should be avoided until robust efficacy and safety data are available.

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  • Successful design and conduct of the needed studies will require participation of the various stakeholders. Academic research groups and cooperative trial networks, in collaboration with industry partners, may be best poised to lead designing studies in understudied populations that may not be studied otherwise. Regulatory bodies could demand follow-up studies to address questions such as drug dosing and duration. To fully develop an effective immuno-oncology therapeutic strategy and overcome the limitations addressed will require collaboration among industry, academia, and regulatory bodies where sharing and pooling of information will be crucial.

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    Forde , Janice M. Mehnert , Deborah Collyar , Marcus O. Butler , Erica L. Dixon and Laura Q. Patient Advocates in Research, Danville, California. The Emmes Corporation, Rockville, Maryland.

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    DOI: Abstract Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Introduction Immune checkpoint inhibitors ICI have taken the oncology world by storm and the rapidity of clinical trial enrollment and Food and Drug Administration FDA -accelerated approvals have left many unanswered questions to meet the next wave of immuno-oncology trials.

    Figure 1. Patients and disease characteristics in clinical trials The restrictive eligibility criteria common in early trials of ICI therapy, have resulted in insufficient data to guide treatment decisions in many important patient populations insufficiently represented in clinical trials such as patients with asymptomatic autoimmune disease, well-controlled viral infections, untreated brain metastases, limited performance status, or those who need concomitant radiation.

    Autoimmune disease. Viral infections viral hepatitis, HIV. Limited performance status. Older patients. Brain metastases. Hematopoietic stem cell transplant. Concomitant therapy—Radiation. Figure 2. View this table: View inline View popup. Table 1. Dosing strategies. Table 2.

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    Differences between the ICI antibodies and the presence of anti-drug antibodies. Toxicity determination and trial design. Clinical response and benefit.