Theranostic Outcomes in Clinical Practice of Oncology: What,So What,Now What? What's More

Abstract

What?

What are the desired outcomes of the theranostic management of metastatic cancer in everyday clinical practice? For nuclear oncology physicians the primary aim is to relieve suffering of the fearful individual cancer patient referred for a personal clinical consultation. The essence of theranostics in the real world is the practice of truly personalized medicine. The outcome sought is control of cancer, with meaningful survival benefit, and enhancement of the quality of life (QOL) of the particular patient upon whom the optimal tumor-targeted treatment is focused. Evaluation of outcome is manifested through the perspective of the person being treated (n = 1).

End points of most significance to the patient with advanced metastatic cancer are, quite simply, overall survival (OS) and QOL. Provision of emotional support, relief of pain, avoidance of toxic side-effects of therapy, and minimization of hospital attendances are very important components of a physician's care in the clinical practice of nuclear oncology.

The direct contrast between clinical practice and a controlled Pharma clinical trial is stark. The focus of randomized controlled clinical trials (RCTs) is transferred from the personal needs of the patient to that of the performance of the therapeutic agent. The objective is no longer the individual welfare of the patient, but has become the demonstration of a statistically measurable effect on the treated population. In RCTs the already highly selected chosen population will be divided so that only a proportion of patients will receive, what is hypothesized to be, the optimal treatment, a decision in which the patient has no choice.

RCTs use surrogate end points, such as progression-free survival (PFS), to define an early statistical benefit over controls, even though PFS is known to be unreliable as a predictor of OS.^1,2 The measurement of PFS requires regular hospital assessment by repeated imaging and biomarker sampling, and this constant medical intervention may be compounded by the need to treat toxic side-effects. These adverse events (AEs), which may affect almost all patients on study, and serious AEs in two thirds³ are usually deemed “manageable” by the oncologist. However, patients often express a contrary view of such degradation of the quality of their compromised life.⁴ When evaluating the risks and benefits of a new cancer drug, an understanding of the ways in which a drug affects how a patient feels and functions is crucial. Most drug developers still do not rigorously and comprehensively collect information directly from patients about symptoms or physical functioning in pivotal RCTs upon which regulatory approval is based.⁵ The advent of patient-reported outcomes (PROs) has demonstrated the magnitude of the disconnect in perception of noisome AEs of clinical trial drugs by oncologists and by their patient cohort.⁵ In clinical practice the one-on-one doctor–patient relationship avoids such miscommunication, and the QOL of the individual patient can be preserved by judicious and timely adjustment to the treatment regimen. Such accommodation at the discretion of the treating physician may be precluded in RCTs where the therapeutic regimen is controlled by a formal protocol, which cannot be “violated.”

Patients are prepared to tolerate AEs associated with their cancer therapy, provided that it delivers a meaningful clinical benefit in terms of OS and QOL. However, they are less likely to put up with toxicity if the novel anticancer agents are associated with only modest, although statistically significant, improvement in PFS, which does not translate into substantial survival benefit. Over the past decade the mean improvement of OS achieved by all the anticancer drugs approved by the Food and Drug Administration (FDA) is 3.4 months.⁶

Comparative assessment of RCT clinical benefit of cancer therapy in the noncurative setting using the ESMO Magnitude of Clinical Benefit Scale, and the ASCO Value Framework Net Health Benefit Score, aspires to provide a valid, clear, unbiased, and reliable approach to data analysis.⁷ Both assign lesser weight to outcome measures derived from surrogates for survival and incorporate in the benefit evaluation of other outcome measures, including long-term survival, QOL, and AEs, which include financial toxicity.

So What?

Study populations in RCTs are highly selected, and even when clinical benefit is demonstrated statistically, the outcomes may not be replicated in real-world clinical oncology practice. The current RCT system has other major disadvantages, which may perhaps now render it unfit for clinical evaluation purposes. RCTs are very expensive and take 5–10 years to perform, during which time the treatment regimen they seek to evaluate may often have been superseded by the advent of more recent drug developments. For example, the exponential increase in cancer immunotherapies such as cancer immune check point inhibitors and chimeric antigen receptor therapy, and their unlimited potential combinations with chemotherapy, imposes insurmountable logistic constraints on traditional assessments by RCT.

There are also technical problems associated with RCT measurements of tumor response to the new immune chemotherapies which challenge objective assessment by response evaluation criteria in solid tumors (RECIST) criteria, since phenomena such as pseudoprogression may confound monitoring by conventional imaging, and attempts to modify standard RECIST protocols are yet to be validated.⁸ To adapt imaging approaches for the optimal visualization of responses to targeted therapies, changes in the cellular and molecular characteristics of tumors, beyond tumor diameter, need to be considered. Depending on the tumor entity and the specific therapy, spatial heterogeneity, as well as biology, pathology, and the metabolic profile of the tumor, all require attention.⁹

The old chemotherapy paradigm of RCT evidence-based best practice, epitomized by the Cochrane model, was always out-of-date given the 5–10 years required to collect, collate, analyze, and publish the data. The mortal blow to the RCT paradigm, however, is cost. Currently cancer drug development, evaluation, regulatory approval, and marketing are associated with an exponential, unsustainable, uncontrollable, and unacceptable rise in cost.^10,11 Many drug approvals are indeed based on the result of a single trial, which does not always meet the threshold for meaningful clinical benefit.¹² When coupled with unrepresentative outcomes in very restricted patient populations, and the concomitant increase in protean toxicities of novel immune therapies which not only degrade QOL¹³ but also necessitate modification of treatment regimens under study, the RCT paradigm, having been in place for the past half-century, would appear to have outlived its usefulness, in its present form.

The trend toward personalized medicine, with molecular therapies informed by individual tumor characteristics in each patient, demands a new evaluation paradigm, which emphasizes control of cancer with prolonged survival and enhanced QOL. For novel cancer therapies to be shown to achieve these hoped-for clinical outcomes, the proof of the pudding is in the eating and should be manifested in real-world oncology practice worldwide.

Theranostic nuclear oncology is ideally positioned to establish such a new paradigm for evaluation of novel tumor-targeted therapy with personalized molecular biomarkers in specific cancers, alone or in combination with immune chemotherapy. The 75-year theranostic radioiodine real-world experience treating thyroid cancer eschewed the RCT model and depended upon clinical outcomes in huge patient populations, with mature long-term survival data.¹⁴

Novel theranostic agents have been, almost exclusively, developed in university laboratories and have entered clinical practice in academic hospitals on compassionate patient usage or on small physician-sponsored clinical trial protocols. The advantages of being unconstrained by RCT exigencies of the pharmaceutical industry include freedom to modify treatment regimens in the light of ongoing clinical experience, especially when exploring novel chemo-immunotherapeutic combinations with tumor-targeted radionuclide ligands in nonselective patient populations. Investigator-initiated studies promote rapid clinical application of the most recently reported advances in theranostics, with the intellectual freedom to innovate and adapt management protocols, unconstrained by contract research organizations, for the personalized and individual benefit of their patients.

The major disadvantage of ad hoc academic evaluation of novel theranostic agents, all too often performed retrospectively on heterogeneous patient populations in small centers, is the inability to obtain rigorous statistical validation of efficacy and the consequent failure to persuade medical oncologists to incorporate theranostics into their routine clinical practice. Their reluctance is also due to the absence of a Pharma RCT imprimatur, regulatory approval, and insurance reimbursement.

Now What?

Theranostics has the potential to harness the complementary strengths of real-world clinical outcome evaluation in large patient populations with those of Pharma RCTs on harmonized theranostic protocols, to facilitate timely provision of effective, safe, affordable approved cancer therapy worldwide.

Specific instances of such pathfinder studies may be found in I-131-Rituximab radio-immunotherapy (RIT) of non-Hodgkin's lymphoma (NHL), Ga-68/Lu-177-octreotate peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs), and Ga-68/Lu-177/Ac-225-prostate-specific membrane antigen (PSMA) therapy of metastatic castrate-resistant prostate cancer (mCRPC).

Iodine-131-anti CD20 Mab RIT NHL

Studies of I-131-tositumomab (Bexxar GSK) for first-line RIT of follicular lymphoma (FL) achieved 5-year OS of 89%.¹⁵ Long-term follow-up of relapsed or refractory indolent NHL achieved promising clinical outcomes with minimal toxicity, and 10-year OS was estimated to be 42%.¹⁶ The relative absence of AEs was attributable to individual prospective dosimetry with prescription of 0.75 Gy radiation absorbed dose to whole body. However, the definitive metric for outcome evaluation was not the RCT results of efficacy and safety, but subsequent sales,¹⁷ which did not fulfil Pharma expectations, and Bexxar was withdrawn from the market in 2014. The tension between commercial business profit maximization and longer-term assessments of patient outcome optimization remains a problem to be resolved.¹⁸

The author introduced I-131-rituximab RIT of relapsed/refractory low-grade NHL 20 years ago, and prospective evaluation of routine clinical practice showed that after 10-year follow-up of 142 consecutive patients, median OS (mOS) was 87 months for intermediate risk and 81 months for high risk groups.¹⁹

First-line I-131-rituximab induction RIT of advanced FL in 68 consecutive patients followed for 10 years, with none lost to follow-up, showed that 84% remain alive and that 80% have required no further treatment INITIAL Study (ANZ CTR12607000153415). [Kesavan M, Turner JH, McQuillan AD. Follicular non-Hodgkin lymphome chemo-free first line iodine-131 rituximab radioimmunotherapy: Ten year follow-up of the Phase 2 INITIAL study. J Clin Oncol 2019 in review]. Furthermore, there were no clinically apparent adverse sequelae attributable to their chemo-free, first-line I-131-rituximab RIT. In particular there was no instance of myelodysplastic syndrome (MDS) or acute leukemia (AL), and the incidence of second malignancy was low (3%).²⁰

Validation of these very favorable and cost-effective clinical outcomes is under active contemplation, not by RCT, but in a large population of NHL patients in India. [Calais PJ, Sen IB, Turner, JH. Radioimmunotherapy of low-grade lymphoma in India: Rationale and practicum for routine clinical application of iodine-131 rituximab. Indian J Hematol Blood Trans, 2019, in review]. This real-world theranostics initiative will address a major unmet need for affordable, safe effective treatment and will, at the same time, generate prospective clinical outcome real-world data (RWD), which would inform potential Pharma drug registration RCT of I-131-rituximab RIT of NHL.

Gallium-68/lutetium-177-octreotate PRRT NET

Four hundred forty three Dutch patients undergoing routine clinical theranostic PRRT of NETs on a standard Lu-177-DOTATATE protocol in Rotterdam since 2000 were followed up for a median of 78 months.²¹ In this real-world prospective study, over two-thirds of patients were on prior treatment with somatostatin analogs. More than 80% of patients with progressive mid-gut NETs and pancreatic NETs at baseline achieved disease control. Median PFS was 31 months, and median OS 60–80 months. In particular, mid-gut NETs with stable disease had mOS 82 months as against those with progressive disease (PD) at baseline, where mOS was 50 months. For pNETs PD mOS was 71 months.²¹ Safety evaluation in 600 NET patients followed for a median of 64 months showed mild self-limited Grade 3/4 hematological toxicity with thrombocytopenia 5%, neutropenia 5%, and anemia 4%. MDS occurred in 1.5%.²¹

The excellent outcome and toxicity RWD generated by this exemplary prospective single-center clinical study underpinned the design of the subsequent Pharma RCT of Lu-177-DOTATATE (Lutathera AAA) for PRRT of mid-gut NETs. This NETTER-1 Study (NCT01578239)²² led to drug registration and eventual acceptance into mainstream clinical oncologist practice, albeit a decade late.

Retreatment with Lu-177-octreotate in 168 Dutch NET patients after relapse with PD more than 18 months after initial PRRT, followed up for a median of 88 months, achieved mOS of 81 months.²³

Even before the NETTER-1 RCT commenced, clinical management of gastroenterological NETs (GEP-NETs) had evolved with the addition of radio-sensitizing chemotherapy to augment efficacy of PRRT. Combination of standard PRRT regimens with 5-fluorouracil (5-FU) or with capecitabine improved clinical response.^24,25 This meaningful improvement in efficacy of PRRT was achieved without additional toxicity. Radio-sensitizing 5-FU when combined with Lu-177-octreotate PRRT in 68 patients followed up for 60 months achieved 2-year OS in 72% and 5-year OS in 52%.²⁴ Capecitabine and Lu-177-octreotate PRRT achieved tumor control in 94% of 33 patients, and at median follow-up 1 year OS was 91% and at 2 years 88%.²⁵

In addition to enhancing efficacy, innovative clinical regimens for Lu-177-octreotate PRRT of GEP-NETs have minimized infusion-related AEs. Continual ongoing refinement of clinical protocols, particularly with the advent of oral aprepitant (Emend MSD), sublingual ondansetron, and intravenous dexamethasone antiemesis prophylaxis, has rendered nausea a rare occurrence, whereas the inflexible RCT premedication regimen of the NETTER-1 study was associated with frequent AEs of nausea (59%) and vomiting (47%).^22,26

Durable enhancement of QOL has been reported in all clinical studies,^27,28 and symptoms, when present, have almost always resolved within one to two cycles of PRRT.

The ability of physician-sponsored clinical studies to quickly adopt new strategies, in the light of emerging pilot study data, is exemplified by the incorporation of an innovative capecitabine-temozolomide chemotherapy combination reported by Strosberg et al. in 2008, into the standard Lu-177-octreotate GEP-NET PRRT regimen within weeks of his conference presentation of data, subsequently published in 2011.²⁹ The ensuing investigator-initiated Phase 2 clinical study (ACTRN 12610000440022) of Lu-177-octreotate/capecitabine/temozolomide in progressive disseminated GEP-NETs showed very encouraging disease control with 94% objective response rate, and OS of 88% at 2 years, achieved with minor toxicity.³⁰

These outcome RWD are currently being validated in a formal multicenter RCT (CONTROL-NETS CTC0120/AGO14 NET).

Gallium-68/lutetium-177/actinium-225-PSMA mCRPC

Prospective clinical study of Lu-177-PSMA therapy of advanced mCRPC on compassionate patient usage protocols commenced in Bad Berka in 2013. In this real-world clinical experience of over 4000 patients, the mOS was 31 months.³¹ In chemotherapy-naive patients (n = 110) mOS was 38 months, while in the salvage setting of prior chemotherapy the survival was halved, mOS 19 months. Toxicity was minimal, with self-limited hematologic AEs 2–5%, no nephrotoxicity, and xerostomia in less than 3%.³¹

The German multicenter clinical study analyzed RWD retrospectively, reporting on 145 mCRPC patients treated with Lu-177-PSMA and followed up for a median of 16 weeks. It showed comparable modest toxicity, and the primary end point of prostate-specific antigen (PSA) decline of greater than 50% was indicative of response in 57% of all patients.³² Translation of this preliminary indication of objective response data into mOS outcomes will be addressed in a larger real-world, retrospective, multinational, multicenter study of standardized routine Lu-177-PSMA theranostics of mCRPC, currently in progress under the auspices of the World Association of Radiopharmaceutical and Molecular Therapy (WARMTH) and the International Atomic Energy Agency (IAEA).

The Pharma-sponsored drug-registration Phase 3 RCT (VISION Endocyte NCT03511664) has commenced recruitment with a primary end point of OS in 750 patients with progressive PSMA-positive mCRPC treated with Lu-177-PSMA-617. Secondary objectives of QOL assessment will be performed on standard questionnaires HRQoL, EQ-5D-5L, FACT-P, and BPI-SF. Novel androgen axis drugs, such as abiraterone or enzalutamide, are allowed, but patients on investigational agents, cytotoxic chemotherapy, or other systemic radioisotopes are excluded.

Meanwhile, a prospective Phase 2 investigator-initiated clinical study of Lu-177-PSMA-617 in 30 mCRPC patients showed objective response in 62%, with PSA decline greater than 50% and clinically meaningful improvements in pain severity and global health score.³³ This study has informed a formal multicenter Australian Phase 2 RCT; Lu-177-PSMA-617 versus cabazitaxel in 200 progressive mCRPC patients (TheraP NCT03392428).

The gestational period of these RCTs is predicated at 4–5 years, but definitive outcomes in terms of mOS will inevitably require a longer time frame. To obviate the inordinate delay in provision of Lu-177-PSMA theranostics to all mCRPC patients worldwide, WARMTH is sponsoring a prospective, multicenter, international, coordinated clinical practice study on standardized eligibility criteria and harmonized treatment protocols on the NIGHTCAP Study (National Investigators Global Harmonization Theranostics of Cancer of Prostate). The WARMTH NIGHTCAP Study will promote harmonized, practical, safe, and effective management of mCRPC in routine clinical practice worldwide in a large real-world population of 4000 patients in 50 centers. The primary end points of this prospective RWD clinical audit are, quite simply, OS and QOL.

QOL assessment on the NIGHTCAP Study will not require completion of formal questionnaires by patients, or their doctors, but PROs will be evaluated on a daily basis by a personal mobile phone application which records self-selection of one of five standard emoji, which best represents how each patient is feeling that day. This innovative methodology of real-time real-world collection of PRO data has been validated against standard QOL questionnaires³⁴ and does not require hospital visits.

Subject to regulatory and ethics authority approvals for data collection, transfer, and sharing, the continuum of outcome RWD reporting will inform refinement of the protocol in an adaptive approach not possible in formal RCTs.

Already, the advent of Ac-225-PSMA α therapy of refractory mCRPC³⁵ has changed the landscape of Lu-177-PSMA management, and the combination of both α and β radionuclide targeted therapy has shown the potential to increase efficacy and ameliorate toxicity, particularly in relation to salivary glands, where the TANDEM study has achieved early control of aggressive disease with Ac-225-PSMA, with subsequent cycles of less toxic Lu-177-PSMA.¹⁴

It is to be anticipated that other combinations with chemotherapeutic, hormonal, and immunological agents will become available to clinicians within the 5-year gestation period required for results from the VISION Pharma RCT, which has only just started. There is an imperative to immediately address the unmet need for provision of effective safe treatment of mCRPC, which is now the commonest cause of cancer death in men worldwide.

The general adoption of Ga-68-PSMA PET/CT diagnosis and staging of patients,^36,37 and the recent availability of a kit formulation for rapid, simple, reliable bench-top radiolabeling,³⁸ will result in an exponential and global increase in demand for a treatment which significantly prolongs OS, without toxicity, and which actually enhances QOL. In the interim, the ready access to therapy monitoring with Ga-68-PSMA PET/CT will lead to repeat cycles of Lu-177-PSMA, or addition of Ac-225-PSMA, for disease progression.

What's More

Within the oncology community there is a growing trend to use RWD to address clinical and policy relevant questions, which cannot be answered with data from RCTs.³⁹ RWD are increasingly being used to support regulatory drug approval and funding decisions as evidenced by the new strategic framework of the FDA to advance use of real-world evidence to support development of drugs and biologics.^39,40 In addition, the authorities conducting health technology assessments to evaluate new therapeutic agents are demanding RWD, seeking evidence that clinical interventions provide meaningful benefits; improved OS, QOL, and cost to patients.⁴¹

One of the greatest strengths of RWD is the ability to improve the generalizability of conclusions from clinical research and to contribute knowledge by enabling the study of much larger cohorts and allowing longer follow-up than is typical for RCTs. RWD can document outcomes of patients with common cancers, such as mCRPC, in routine practice to provide a fundamental evaluation of QOL, which is not confined only to patients who live in developed countries.

RWD are, at the present time, collected retrospectively, often from population-based cancer registries, comprising information from various sources. To enhance the reliability of assessment of RWD to determine treatment efficacy it is recommended that the fundamental domains of appropriate selection of participants, measurement of exposure and outcome, and control of confounding be evaluated.⁴² A checklist has been formulated for the evaluation and interpretation of population-based studies of treatment effectiveness.⁴²

While hitherto RWD have been collected retrospectively, the valid extrapolation of such representative population outcomes may be considerably enhanced by concomitant prospective real-world studies performed concurrently with formal RCTs. Using a harmonized protocol, designed and managed in collaboration with the drug registration RCT, the resulting RWD would complement the Pharma studies and aid extrapolation to routine clinical application.

Real-world, real-time prospective evaluation of tumor-targeted theranostic regimens, in large populations on harmonized management protocols, will not only document achievable meaningful outcomes of OS and QOL in actual clinical practice but also, at the same time, make immediately available, best current theranostics practice to all eligible patients worldwide.

Res ipsa loquitur

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