Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol.

BACKGROUND: The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI). METHODS: Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed. FINDINGS: Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups. INTERPRETATION: Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers. FUNDING: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.

The Value of Addressing Patient Preferences.

Recent scientific progress is, in some cases, leading to transformative new medicines for diseases that previously had marginal or even no treatment options. This offers great promise for people affected by these diseases, but it has also placed stress on the health care system in terms of the growing cost associated with some new interventions. Effort has been taken to create tools to help patients and health care providers assess the value of new medical innovations. These tools may also provide the basis for assessing the price associated with new medical products. Given the growing expenditures in health care, value frameworks present an opportunity to evaluate new therapeutic options in the context of other treatments and potentially lead to a more economically sustainable health care system. In summary, the contribution to meaningful improvements in health outcomes is the primary focus of any assessment of the value of a new intervention. A component of such evaluations, however, should factor in timely access to new products that address an unmet medical need, as well as the magnitude of that beneficial impact. To achieve these goals, value assessment tools should allow for flexibility in clinical end points and trial designs, incorporate patient preferences, and continually evolve as new evidence, practice patterns, and medical progress advance.

Novel Approach to Accelerate Lung Cancer Research: Lung-MAP and the Potential of Public-Private Partnerships.

The National Cancer Institute recently found that death rates for non-small cell lung cancer (NSCLC) have been reduced by over 6% overall in recent years. This reduction in mortality has been accompanied by an average increase in overall survival and largely credited to the therapeutic advancements for the effective treatment of NSCLC. Numerous molecular alterations have been identified in NSCLC that have enabled the development of new drugs capable of targeting these changes and efficiently kill cancerous cells. New treatments to modulate patients' immune systems have been shown to be effective in stimulating natural immune cells to have an improved anti-cancer effect. While these types of approaches to treat cancer are providing new options for patients, leadership from the Food and Drug Administration (FDA) recognized that the expansion of targeted therapy in NSCLC presented significant promise, but evaluation of the safety and efficacy of these new drugs would be slowed if new models for conducting clinical studies were not identified. Specifically, the FDA recommended that a comprehensive approach be implemented to identify the patients that are the best candidates for these, and other new treatments based upon the molecular characteristics of their tumors, and more efficiently conduct the clinical studies necessary to evaluate the safety and efficacy of new drugs. To address this growing challenge, leading lung cancer experts and stakeholders across academia, government, industry, and patient advocacy came together to design a clinical research approach that could serve as a sustainable infrastructure for new lung cancer treatments called the Lung Cancer Master Protocol.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

Quality-of-life outcomes and risk prediction for patients randomized to nivolumab plus ipilimumab vs nivolumab on LungMAP-S1400I.

BACKGROUND: An important issue for patients with cancer treated with novel therapeutics is how they weigh the effects of treatment on survival and quality of life (QOL). We compared QOL in patients enrolled to SWOG S1400I, a substudy of the LungMAP biomarker-driven master protocol. METHODS: SWOG S1400I was a randomized phase III trial comparing nivolumab plus ipilimumab vs nivolumab for treatment of immunotherapy-naïve disease in advanced squamous cell lung cancer. The primary endpoint was the MD Anderson Symptom Inventory-Lung Cancer severity score at week 7 and week 13 with a target difference of 1.0 points, assessed using multivariable linear regression. A composite risk model for progression-free and overall survival was derived using best-subset selection. RESULTS: Among 158 evaluable patients, median age was 67.6 years and most were male (66.5%). The adjusted MD Anderson Symptom Inventory-Lung Cancer severity score was 0.04 points (95% confidence interval [CI] = -0.44 to 0.51 points; P = .89) at week 7 and 0.12 points (95% CI = -0.41 to 0.65; P = .66) at week 13. A composite risk model showed that patients with high levels of appetite loss and shortness of breath had a threefold increased risk of progression or death (hazard ratio [HR] = 3.06, 95% CI = 1.88 to 4.98; P < .001) and that those with high levels of both appetite loss and work limitations had a fivefold increased risk of death (HR = 5.60, 95% CI = 3.27 to 9.57; P < .001)-compared with those with neither risk category. CONCLUSIONS: We found no evidence of a benefit of ipilimumab added to nivolumab compared with nivolumab alone for QOL in S1400I. A risk model identified patients at high risk of poor survival, demonstrating the prognostic relevance of baseline patient-reported outcomes even in those with previously treated advanced cancer.

COVID-19 Evidence Accelerator: A parallel analysis to describe the use of Hydroxychloroquine with or without Azithromycin among hospitalized COVID-19 patients.

BACKGROUND: The COVID-19 pandemic remains a significant global threat. However, despite urgent need, there remains uncertainty surrounding best practices for pharmaceutical interventions to treat COVID-19. In particular, conflicting evidence has emerged surrounding the use of hydroxychloroquine and azithromycin, alone or in combination, for COVID-19. The COVID-19 Evidence Accelerator convened by the Reagan-Udall Foundation for the FDA, in collaboration with Friends of Cancer Research, assembled experts from the health systems research, regulatory science, data science, and epidemiology to participate in a large parallel analysis of different data sets to further explore the effectiveness of these treatments. METHODS: Electronic health record (EHR) and claims data were extracted from seven separate databases. Parallel analyses were undertaken on data extracted from each source. Each analysis examined time to mortality in hospitalized patients treated with hydroxychloroquine, azithromycin, and the two in combination as compared to patients not treated with either drug. Cox proportional hazards models were used, and propensity score methods were undertaken to adjust for confounding. Frequencies of adverse events in each treatment group were also examined. RESULTS: Neither hydroxychloroquine nor azithromycin, alone or in combination, were significantly associated with time to mortality among hospitalized COVID-19 patients. No treatment groups appeared to have an elevated risk of adverse events. CONCLUSION: Administration of hydroxychloroquine, azithromycin, and their combination appeared to have no effect on time to mortality in hospitalized COVID-19 patients. Continued research is needed to clarify best practices surrounding treatment of COVID-19.

New drug approvals in oncology.

The traditional regulatory drug approval paradigm comprising discrete phases of clinical testing that culminate in a large randomized superiority trial has historically been predominant in oncology. However, this approach has evolved in the current era of drug development, with multiple other development pathways now being utilized. Indeed, treatment approaches designed on the basis of an improved understanding of cancer biology have led to unprecedented responses in early phase trials, sometimes resulting in drug approvals in the absence of large-scale trials. At the same time, improved molecular diagnostic technologies have led to the identification of ever-smaller patient subgroups for molecularly targeted therapy. Moreover, new FDA regulatory paradigms have enabled the rapid review and accelerated approval of certain drugs in the absence of survival data. Regulatory approvals based on large-cohort trials with surrogate or intermediate clinical end points or on non-inferiority trials, as well as new tumour-agnostic indications, also set important precedents in the field. In this Viewpoint, we asked two leading oncologists involved in clinical drug development, an expert in regulatory science and prescription drug policy and a prominent patient advocate, to provide their opinions on the implications of these changes in regulatory practices for patient care.

A National Assessment of Diagnostic Test Use for Patients with Advanced NSCLC and Factors Influencing Physician Decision-Making.

BACKGROUND: Diagnostic tests, including US Food and Drug Administration (FDA)-approved tests and laboratory-developed tests, are frequently used to guide care for patients with cancer, and, recently, have been the subject of several policy discussions and insurance coverage determinations. As the use of diagnostic testing has evolved, stakeholders have raised questions about the lack of standardized test performance metrics and the risk this poses to patients. OBJECTIVES: To describe the use of diagnostic testing for patients with advanced non-small-cell lung cancer (NSCLC), to analyze the utilization of FDA-approved versus laboratory-developed diagnostic tests, and to evaluate the impact of existing regulatory and coverage frameworks on diagnostic test ordering and physician treatment decision-making for patients with advanced NSCLC. METHODS: We conducted a 2-part study consisting of an online survey and patient chart review from March 1, 2019, to March 25, 2019, of physicians managing patients with advanced NSCLC. Respondents qualified for this study if they managed at least 5 patients with advanced NSCLC per month and had diagnosed at least 1 patient with advanced NSCLC in the 12 months before the survey. A total of 150 physicians completed the survey; before completing the survey, they were instructed to review between 4 and 8 charts of patients with stage IV NSCLC from their list of active patients. RESULTS: A total of 150 practicing oncologists who manage patients with advanced NSCLC responded to the survey and reviewed a total of 815 patient charts. Of these 815 patients, 812 (99.6%) were tested for at least 1 biomarker, including 73% of patients who were tested for EGFR, 70% tested for ALK, 58% tested for BRAF V600E, and 38% of patients tested for ROS1, by FDA-approved diagnostic tests. In all, 185 (83%) patients who tested positive for EGFR and 60 (83%) patients who tested positive for ALK received an FDA-approved targeted therapy for their biomarker. A total of 98 (65%) physicians responded that the patient's insurance coverage factored into their decision to order diagnostic tests and 69 (45%) physicians responded that cost or the patient's insurance coverage could influence them not to prescribe an indicated targeted therapy. CONCLUSION: The survey results indicate that diagnostic testing has become routine in the treatment of patients with advanced NSCLC, the use of FDA-approved diagnostic tests has increased, and insurance coverage and cost influence patient access to diagnostic testing as well as to targeted treatment options.

Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400.

The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy "Master Protocol," using a common platform (next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care.

Use of multiple endpoints and approval paths depicts a decade of FDA oncology drug approvals.

This study explores the historic use of different endpoints to support regular and accelerated approval of cancer drugs between 2002 and 2012. In the past 10 years, two thirds of oncology regular approvals were based on endpoints other than overall survival. More than three quarters of accelerated approvals were based on response rates. The accelerated approval program has been heavily used over this time period, with one third of all approved oncology indications receiving accelerated approval. At times, critics have characterized the agency as rigid and unpredictable. This research describes the degree of regulatory flexibility that U.S. Food and Drug Administration and drug sponsors have used over the past decade in the development of new treatments for cancer.

Considerations for the successful co-development of targeted cancer therapies and companion diagnostics.

As diagnostic tests become increasingly important for optimizing the use of drugs to treat cancers, the co-development of a targeted therapy and its companion diagnostic test is becoming more prevalent and necessary. In July 2011, the US Food and Drug Administration released a draft guidance that gave the agency's formal definition of companion diagnostics and introduced a drug-diagnostic co-development process for gaining regulatory approval. Here, we identify areas of drug-diagnostic co-development that were either not covered by the guidance or that would benefit from increased granularity, including how to determine when clinical studies should be limited to biomarker-positive patients, defining the diagnostically selected patient population in which to use a companion diagnostic, and defining and clinically validating a biomarker signature for assays that use more than one biomarker. We propose potential approaches that sponsors could use to deal with these challenges and provide strategies to help guide the future co-development of drugs and diagnostics.

Developing standards for breakthrough therapy designation in oncology.

In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential "breakthrough" drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a "Breakthrough Therapy", the U.S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy.

Despite criticism of the FDA review process, new cancer drugs reach patients sooner in the United States than in Europe.

The US Food and Drug Administration is often criticized as inefficient compared to its European counterpart, the European Medicines Agency. This criticism is especially common in the field of oncology, where severely ill patients have few therapeutic options. We conducted a direct drug-to-drug comparison of the two regulatory agencies' approvals of new oncology drugs. We found that contrary to public assertions, the median time for approval for new cancer medicines in the United States was just six months--and that these new anticancer medicines are typically available in the United States before they are in Europe. Our findings reinforce the need for strong financial and public support of the Food and Drug Administration, so that such medicines can continue to be made available speedily to patients in need.