Outstanding Issues with Umbrella and Basket Studies
Authors: Kaushal Parikh, Alex A. Adjei
Journal: Journal of Thoracic Oncology (2019)

Identification of actionable oncogenic drivers has changed the treatment landscape of NSCLCs. Large-scale tumor sequencing has uncovered a number of aberrations in putative oncogenic genes, which have been seen as targets for cancer therapy. To efficiently test drugs targeting protein products of these putative oncogenes, multiarm trials have been designed over the last few years. The two most common trial designs are umbrella trials and basket trials. Umbrella trials are biomarker-driven trials in one specific tumor type, whereas basket trials are histologic subtype–agnostic biomarker trials. The best-known basket trials are the National Cancer Institute (United States)-sponsored Molecular Analysis for Therapy Choice (MATCH) and Molecular Profiling–Based Assignment of Cancer Therapeutics (MPACT) trials.1Coyne G.O. Takebe N. Chen A.P. Defining precision: the precision medicine initiative trials NCI-MPACT and NCI-MATCH.Curr Probl Cancer. 2017; 41: 182-193Crossref PubMed Scopus (65) Google Scholar The Lung Master Protocol (Lung-MAP) study (SWOG1400) is one of the earliest umbrella trials for squamous cell lung cancer (LUSC) to be conducted. In this trial, patients with LUSC who underwent genomic screening for molecular markers were assigned to biomarker-specific substudies. Out of the five initial substudies, four were biomarker-driven studies of taselisib for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutations (S1400B), AZD4547 for fibroblast growth factor receptor (FGFR) gene alterations (S1400C), palbociclib for cyclin-dependent kinase (CDK) gene alterations (S1400D), and AMG102 combined with erlotinib for MNNG HOS Transforming gene (MET) overexpression (S1400A). The fifth substudy was a nonmatched study with the anti–programmed death ligand 1 agent durvalumab (MEDI4736) (S1400E) for patients without any of the aforementioned biomarkers. The MET substudy was closed as a result of toxicity concerns, and the "no-match" substudy with durvalumab was closed after the approval of nivolumab, an anti–programmed cell death 1 agent for second-line NSCLC.2Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6236) Google Scholar The three completed substudies (S1400B, S1400C, and S1400D) are presented as brief reports in this issue of the Journal of Thoracic Oncology.3Langer C.J. Redman M.W. Wade III, J.L. et al.Brief report: SWOG S1400B (NCT02785913), a phase II study of GDC-0032 (taselisib) for previously treated PI3K-positive patients with stage IV squamous cell lung cancer (Lung-MAP substudy).J Thorac Oncol. 2019; 14: 1839-1846Abstract Full Text Full Text PDF Scopus (39) Google Scholar, 4Edelman M.J. Redman M.W. Albain K.S. et al.Brief report: SWOG S1400C (NCT02154490)-a phase II study of palbociclib for previously treated cell cycle gene alteration-positive patients with stage IV squamous cell lung cancer (Lung-MAP substudy).J Thorac Oncol. 2019; 14: 1853-1859Abstract Full Text Full Text PDF Scopus (42) Google Scholar, 5Aggarwal C. Redman M.W. Lara Jr., P.N. et al.SWOG S1400D (NCT02965378), a phase II study of the fibroblast growth factor receptor inhibitor AZD4547 in previously treated patients with fibroblast growth factor pathway-activated stage IV squamous cell lung cancer (Lung-MAP substudy).J Thorac Oncol. 2019; 14: 1847-1852Abstract Full Text Full Text PDF Scopus (48) Google Scholar In 21 eligible patients with LUSC with PIK3CA alterations, taselisib (GDC-0032) demonstrated a partial response (PR) in one patient, corresponding to an objective response rate (ORR) of 5%, as a result of which the study was closed for futility. The median progression-free survival (PFS) and overall survival (OS) times in the primary analysis population were 2.9 months (95% confidence interval [CI]: 1.8–4.0 months) and 5.9 months (95% CI: 4.2–7.8 months), respectively. Two treatment-related deaths were observed. S1400C with palbociclib monotherapy in cell cycle gene–altered LUSC also failed to meet its end point and was terminated early. It showed an ORR of 6%; two of 32 patients had a PR with median PFS and OS times of 1.7 and 7.1 months, respectively. Lastly, in the S1400D substudy with AZD4547 in 27 FGFR-altered patients, one patient (7%) had a confirmed PR with median PFS and OS times of 2.7 months (95% CI: 1.4–4.5 months) and 7.5 months (95% CI: 3.7–9.3 months), respectively. Thus, AZD4547 also had minimal activity in FGFR-altered LUSC. Therefore, the much-anticipated results in this genomic-driven umbrella study are negative and disappointing. There have been other high-profile genomic-driven studies that have yielded negative results, such as the French MOSCATO trial.6Massard C. Michiels S. Ferte C. et al.High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial.Cancer Discov. 2017; 7: 586-595Crossref PubMed Scopus (420) Google Scholar There are at least two potential reasons for the negative results from these studies. First, mutations alone, particularly those defined by gene panels, are insufficiently informative to successfully treat most patients because information on the tumor microenvironment and epigenetic factors that may regulate gene expression and function are not covered. Functional studies need to document that the aberrations are dominant oncogenes or "trunk" events driving the tumor so that their inhibition will lead to tumor cell death. A number of aberrations identified in sequencing panels may be secondary somatic or branch mutations that cooperate with multiple other mutations to maintain the malignant phenotype. Some of these potentially nondominant oncogenes may play pivotal roles in certain disease contexts, and the inhibition of their protein products may be efficacious in certain situations. Enthusiasm for genomic-driven studies has been fueled by the tremendous success that has been achieved in lung cancer with drugs targeting EGFR, ALK receptor tyrosine kinase, and ROS1 earlier and newer agents targeting neurotropic tropomyosin receptor kinase gene (NTRK), MET, BRAF, and ret proto-oncogene gene (RET) alterations.7Hirsch F.R. Scagliotti G.V. Mulshine J.L. et al.Lung cancer: current therapies and new targeted treatments.Lancet. 2017; 389: 299-311Abstract Full Text Full Text PDF PubMed Scopus (1741) Google Scholar These drugs are serine/threonine or tyrosine kinase inhibitors that directly inhibit their protein products and block subsequent downstream signaling. The oncogenic driver potential of these mutations was studied extensively in vitro before the clinical studies were performed. For example, introduction of the EGFR L858R mutation in lung adenocarcinoma cell lines increased EGFR phosphorylation twofold to threefold in the presence of its ligand, and these cells were exquisitely sensitive to gefitinib.8Lynch T.J. Bell D.W. Sordella R. et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med. 2004; 350: 2129-2139Crossref PubMed Scopus (10000) Google Scholar The echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion was engineered in mouse models and was shown to independently cause multiple lung adenocarcinomas, thus providing the basis of its inhibition as a treatment strategy.9Soda M. Takada S. Takeuchi K. et al.A mouse model for EML4-ALK-positive lung cancer.Proc Natl Acad Sci U S A. 2008; 105: 19893-19897Crossref PubMed Scopus (452) Google Scholar In vitro and in vivo inhibition of the EML4-ALK fusion kinase product in xenograft models resulted in complete tumor shrinkage. Such examples of biologic validation can be demonstrated for other approved kinase inhibitors in lung cancer. Moreover, these drivers are more often than not discovered in patients without prolonged carcinogenic exposures, such as smoking or older age, and they are almost exclusively associated with adenocarcinomas. LUSC on the other hand is usually associated with a higher mutational burden than adenocarcinomas are, and it is often a result of prolonged carcinogenic exposure.10Alexandrov L.B. Nik-Zainal S. Wedge D.C. et al.Signatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (6221) Google Scholar Phosphatidylinositol 3-kinase (PI3K) inhibition has a sound biologic rationale in treatment of hormone receptor (HR)-positive breast cancer. Activation of the PI3K/AKT/mechanistic target of rapamycin kinase pathway is well established as an escape mechanism from long-term estrogen deprivation in HR-positive breast cancer.11Miller T.W. Hennessy B.T. Gonzalez-Angulo A.M. et al.Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer.J Clin Invest. 2010; 120: 2406-2413Crossref PubMed Scopus (400) Google Scholar Thus, alpelisib, which is a PI3K inhibitor, was recently approved in combination with fulvestrant for PIK3CA-mutated, HR-positive breast cancer.12Andre F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.N Engl J Med. 2019; 380: 1929-1940Crossref PubMed Scopus (1068) Google Scholar These agents have also demonstrated activity in lymphoma.13Gopal A.K. Kahl B.S. de Vos S. et al.PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma.N Engl J Med. 2014; 370: 1008-1018Crossref PubMed Scopus (826) Google Scholar, 14Dreyling M. Morschhauser F. Bouabdallah K. et al.Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma.Ann Oncol. 2017; 28: 2169-2178Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar In LUSC, however, the PI3K pathway is not established as a primary oncogenic driver. The S1400B substudy included patients with PIK3CA mutations, whereas all PIK3CA fusions or amplifications were excluded. However, these patients also had other mutations, most notably tumor protein p53 gene (TP53) mutations (96%). It should also be noted that a number of studies with other PI3K inhibitors in a variety of solid tumors with PIK3CA aberrations have yielded negative results.15Vansteenkiste J.F. Canon J.L. De Braud F. et al.Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: results from the phase II BASALT-1 study.J Thorac Oncol. 2015; 10: 1319-1327Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 16Sarker D. Ang J.E. Baird R. et al.First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.Clin Cancer Res. 2015; 21: 77-86Crossref PubMed Scopus (219) Google Scholar, 17Patnaik A. Appleman L.J. Tolcher A.W. et al.First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.Ann Oncol. 2016; 27: 1928-1940Abstract Full Text Full Text PDF PubMed Google Scholar Cyclin D1 complex activation by cyclin dependent kinase 4 (CDK4) and CDK6 is a direct result of estrogen receptor activation and downstream signaling in breast cancer. This provides the basis for CDK 4/6 inhibition in HR-positive breast cancer, regardless of any underlying molecular alterations. These CDK 4/6 inhibitors are highly efficacious in breast cancers, leading to approval of palbociclib, ribociclib, and abemaciclib. The authors also mention the encouraging results of a phase II trial of palbociclib in well-differentiated liposarcomas and dedifferentiated liposarcomas.18Dickson M.A. Schwartz G.K. Keohan M.L. et al.Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial.JAMA Oncol. 2016; 2: 937-940Crossref PubMed Scopus (185) Google Scholar Although most patients with well-differentiated liposarcomas or dedifferentiated liposarcomas demonstrate CDK amplification, they rarely have other activating mutations and often have a low tumor mutational burden.19Cote G.M. He J. Choy E. Next-generation sequencing for patients with sarcoma: a single center experience.Oncologist. 2018; 23: 234-242Crossref PubMed Scopus (37) Google Scholar Therefore, CDK amplification is likely the sole or predominant oncogenic driver in these cancers. Although the patients included in S1400C had cyclin D4 gene (CCND4), cyclin D1 gene (CCND1), cyclin D2 gene (CCND2), or cyclin D3 gene (CCND3) amplifications, they also had other oncogenic mutations, including TP53, cyclin D2 (CCND2A), lysine methyltransferase 2D (MLL2), and phosphatase and tensin homolog gene (PTEN) mutations. This further suggests that the cyclin D1 complex may not be a driver of oncogenesis of LUSC. FGFR gene amplifications are seen in nearly 20% of LUSCs. The S1400D substudy required all qualifying patients to have an FGFR amplification, substitution, or fusion as an eligibility criterion. Erdafitinib, an FGFR inhibitor, was recently approved (on the basis of a 32.2% ORR in a single-arm phase II study) for the treatment of advanced bladder cancer harboring fibroblast growth factor receptor 3 gene (FGFR3) mutations or fibroblast growth factor receptor 2 gene (FGFR2) or FGFR3 fusions.20Loriot Y. Necchi A. Park S.H. et al.Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): phase 2 continuous versus intermittent dosing [abstract].J Clin Oncol. 2018; 36: 411Google Scholar In LUNG-MAP, most patients had FGFR amplifications, which are perhaps biologically different from fusions or mutations. FGFR inhibitors may not be efficacious in tumors with these aberrations. In the S1400D substudy, all patients had other somatic mutations that affected critical pathways of cell growth and division, notably in TP53, MLL2, and cyclin dependent kinase inhibitor 2A gene (CDKN2A). Thus, FGFR amplification alone may not be a critical driver aberration in LUSC. Second, one could have a valid oncogenic target, but the agents being tested against these targets may lack significant potency and will therefore be ineffective against that target. For example, it is now known that buparlisib is a relatively weak PI3K inhibitor, and a major part of its mechanism of cytotoxicity may be due to antitubulin effects.21Brachmann S.M. Kleylein-Sohn J. Gaulis S. et al.Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations.Mol Cancer Ther. 2012; 11: 1747-1757Crossref PubMed Scopus (104) Google Scholar The development of taselisib, the PI3K inhibitor used in S1400B, has been discontinued on the basis of disappointing results in a breast cancer study. Earlier ret proto-oncogene (RET) inhibitors, such as cabozantinib, sunitinib, and alectinib, were multikinase inhibitors with other primary targets but with some activity against RET kinase.22Gautschi O. Milia J. Filleron T. et al.Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry.J Clin Oncol. 2017; 35: 1403-1410Crossref PubMed Scopus (238) Google Scholar These drugs have yielded modest results in RET-rearranged NSCLC. However, the more potent and selective RET inhibitors, such as BLU-667 and Loxo-292, have demonstrated impressive ORRs of around 60% in early studies.23Gainor J.F. Lee D.H. Curigliano G. et al.Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC) [abstract].J Clin Oncol. 2019; 37: 9008Google Scholar, 24Oxnard G. Subbiah V. Park K. et al.OA12.07 Clinical activity of LOXO-292, a highly selective RET inhibitor, in patients with RET fusion+ non-small cell lung cancer.J Thorac Oncol. 2018; 13: S349-S350Abstract Full Text Full Text PDF Google Scholar Thus, it is conceivable that AZD4547 may be a less effective FGFR inhibitor. Although none of the three substudies presented here met its end points, the investigators need to be commended for mounting one of the first lung cancer umbrella studies in the genomic era. A number of logistical challenges had to be overcome, and this study has served as a paradigm for other studies. A "master protocol" as utilized here can readily be amended to facilitate faster enrollment of patients and a shorter time line for effective agents to be available to patients. Ultimately, the lesson provided by this study is twofold. First, unless a genomic aberration is validated as a true driver, in which case inhibition of its protein product leads to dramatic tumor shrinkage in appropriate preclinical in vivo models, a genomic-driven study may not be any different from traditional phase II studies in which designs were based on empirical, and (occasionally) a few signals of activity in phase I studies. Second, once driver genetic aberrations have been identified, studies should utilize potent drugs that have been developed to specifically target such an aberration. What then should be the future of genomic-driven studies? It needs to be acknowledged that not all cancer driver genes are detectable by mutation status. In addition, not all cancers are rich in therapeutic targets. To accelerate our understanding of drug resistance, we need genomic cohorts focused on the phenotypes of drug sensitivity and resistance. Distinct efforts need to be undertaken to identify true driver mutations from other branch or passenger mutations by using in vitro models. Use of clustered regularly interspaced short palindromic repeats/Cas9 to perform knockout studies in patient-derived tumors is one novel way of identifying true drivers of malignancy. Although these agents have sometimes been effective in cell lines and mouse models, these models incorporate only the specific alterations and not the complex milieu of LUSC. Patient-derived tumor organoids are an exciting way to study the activity of multiple targeted agents in vitro. These organoids have a distinct advantage in which complex tumor biology is preserved and minimal tissue is required for drug testing. A combination of organoids and patient-derived xenografts should provide preclinical models that may be more predictive of success in the clinic. As large-scale sequencing becomes more readily available and affordable, it is imperative to identify actionable targets and effective therapies to optimize patient care and develop studies that may not just recapitulate our past paradigm of testing new drugs empirically in tumor models in which there seemed to be a good biologic rationale even though data on potential effectiveness of these drugs were lacking. There were very few successful outcomes with such studies, and this is definitely a past we do not want to revisit. SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients With Fibroblast Growth Factor Pathway–Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)Journal of Thoracic OncologyVol. 14Issue 10PreviewS1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting. Full-Text PDF Open ArchiveSWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study)Journal of Thoracic OncologyVol. 14Issue 10PreviewS1400B is a biomarker-driven Lung-MAP substudy evaluating the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (sqNSCLC). Full-Text PDF Open ArchiveSWOG S1400C (NCT02154490)—A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration–Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)Journal of Thoracic OncologyVol. 14Issue 10PreviewLung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous NSCLC. The objective of study C (S1400C) was to evaluate the response rate to palbociclib, a cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor, in patients with cell cycle gene abnormalities. Full-Text PDF Open Archive