Agnostic-Histology Approval of New Drugs in Oncology

Published OnlineFirst January 22, 2019; DOI: 10.1158/1078-0432.CCR-18-3694

Review Clinical Cancer Research Agnostic-Histology Approval of New Drugs in Oncology: Are We Already There? Cinta Hierro1,2, Ignacio Matos1,2, Juan Martin-Liberal2,3, Maria Ochoa de Olza1,2, and Elena Garralda1,2

Abstract

Over the last several years, several molecular aberrations new clinical, regulatory, and reimbursement challenges. In have been unevenly described across cancers, although the this article, we will highlight many of the biologic issues and distinct functional relevance in each biological context is not clinical trial design challenges characterizing the development yet fully understood. Novel discoveries have led to the devel- of tissue-agnostic compounds. Also, we will review some of opment of drugs tailored to the molecular profile of patients, the key factors involved in the development of pembrolizu- thus increasing the likelihood of response among biomarker- mab and larotrectinib, the first two drugs that have been selected patients. In this context, there has been a progres- approved by the U.S. Food and Drug Administration in sive redefinition of a precision medicine framework where an histology-agnostic manner. Because we anticipate that evidence-based development and earlier approvals might agnostic-histology approvals will continue to grow, we aim now be driven by this molecular information. Innovative trial to provide insight into the current panorama of targeted designs have greatly facilitated the evaluation and approval drugs that are following this strategy and some premises to of new drugs in small cohorts of orphan cancers in which take into consideration. Clinicians and regulators should be histology-dependent molecularly defined trials might be prepared to overcome the associated potential hurdles, ensur- logistically difficult. However, accelerated approvals based on ing that uncertainties are dealt with properly and allowing this agnostic-histology development model have brought new, promising agents to arrive faster to the market.

Oncology (ESMO) Scale for Clinical Actionability of molecular Introduction Targets (ESCAT); ref. 5]. In this context, histology-agnostic trials In recent years, advances in high-throughput technologies have might represent the ideal scenario for gaining a better under- yielded impressive insights into the molecular biology behind standing of the functional relevance of a certain molecular aber- cancers. Novel discoveries have resulted in the development of ration across multiple tumor types (6). several innovative drugs, representing a paradigm shift in the In this article, we will review the clinical development of a oncology early drug development panorama (1, 2). Cancer-omics number of compounds that were early assessed in agnostic- have become a powerful ally for applying biomarkers and focus- histology trials and which lessons were learnt from these initial ing clinical development in molecularly selected populations, studies. Moreover, we will then depict the key factors involved in although they have also brought another layer of complexity (3). the development of pembrolizumab and larotrectinib, the first In consequence, we are witnessing the emergence of a new era drugs approved by the U.S. Food and Drug Administration (FDA) characterized by the recognition of tumors as genetic diseases, in an histology-agnostic manner, although not yet by the Euro- accelerating the development timings from the molecular aber- pean Medicines Agency. Finally, we aim to provide insight into ration discovery to the approval of new drugs (Fig. 1; ref. 4). the current panorama of promising drugs that are following this Although more clinical evidence-based information is gathered, strategy and its associated potential hurdles. several classifications have been developed to guide clinicians to prioritize molecular biomarkers to tailor patients with the most appropriate targeted agents [e.g., European Society for Medical Where Do We Come From? The biological relevance of molecular aberrations and the 1Medical Oncology Department, Vall d'Hebron University Hospital, Universitat response to targeted agents can substantially differ depending on Autonoma de Barcelona (UAB), Barcelona, Spain. 2Molecular Therapeutics tumor type (7). Two of the most illustrative cases are the devel- Research Unit (UITM), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, opment of the v-Raf murine sarcoma viral oncogene homolog B1 3 Spain. Medical Oncology Department, Catalan Institute of Oncology (ICO) (BRAF) and the HER2 inhibitors. Hospitalet, Hospitalet de Llobregat, Spain. The BRAF inhibitor (BRAFinh) vemurafenib, showed encour- Corresponding Author: Cinta Hierro, Medical Oncology Department, Vall d'Heb- aging efficacy among patients with melanoma enrolled in a ron University Hospital, Universitat Autonoma de Barcelona (UAB), and Molec- phase I trial (81% complete or partial response; ref. 8). Posterior ular Therapeutics Research Unit (UITM), Vall d'Hebron Institute of Oncology identification of reactivation of the mitogen-activated protein (VHIO), Barcelona, Spain. Phone: 349-3274-6100; Fax: 349-3274-6059; E-mail: [email protected] kinase (MAPK) pathway as an escape mechanism led to the approval of an evidence-based combination strategy of BRAFinh Clin Cancer Res 2019;25:3210–9 and mitogen-activated extracellular signal-related kinase (MEK) doi: 10.1158/1078-0432.CCR-18-3694 inhibitors for BRAF mutant (BRAFmut) patients with melano- 2019 American Association for Cancer Research. ma (9). This combined approach drastically changed the outcome

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Are We Ready for Agnostic-Histology Approvals in Oncology?

1) Traditional drug approval based on tumor type

Approval

ph1 ph2 ph3 Paclitaxel in Pemetrexed in Dacarbazine in gastric cancer lung cancer melanoma 2) Genomically driven drug approval based on a biomarker-deﬁned population within a tumor type Conditional approval

ph1 ph2 ph3

Trastuzumab in Crizotinib in Vemurafenib in HER2amp gastric ALKtrans lung BRAFmut cancer cancer melanoma 3) Agnostic-histology approval based on a molecular biomarker that deﬁnes a disease, not an organ Accelerated Shared molecular alteration approval

ph1 ph2 ph3

Pembrolizumab in MSI-H/dMMR solid tumors

Validated predictive biomakers HER2amp (human epidermal growth factor receptor 2 ampliﬁed) ALKtrans (anaplastic lymphoma kinase translocated) BRAFmut (BRAF mutant) MSI-H/dMMR (microsatellite instability high/deﬁcient mismatch repair)

Figure 1. The evolving framework of clinical trials used to support oncology drug approval. Trials have shifted from enrolling (i) unselected patients exclusively based on the type of tumor to an exquisite, appropriate selection of biomarker-defined populations either (ii) within a specific tumor type or (iii) across a variety of different cancers that share a common molecular abnormality. Consequently, phase III (ph3) clinical trials have been gradually replaced by redesigned phase I (ph1) and II (ph2) clinical trials, recently leading to accelerated and conditional approvals of new anticancer agents based on the results of phase I/II "basket"trialsandlarge expansion cohorts of molecularly selected patients, thus redefining the traditional phase I/II/III model that previously worked with cytotoxic chemotherapies. of this disease. However, only 5% of BRAFmut patients with seemed to retain clear oncogene-addiction to BRAFmut, achiev- colon cancer responded to BRAFinh monotherapy, translating ing an overall response rate (ORR) of 42% [95% confidence the heterogeneous pattern of BRAF activation within this histol- interval (CI), 20-67] and 43% (95% CI, 18–71), respectively. ogy (10). Further preclinical insights evidenced that the BRAFinh Remarkably, the results of this study led to the FDA approval for effect could be rapidly bypassed by ERK reactivation through an vemurafenib in ECD in 2017 (15). Furthermore, the study EGFR-mediated activation of RAS and C-RAF (11, 12). Unfortu- highlighted that BRAFinh would not act homogenously across nately, triple strategies of BRAF/MEK/EGFR inhibition have not histologies, since depending on the biological role of BRAF, paralleled the efficacy reached in melanoma, mainly due to the distinct resistance mechanisms might develop. continued adaptive feedback reactivation of the MAPK signaling Another example worth mentioning is the case of HER2 inhi- in the colorectal cancer context (13). bitors (HER2inh). Trastuzumab, the first humanized HER2- Similarly, the VE-Basket trial testing vemurafenib in BRAFmut directed monoclonal antibody (mAb), received FDA approval V600 non-melanoma cancers, reported isolated responses after demonstrating survival benefit for patients with HER2- among a myriad of tumor types (14). Non–small cell lung cancer amplified (HER2amp) metastatic breast cancer (16). In 2010, (NSCLC) cases and patients with Erdheim-Chester disease (ECD) trastuzumab also showed increased overall survival (OS) from

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Hierro et al.

11.1 to 13.8 months [hazard ratio (HR) for death 0.74; 95% CI, Patients with dMMR colorectal cancer, mismatch repair- 0.60–0.91; P ¼ 0.0046] in patients with HER2amp gastroeso- proficient (MMR) colorectal cancer, and patients with dMMR phageal cancer (GE) in the ToGA trial (17). The HERACLES study non-colorectal cancer refractory cancers were enrolled in the demonstrated that the combination of lapatinib plus trastuzu- KEYNOTE-016 study. The co-primary endpoints were immune- mab was active in a subset of HER2amp patients with refractory related objective response rate (irRR) and 20-week immune- colorectal cancer (5%), achieving an ORR of 30% (95% CI, 14– related progression free survival (irPFS) rate. irRR were 40% and 50; ref. 18). Noteworthy, low prevalence of HER2amp has also 71% for patients with dMMR colorectal cancer and dMMR non- been reported among other miscellaneous tumor types, thus colorectal cancer tumors, respectively. The median progression- encouraging the research of novel HER2inh beyond the classical free survival (mPFS) and mOS were not reached at the time of the indications. ZW25, a bispecific antibody targeting ECD2–ECD4 report, and the irPFS rates were 78% for the dMMR colorectal HER2 domains, showed a disease control rate (DCR) of 33% in cancer cohort and 67% for the dMMR non-colorectal cancer non-breast/GE tumors overexpressing HER2 (19). Also, trials test- group. Noteworthy, the efficacy among MMR colorectal cancer ing different antibody–drug conjugates, such as ado-trastuzumab was meaningless, with 0% irRR, 11% irPFS, and a mOS of 5 emtansine (T-DM1; ref. 20) and trastuzumab deruxtecan (DS-8201a; months (HR, 0.22; P ¼ 0.05). Whole-exome sequencing (WES) ref. 21), have confirmed clinical activity of the HER2 blockade revealed that dMMR tumors presented almost 24 times more among other HER2-expressing cancers (e.g., salivary gland). somatic mutations compared with MMR ones (P ¼ 0.007). As Lately, rising evidence of mutations in HER2 (HER2mut) expected, higher mutation loads were associated with prolonged widened further exploration of anti-HER2 therapies (22). The mPFS (P ¼ 0.02; ref. 28). MOSCATO-01/02 trials showed that the clinical benefit rate In addition to KEYNOTE-016 (n ¼ 58), two subsequent (CBR) to HER2 blockade for HER2amp patients was significantly studies also provided robust evidence of antitumor activity of higher (CBR 64%) compared with those HER2mut (CBR 25%; pembrolizumab and durable responses in heavily pretreated ref. 23). In the SUMMIT trial, patients with HER2/3mut across 21 dMMR patients. The KEYNOTE-164 trial enrolled patients with tumor types were treated with neratinib, a pan-HER multikinase MSI-H colorectal cancer who had received at least 2 prior lines of inhibitor. No activity was observed in the HER3mut cohort. On therapy (n ¼ 61), whereas the multi-cohort KEYNOTE-158 study the contrary, among HER2mut patients (n ¼ 124), responses were included patients with MSI-H non-colorectal cancer treated with reported among NSCLC, breast, biliary, salivary and cervical at least one prior regimen (n ¼ 19; refs. 29, 30). Furthermore, cancers, with the greatest activity being seen in kinase domain patients with PD-L1–positive tumors and MSI-H enrolled in missense mutations. To date, this study has provided the most phase I studies assessing pembrolizumab were retrospectively comprehensive data that exist on the differential clinical action- identified [KEYNOTE-012, n ¼ 6 (refs. 31–33); KEYNOTE-028, ability of HER2/3mut (24). n ¼ 5 (refs. 34–38)]. Several concepts were learnt from these initial trials developing On May 23, 2017, the FDA granted the accelerated approval of BRAFinh and HER2inh. First, it became clear that the molecular pembrolizumab for the treatment of adult and pediatric patients status alone is not enough to predict response, as the signaling with unresectable or metastatic refractory MSI-H/dMMR tumors. pathway might play different roles in each specific histologic The first FDA tissue-agnostic approval became a reality, based on context, where different mechanistic explanations could mediate 149 patients with MSI-H/dMMR tumors across the five uncon- resistances. Second, the results revealed that efficacy might be trolled, single-arm trials depicted in Table 1 (ref. 39). ORR was influenced by the class of molecular alteration (amp > mut), similar irrespectively of the origin (36% in colorectal cancer vs. the involved gene (HER2 > HER3) or, the type of allele (mut in the 46% in 14 other cancer types). Despite this accelerated approval, kinase domain > frameshifts in receptor domain). Finally, these continued approval of pembrolizumab for this indication will studies demonstrated that molecularly guided trials could be used rely on the final results of clinical benefit in the ongoing confir- to refine our biological understanding of targets, and that con- matory trials. ventional cancer therapy should not be solely replaced by the What have we learnt from this historical approval? First, a molecular findings. Investigators should be careful when extrap- strong biologic preclinical and clinical rationale was needed, olating the outcomes seen with one drug from one cancer to ensuring the homogeneity of effects of this alteration among another, keeping in mind that significant differences exist between different tissues. In this case, MSI tumors were found across different histologies, and profound heterogeneity has been multiple histologies at varying frequencies (40), sharing common observed even within one same cancer type. features known to be predictive of response to immunotherapy, such as PD-L1 expression, high tumor mutational burden (TMB) fi Where Do We Stand Now? and lymphocyte T in ltration (41). Also, MSI tumors undergo immune-editing processes that provide them with genetic advan- Microsatellite instability-high (MSI-H) tumors can have up to tages for immune escape, most likely a common resistance trait eight times more somatic mutations than microsatellite stable across MSI cancers (42). Second, it was important to measure the (MSS) cancers, translating into a higher presence of neoantigens expected efficacy with a reliable endpoint, facilitating the inter- able to triggering an immune response (25). Checkpoint block- pretation of results across histologies inside one trial and between ade with anti-programmed death-1 (PD-1) antibodies was hypo- studies. Noteworthy, similar ORR and OS/PFS rates were reported thesized to enhance immune responses in MSI-H/deficient mis- in at least 14 tumor types in the pooled analysis for pembroli- match repair (dMMR) tumors, supported by the idea that a zumab, with no differential pattern of efficacy indicating a his- higher mutational load was correlated with responses in mela- tology qualitative effect (29). Third, a truly agnostic indication noma (26) and NSCLC (27). All these observations provided the would embrace the treatment of both, adult and pediatric incentive for the development of the KEYNOTE-016 trial, which patients, ensuring an appropriate formulation for the younger. selectively investigated pembrolizumab in MSI/dMMR patients. In fact, the biology of MSI-H/dMMR was expected to be similar in

3212 Clin Cancer Res; 25(11) June 1, 2019 Clinical Cancer Research

Are We Ready for Agnostic-Histology Approvals in Oncology? 38) 30)

33) pediatric tumors (43), and there was an already established – – – dose of pembrolizumab for pediatric Hodgkin lymphoma (KEYNOTE-051 study; ref. 44). Finally, the possibility of identi- fying those patients whose tumors harbor the predictive biomarker with a validated companion diagnostic is a key limitant factor for ensuring the attrition of patients. In this case, immunohistochemistry (IHC) testing or polymerase chain reaction (PCR)– based assays were commercially available (45).

ClinicalTrial.gov ID Ref Following the approval of pembrolizumab, another milestone revolutioned the agnostic-histology scene in 2017. Patients with neurotrophin tropomyosin receptor kinase (NTRK) rearranged (rear) tumor types were prospectively identiﬁed and enrolled into

, number of patients enrolled; PCR, polymerase the adult phase I (n ¼ 8) or "basket" phase II (n ¼ 35), and N the pediatric phase I/II (n ¼ 12) trials evaluating larotrectinib, a first-in-class pan-TRK inhibitor (TRKinh; ref. 46). The ORR was 75% (95% CI, 61–85) among 12 different histologies, ranging in Dose 10 mg/kg every 2 weeks NCT02054806 (34 10 mg/kg every 2 weeks NCT01848834 (31 200 mg every 3 weeks NCT02460198 200 mg every 3 weeks NCT02628067 10 mg/kg every 2 weeks NCT01876511 (28 ages from 4 months to 76 years. The most common cancers were salivary gland (22%), soft tissue sarcoma (20%), infantile fibro- sarcoma (13%) and thyroid (9%). Strikingly, larotrectinib demonstrated clinical benefit regardless of tumor type, NTRK gene, fusion partner or age of the patient. Also, encouraging central nervous system activity was seen in primary malignancies and metastatic lesions, with rapid and prolonged responses. On the basis the results of these 55 patients, on November 26, 2018, the FDA granted accelerated approval of larotrectinib for the treat-

CRC rare tumors) or IHC ment of adult and pediatric NTRKrear tumors (47). MSI-H/dMMR testing Central PCR Local PCR (central for non- Central PCR Local PCR or IHC Local PCR or IHC Interestingly, the treatment of larotrectinib has been approved

based on the presence of a NTRKrear in tumor specimens. How- ever, unlike the approval of pembrolizumab for MSI-H/dMMR tumors, there is not an FDA-approved test for the detection of NTRKrear. Recently, updated results of efﬁcacy with larotrectinib were presented with the expanded 122-patient integrated dataset, 2 prior regimen – uoropyrimidine, showing an ORR of 81% (95% CI, 72 88). Remarkably, 84% of ﬂ the responding patients and 73% of all patients remained on and CRC anti-VEGF/EGFR mAb oxaliplatin, irinotecan 1 prior regimen 1 prior regimen non-CRC 1 prior regimen 1 prior regimen Prior Prior therapy larotrectinib or underwent surgery with curative intent (48). These highly consistent results might have fostered the approval of larotrectinib, allowing the detection of NTRKrear based on local NGS or FISH.

Where Do We Go? Pembrolizumab was the ﬁrst tissue-agnostic drug approved but breast, endometrial, or biliary TNBC

Tumors larotrectinib was the ﬁrst drug developed with an agnostic-histology indication in mind. The truth is, gene fusions have emerged 6 Gastric, bladder, or 5 Esophageal, CRC, N as an important class of somatic alterations, acting as oncogenic drivers in approximately 16.5% of human cancers (49). It is understandable then that these druggable fusions have focused the attention of the clinical research ﬁeld. Pooled data from phase I/II entrectinib trials showed an ORR of 57.4% (95% CI, 43.2–70.8) among NTRKrear adult patients from 19 different histopathologies, also with durable intracraneal responses (54.5%; ref. 50). In parallel, the discovery of early acquired mechanisms of resistance, has led the fast development of successful second-generation TRKinh [e.g., loxo-195 (ref. 51),

cation of patients with MSI-H/dMMR tumors repotrectinib (ref. 52) or merestinib (ref. 53)]. Moreover, ﬁ

Design debio1347, a selective FGFR1/2/3 inhibitor (FGFRinh), showed promising efficacy among patients harboring fibroblast growth factor receptor (FGFR) fusions. A DCR of 87% was reported in 5 Studies that supported the agnostic-histology approval of pembrolizumab for MSI-H/dMMR solid tumors by the FDA different histologies with FGFRrear (n ¼ 8; ref. 54). In view of these results, other "basket" trials are further developing FGFRinh fi fi KEYNOTE-028 Multicenter ph1 Abbreviations: Anti-VEGF/EGFR mAb, anti-vascular endothelial growth factor/epidermal growth factor receptor mAb; CRC, colorectal cancer; IHC, immunohistochemistry; Prospective enrollment of patients withKEYNOTE-016 MSI-H/dMMR tumors Investigator-initiated ph2 at 6 sites 58 Multiple KEYNOTE-158 International and multicenterKEYNOTE-164 ph2 International and multicenter 19 ph2Retrospective identi Multiple 61KEYNOTE-012 CRC Multicenter ph1b chain reaction; ph1, phase I clinical trial; ph2, phase II clinical trial; Ref, Reference; TNBC, triple-negative breast cancer. Table 1. Study in this dif cult-to- nd FGFRrear population (e.g., TAS-120;

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Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. 3214 lnCne e;2(1 ue1 2019 1, June 25(11) Res; Cancer Clin iroe al. et Hierro Downloaded from Published OnlineFirstJanuary22,2019;DOI:10.1158/1078-0432.CCR-18-3694 clincancerres.aacrjournals.org Table 2. Selected tyrosine kinase inhibitors under agnostic-histology clinical development Drug Target Molecularly selected population FDA status EMA status ClinicalTrial.gov ID Debio1347 FGFR1/2/3 Ph1/2 "basket" in solid tumors with FGFR fusions. May 2018: Fast Track designation for tumors November 2017: Orphan Drug NCT01948297 with speciﬁc FGFR alteration. designation for BTC. TAS-120 FGFR1/2/3/4 Ph1/2 "basket" in solid tumors with FGFR fusions. May 2018: Orphan Drug designation for iCCA. N/E NCT02052778 Larotrectinib TRK Ph2 "basket" in adults with NTRKrear solid tumors (NAVIGATE November 2018: Accelerated Approval. August 2018: Marketing NCT02576431 study). Authorization Application submitted. Ph1/2 "basket" in children with NTRKrear solid tumors (SCOUT NCT02637687 study). Ph1 in adults with NTRKrear solid tumors (LOXO-TRK-14001 NCT02122913 study). Entrectinib (RXDX-101) TRK/ALK/ROS1 Ph2 "basket" in adults with NTRK/ALK/ROS1rear solid tumors July 2017: Orphan Drug designation for October 2017: Priority NCT02568267 on September 28, 2021. © 2019American Association for Cancer (STARTRK-2 study). adult/children with NTRKrear solid tumors. Medicines designation for Research. adult/children with NTRKrear solid tumors. Ph1/1b in children with NTRK/ALK/ROS1rear solid tumors NCT02650401 (STARTRK-NG study). Merestinib (LY2801653) TRK/MET Ph2 in NSCLC MET exon 14 mut or "basket" for NTRKrear solid October 2017: Orphan Drug designation for N/E NCT02920996 tumors. BTC. Repotrectinib (TPX-0005) TRK/ALK/ROS1 Ph1/2 in NTRK/ALK/ROS1rear solid tumors (TRIDENT-1 study). June 2017: Orphan Drug designation for N/E NCT03093116 NTRK/ALK/ROS1rear NSCLC. Loxo-195 TRK Ph1/2 in adult and children previously treated with NTRKrear May 2018: NDA accepted and granted N/E NCT03215511 cancers. Priority Review for adults and children with NTRKrear tumors. Loxo-292 RET Ph1/2 in RETrear solid tumors and MTC (LIBRETTO-001 study). September 2018: Breakthrough designation N/E NCT03157128 for RETrear NSCLC and RETmut MTC. Agerafenib (RXDX-105) RET/BRAF Ph1/1b in patients with advanced solid tumors. N/E N/E NCT01877811 BLU-667 RET Ph1 in RET-altered solid tumors and MTC (ARROW study). N/E N/E NCT03037385 Abbreviations; ALK, anaplastic lymphoma kinase; BTC, biliary tract cancers; EMA, European Medicines Agency; iCCA, intrahepatic colangiocarcinoma; MTC, medullary thyroid cancer; mut, mutant; N/E, not evaluated; NDA, New Drug Application; Ph1, phase I clinical trial; Ph2, phase II clinical trial; rear, rearranged. lnclCne Research Cancer Clinical Published OnlineFirst January 22, 2019; DOI: 10.1158/1078-0432.CCR-18-3694

Are We Ready for Agnostic-Histology Approvals in Oncology?

ref. 55). Later this year, the RET inhibitor (RETinh) loxo-292 agents (MTA), the early drug development panorama is becoming showed an encouraging ORR of 77% (95% CI, 61–89) in RETrear increasingly busy, and what matters most, it seems more prom- evaluable tumors (77% in NSCLC and 78% in other cancers), ising than ever. Table 2 summarizes the current approval status of including intracranial responses in NSCLC (56). Also, many other some of these MTA. promising compounds are focusing their development in this With the increasing evidence of immune-predictive biomarkers small RETrear population [e.g., agerafenib (ref. 57) and BLU-667 commonly displayed by cancers, tissue-agnostic development is (ref. 58)]. With the arrival of these best-in-class molecular targeted focusing on the immune-checkpoint inhibitors arena (59). In

Translational framework

• Biobanking Vehicle • Biomarker discovery ) • Characterize rare variants 3 • Study concurrent alterations (mm Drug X • Elucidate resistance Clinical trial

mechanisms volume Tumoral Time (days) targeted agent Tumoral biopsies PDX generation PDX expansion Molecularly selected single cases • Blood (cfDNA) Genomic analyses (DNA) Redefining • Expression profiles (RNA) target • Epigenetic signatures • Immune profile population • Heterogeneity mapping Responder drug X Biomarker positive Metastatic biopsies Deep sequencing

Platform Umbrella Matched targeted drugs in one tumor type Gastric cancer Drug Drug leaves enters

FGFR inhibitor TRK inhibitor RET inhibitor

Lung cancer

Melanoma

Basket Basket Basket Other cancers in multiple in multiple in multiple FGFRtrans tumors NTRKtrans tumors RETtrans tumors

Potential predictive biomarkers: trans (translocation) FGFR (ﬁbroblast growth factor receptor) NTRK (neurotrophic tyrosine receptor kinase) RET (rearranged during transfection proto-oncogene)

Figure 2. Integration of clinical-translational strategies into precision medicine drug development. Sophisticated master protocols are currently being used in the early drug development of new molecularly targeted drugs. "Umbrella" trials serve to study multiple targeted therapies in the context of a single disease (e.g., TRK/ FGFR/RETinh in a specific tumor type). "Platform" trials have evolved as a more adaptable design, also aiming to study multiple targeted therapies in the context of a single disease but allowing therapies to enter or leave the platform on the basis of preclinical or clinical data becoming available throughout the study. "Basket" trials test a particular targeted therapy among patients that share a common molecular aberration (colored stars) across multiple cancer types (e.g., TRKinh in multiple histologies). These precision medicine approaches arise as the ideal scenario for implementing smart translational programs, based on the acquisition of biological samples from molecularly selected extraordinary responders. The collection of serial tumor biopsies and plasma samples, allowing the generation of patient-derived xenografts (PDX), has emerged as a powerful tool for integrating a deeper molecular knowledge from a specific target, fine-tuning optimal predictive biomarkers, early discovery of resistance mechanisms, and hypothesis generating of new therapeutic strategies. cfDNA, cell-free DNA.

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light that anti–PD-1 therapies have shown efficacy across different certainly require more flexibility from all the participants cancers, efforts have now focused on the identification of tissue- involved (62). agnostic immune-biomarkers. In reality, MSI-H might have been First, the clinical framework for drug development will need to a surrogate marker of high TMB (60). Therefore, TMB is emerging adapt accordingly. Sophisticated master protocols, including as an independent promising biomarker for anti–PD-1/-L1 ther- "umbrella," "platform," and "basket" trials, have been designed apy, and WES methods are investigating its applicability across a to answer multiple questions in less time (63). Two examples of full spectrum of tumor types (61). these ambitious approaches are the NCI-MATCH trial, which Although there continues to be an urgent unmet medical pretends to enroll more than 1,000 all-comer patients in 25 need for patients with refractory cancers, the development of targeted arms (64), or the Basket of Baskets trial, the largest new drugs in an agnostic-histology manner will probably personalized cancer medicine trial in Europe (65). Figure 2 increase. However, this model of accelerated drug develop- illustrates the integration of these innovative designs with early ment, based on unprecedented efficacy coming from single- translational strategies, serving as platforms to advance arm small cohorts of biomarker-selected patients will be an research (66). Agnostic-histology "baskets" seek the simultaneous exception rather than a rule. detection of early efficacy signals among different histologies, to depict the influence that tumor lineage exerts in drug sensitivity. Considerations for Agnostic-Histology These studies can serve to interrogate uncharacterized genomic variants and to examine the effects of concurrent genomic Approvals alterations, whereas offering a real-time elucidation of acquired The increasing evidence of a significant myriad of genomic resistance mechanisms (67). Also, "basket" trials can unveil the alterations across different cancers has highlighted that it is getting toxicity effects of new drugs across multiple tumor types, allowing more difficult to explore rare signatures in one single histology. the investigators to have well-established safety profiles to sup- Tumor agnostic drug development strategies could address this port a favorable benefit:risk ratio in biomarker-selected patients. myriad, although improving precision medicine in cancer will However, the obtained results must be interpreted with caution,

Agnostic-histology development of new oncology drugs

Strong belief of the superiority of the experimental drug compared to alternatives

mechanisms Rare disease or biomarker makes randomization impossible Adequate central nervous system penetration Disease has a predictable course

Reliable objective endpoints (consider adult and pediatric patients ORR if randomization not feasible) Companion diagnostic validation distinct histologies Incidence of biomarker across Real unmet medical need tumor types deﬁned controls available (real-world evidence) Feasibility of patient attrition (enrollment challenges)

Adapted formulations for pediatric populations (liquid, intravenous)

regulatory agencies, sponsors, academia, and patients

Scientiﬁc Logistic Regulatory rationale challenges requirements

Figure 3. Considerations for agnostic-histology development of new drugs in oncology.

3216 Clin Cancer Res; 25(11) June 1, 2019 Clinical Cancer Research

Are We Ready for Agnostic-Histology Approvals in Oncology?

as inferences from small number of patients might not be a secure Conclusions source to make treatment-decisions. Moving away from traditional diagnostic criteria has translated In this sense, regulatory agencies may have to consider into a new taxonomy of human diseases based on molecular changes in drug approval conditions, to deal with the inevitable biology. This has offered unique opportunities to more efficiently degree of uncertainty associated with the efficacy evidence treat cancer patients, although it has brought several challenges. It provided from trials lacking randomization, pooling across seems clear that the positive experience with accelerated approvals heterogeneous populations where sometimes there is no stan- in precision medicine will only continue if there is a collaborative dard of care or limited data on prognosis. Accelerated approval effort between government, regulators, pharmaceutical and bio- translates that the magnitude of benefit-risk assessment per- technology industries, academia and patient groups (72). formed by regulatory agencies is positive, but clinical evidence is We anticipate that agnostic-histology approvals will continue incomplete. Feasible strategies to support these approvals to grow and expand the therapeutic options for patients with should include temporal approvals or approvals at risk, that cancer, because many other candidates are ready-to-go in the can be continuously reviewed once more data from post-autho- pipeline. We just need to be ready for embracing them and to rization studies become available, reflecting the "real-world" calmly deal with the uncertainties while we try to minimize them. data (68). These post-marketing data will be crucial for verifying the real clinical benefit of a new drug, specially when accelerated Disclosure of Potential Conflicts of Interest approvals are based on surrogate or intermediate endpoints, fi C. Hierro reports receiving commercial research grants (to institution) from such as ORR instead of OS. Obviously, if bene t from new drugs Bayer, speakers bureau honoraria from Ignyta and Lilly, and travel/accommodation fi is not veri ed when new information arises, indications should grants from Lilly and Roche. J. Martin-Liberal reports receiving speakers bureau be withdrawn or modified accordingly. In parallel, collaborative honoraria from Roche, Novartis, MSD, Pfizer, and Bristol-Myers Squibb, and travel efforts have focused on developing methods to establish the grants from Ipsen. E. Garralda reports receiving commercial research grants from value of new specific cancer treatments, to support decision- Novartis, speakers bureau honoraria from MSD, and is a consultant/advisory board making (69, 70). member for Roche, Janssen, Boehringer, NeoMed Therapeutics, and Ellypses Pharma. No potential conflicts of interest were disclosed by the other authors. Finally, new adaptive reimbursement strategies will need to be considered. Manufacturers could reduce the price of accelerated- Acknowledgments fi fi approved drugs until robust ef cacy con rmation is available. The authors thank the support received from the Welfare Projects Division of Confirmatory trials should be optimally designed for addressing the "La Caixa" Foundation to the Molecular Therapeutics Research Unit (UITM). the uncertainty of the real clinical effect of a new drug and conducted in a timely fashion, or confirmation could be provided The costs of publication of this article were defrayed in part by the payment of from the data of expanded access programs (71). page charges. This article must therefore be hereby marked advertisement in Figure 3 summarizes some of the premises that should be accordance with 18 U.S.C. Section 1734 solely to indicate this fact. carefully considered when pursuing the agnostic-histology devel- Received November 14, 2018; revised December 23, 2018; accepted January opment of new drugs. 18, 2019; published first January 22, 2019.

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www.aacrjournals.org Clin Cancer Res; 25(11) June 1, 2019 3219

Agnostic-Histology Approval of New Drugs in Oncology: Are We Already There?

Cinta Hierro, Ignacio Matos, Juan Martin-Liberal, et al.

Clin Cancer Res 2019;25:3210-3219. Published OnlineFirst January 22, 2019.

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