NEWS & ANALYSIS
From The Analyst’s Couch Tumour-agnostic therapies
Ann-Marie Looney, Khurram Nawaz and Rachel M. Webster Anthony Nilber Moraes Credit: Stock Photo Paz/Alamy Barros
In an era of increased focus on precision therapy to enter the market. The agent was received tumour-specific FDA approval for medicine, tumour-agnostic therapies have granted FDA approval in November 2018, ROS1-positive metastatic non-small-cell lung emerged as a revolutionary new approach and European Medicines Agency (EMA) cancer (NSCLC). to cancer treatment. Tumour-agnostic approval in September 2019, for the The successful tumour-agnostic therapies target specific genomic anomalies treatment of adult and paediatric patients approvals of pembrolizumab, larotrectinib or molecular features regardless of tumour with solid tumours that have a neurotrophic and entrectinib epitomize the growing site of origin. Pan-tumour approaches tyrosine/tropomyosin receptor kinase importance of ‘basket’ trials in oncology signal an important new paradigm in clinical (NTRK) gene fusion (without a known drug development. By focusing on specific management, whereby tumour genomic acquired resistance mutation), whose molecular features regardless of tumour type, signature supersedes histology in informing disease is metastatic or for whom surgical basket trials can broaden the target patient treatment decisions. In recent years, tumour- resection would lead to severe morbidity, population and include niche and rare agnostic therapies have become a key focus and who have no satisfactory treatment cancers that are often underrepresented area for an increasing number of small and alternatives. These approvals were based in clinical trials; for example, salivary gland large pharmaceutical companies. on three distinct, single-arm trials that cancer and sarcoma were among the most collectively demonstrated clinical efficacy common cancer types in the basket trials Approved therapies of larotrectinib in patients with NTRK that led to the tumour-agnostic approvals of To date, three tumour-agnostic therapies have fusion-positive tumours. larotrectinib and entrectinib. Basket trials received regulatory approval. A third tumour-agnostic therapy, benefit from relatively small sample sizes and In May 2017, the PD-1 inhibitor entrectinib (Rozlytrek; Roche/Chugai), can offer early evidence of clinical activity pembrolizumab (Keytruda; Merck & Co.) another TRK inhibitor, received regulatory by focusing on tumour response end points. became the first drug to receive tumour- approval from Japan’s MHLW in June 2019 for However, they are typically early phase, agnostic approval in oncology — a watershed the treatment of adult and paediatric patients single-arm studies, owing in part to the in the history of precision medicine. with NTRK fusion-positive, advanced challenge in defining appropriate controls The FDA granted accelerated approval for recurrent solid tumours. In August 2019, across disparate tumour types. pembrolizumab as treatment for adult and entrectinib was approved by the FDA for the paediatric patients with unresectable or same patient population (patients with solid Pan-tumour pipeline metastatic, microsatellite instability-high tumours with NTRK gene fusion who have The pipeline for tumour-agnostic therapies (MSI-H) or mismatch repair deficient progressed following treatment or have no is expanding and encompasses multiple (dMMR) solid tumours that have progressed satisfactory alternative therapy). Similar to agents directed at both existing and novel following prior treatment and who have pembrolizumab and larotrectinib, entrectinib targets (Table 1). no suitable alternative treatment options. received regulatory approval based on pooled Selitrectinib (Bayer) is a TRK inhibitor This approval was based on tumour data from four single-arm trials that evaluated under phase I/II development for advanced response rate and durability of response entrectinib in patients with previously treated, solid tumours that harbour NTRK gene across five distinct, single-arm phase I or II unresectable or metastatic solid tumours fusions (approximately 1% of solid tumours). trials. Among 149 evaluable patients with NTRK gene fusions. In addition to its Interestingly, the trial is designed to enrol across 15 tumour types, pembrolizumab tumour-agnostic label, entrectinib has also patients with relapse, no response or demonstrated an overall response rate (ORR) of 40% (including a complete response (CR) rate of 7%). In addition, 78% of responses Table 1 | Select pan-tumour therapies in development lasted 6 months or longer, and no additional Product Companies Target Development phase safety concerns were identified outside of those previously reported. In January 2019, Selitrectinib Bayer TRK I/II pembrolizumab received regulatory Repotrectinib Turning Point Therapeutics ALK, ROS1 and TRK I/II approval by the Ministry of Health, a Labour and Welfare (MHLW) in Japan for Debio1347 Debiopharm Group FGFR II the treatment of advanced or recurrent Pralsetinib Blueprint Medicines Corporation RET I/IIa MSI-H solid tumours that have progressed a after chemotherapy and are refractory or Selpercatinib Eli Lilly RET I/II intolerant to standard therapies, based on TPX-0046 Turning Point Therapeutics RET and SRC I/II results of the phase II KEYNOTE-164 and Dubermatinib Tolero Pharmaceuticals AXL kinase I/IIa KEYNOTE-158 trials. Larotrectinib (Vitrakvi; Bayer), PLX8394 Plexxikon BRAF I/II a tropomyosin receptor kinase (TRK) aIndication-specific development is ongoing for specified agents. ALK, anaplastic lymphoma kinase; inhibitor, was the second tumour-agnostic FGFR, fibroblast growth factor receptor; TRK, tropomyosin receptor kinase.
Nature Reviews | DrUg DiSCovery volume 19 | June 2020 | 383 NEWS & ANALYSIS
900 standard-of-care chemotherapy as a first- Pembrolizumab 800 line therapy would boost overall forecasted Larotrectinib sales of this agent in MSI-H or dMMR 700 Entrectinib advanced colorectal cancer to approximately $260 million in 2028. In advanced 600 endometrial cancer, sales of pembrolizumab 500 are expected to exceed $510 million by 2028, boosted by the relatively high 400 frequency of MSI (approximately 25% of
300 endometrial cancers) and the dearth Sales (US $ millions) of effective treatment options for patients 200 who fail standard first-line chemotherapy. Conversely, in advanced gastric cancer, 100 sales of pembrolizumab for MSI-H or 0 dMMR tumours are forecast to reach only 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 $25 million because these aberrations Fig. 1 | Forecast US sales of currently approved tumour-agnostic therapies. Sales of pem- have a low prevalence and this drug is brolizumab reflect its use for advanced MSI-high/dMMR colorectal cancer, gastric and gastro- also approved for another subset of patients oesophageal junction (GEJ) adenocarcinoma, and endometrial carcinoma. Sales of larotrectinib with this tumour type (PD-L1-positive, and entrectinib reflect use for advanced NTRK fusion-positive tumours. dMMR, mismatch repair previously treated with at least two deficient; MSI, microsatellite instability. prior therapies).
Larotrectinib and entrectinib. We forecast intolerance to prior TRK inhibitor therapy. inhibitor, TPX-0046 (Turning Point that US sales of larotrectinib and entrectinib Repotrectinib (Turning Point Therapeutics) Therapeutics), which also targets SRC, is will reach approximately $470 million is a multitargeting inhibitor directed against under phase I/II development for advanced and $165 million, respectively, for NTRK the kinases TRKA, TRKB, TRKC, ROS1 solid tumours harbouring RET fusions fusion-positive tumours in 2028 (Fig. 1). and ALK. The multi-cohort phase I/II or mutations. The positioning of both TRK inhibitors as TRIDENT-1 trial for repotrectinib includes Other notable agents under pan-tumour later-line therapies will constrain sales, registrational cohorts of patients with NTRK development include the AXL kinase inhibitor as will the rarity of NTRK gene fusions fusion-positive advanced solid tumours who dubermatinib (Tolero Pharmaceuticals), in solid tumours. More importantly, the are TRK inhibitor-naive or TRK inhibitor- which is currently being evaluated in two commercial potential of TRK inhibitors will pretreated. If the results are positive, these phase I/II trials focused on advanced solid likely be tied to adoption of NTRK gene trials could help position selitrectinib tumours and chronic lymphocytic leukaemia, fusion testing as part of standard diagnostic and repotrectinib as suitable therapies for and PLX8394 (Plexxikon), a BRAF protocols. Suitable detection techniques patients who develop resistance to existing inhibitor in phase I/II development for include next-generation sequencing, TRK inhibitors, such as larotrectinib advanced, unresectable BRAF-mutated immunohistochemistry, fluorescence in situ or entrectinib. solid tumours. hybridization, and reverse transcription– Debio1347 (Debiopharm Group) is polymerase chain reaction, each of which a pan-fibroblast growth factor receptor Market indicators offers different logistical and technical (FGFR) inhibitor currently being evaluated Pembrolizumab. MSI occurs most commonly advantages and disadvantages that must be in the basket phase II FUZE trial in patients in colorectal, endometrial and gastric balanced against the variable prevalence with solid tumours that harbour FGFR1, cancers; the prevalence of MSI-H varies of NTRK gene fusions in solid tumours, FGFR2 or FGFR3 gene rearrangements. from 0% to 31% across 39 tumour types particularly in rare cancers. Optimized Debio1347 is also under indication-specific (JCO Precis. Oncol. 10.1200/PO.17.00073; diagnostic algorithms for NTRK fusion- development in a phase I/II trial for 2017). In the USA, we forecast sales positive tumours will be required for metastatic breast cancer. of pembrolizumab to reach nearly larotectinib and entrectinib to fully reach Pralsetinib (Blueprint Medicines US$800 million in 2028 for advanced their target population. Corporation) and selpercatinib (Eli Lilly) MSI-H or dMMR colorectal, endometrial Ann-Marie Looney, Khurram Nawaz are small-molecule inhibitors of RET kinase and gastric cancers (Fig. 1). In advanced and Rachel M. Webster ✉ under phase I/II development for advanced, colorectal cancer, pembrolizumab is facing Decision Resources Group, London, UK. RET-altered solid tumours in the ARROW competition from other immune checkpoint ✉e-mail: [email protected] and LIBRETTO-001 trials. RET aberrations inhibitors in the second-line and later-line https://doi.org/10.1038/d41573-020-00015-1 are present in approximately 2% of all solid metastatic setting; nivolumab (Opdivo; tumours, primarily medullary thyroid Bristol-Myers Squibb) received accelerated Competing interests The authors declare no competing interests. cancer and lung cancer (Clin. Cancer Res. 15, approval for colorectal cancer shortly after 1988–1997; 2017). Both agents are in pembrolizumab (in July 2017), followed Related links phase III trials for NSCLC, based on which by the combination of nivolumab and Pembrolizumab FDA label: https://www.accessdata.fda.gov/ the two developers have declared their ipilimumab (Yervoy; Bristol-Myers Squibb) drugsatfda_docs/label/2019/125514s040lbl.pdf Larotrectinib FDA label: https://www.accessdata.fda.gov/ intention to file for approval. Selpercatinib in June 2018. However, if successful, results drugsatfda_docs/label/2018/211710s000lbl.pdf is also under phase III development for from the phase III KEYNOTE-177 trial, Entrectinib FDA label: https://www.accessdata.fda.gov/ drugsatfda_docs/label/2019/212725s000lbl.pdf medullary thyroid cancer. A third RET which evaluates pembrolizumab versus
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