ASCO 2021: Moving towards combinations
Update | 6 July 2021
ASCO saw solid clinical updates on HUTCHMED’s late stage clinical/early commercial assets, Orpathys, Sulanda and Elunate, which should help inform the design of several new, mostly combination-focussed registration trials. These, plus competitor data, highlighted some potentially underappreciated strengths in relation to the global partnership with AstraZeneca on savolitinib and HUTCHMED’s strategy of exploring combinations with multiple Chinese-originated anti-PD-1 agents. A recent R&D day outlined the potential market opportunities and infrastructure in existing (China) and new markets, and emphasised the ten new registration trials expected to start in 2021, including with haematology assets and combinations with immunotherapies. Investor attention is currently focussed on the competitive dynamics in key markets and the success of clinical and commercialisation efforts in China and the US.
|Year-end: December 31||2019||2020||2021E||2022E|
|Adj. PBT (US$m)||(141.1)||(189.7)||(338.7)||(363.4)|
|Net Income (US$m)||(103.7)||(115.5)||(313.1)||(334.9)|
|Earnings per ADS (US$)||(0.80)||(0.90)||(1.98)||(1.94)|
|Adj. EBITDA (US$m)||(100.7)||(111.6)||(308.5)||(330.3)|
6 July 2021
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HUTCHMED is a Hong Kong headquartered biopharma focused on discovering, developing and commercializing innovative targeted therapeutics and immunotherapies to treat cancer and autoimmune diseases. It has a diverse pipeline of first-in-class/best-in-class selective oral TKIs in development for the China and global markets..
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Solid clinical updates on HUTCHMED’s late-stage/early commercial assets were presented at this year’s American Society of Clinical Oncology (ASCO) conference, which should further refine their market positioning. These data, together with those of competitors emerging at the virtual meeting, highlighted the dynamic nature of key cancer markets. They also hinted at some potentially underappreciated strengths, particularly in relation to HUTCHMED’s global savolitinib partnership with AstraZeneca and its strategic decision to explore combinations with multiple China-originated anti-PD-1 agents. Taken together, we believe the data should inform and guide decisions, including by partners/collaborators, about new registration studies for TKI/IO combinations.
ASCO accepted nine papers (four of which were ‘online only’) from HUTCHMED this year on its three late-R&D/early commercial stage drugs – savolitinib, Sulanda (surufatinib) and Elunate (fruquintinib) – as well as a tenth, on HMPL-306, an early clinical candidate. In this note, we review HUTCHMED’s ASCO presentations (summarised in Exhibit 1) plus key updates from its pre-ASCO R&D event.
HUTCHMED intends to initiate multiple global and China registration studies for savolitinib, its cMET inhibitor, during 2021, in NSCLC (non-small cell lung cancer), PRCC (papillary renal cell carcinoma) and gastric cancer. The status of the various studies currently underway or planned is shown in Exhibit 2.
The ASCO presentation of updated data from the investigator sponsored CALYPSO Phase II study of savolitinib in combination with AstraZeneca’s anti-PD-L1 antibody Imfinzi (durvalumab), in metastatic PRCC clarifies the clinical and strategic rationale for pursuing further clinical development.
The CALYPSO study confirmed a stark difference in activity of the combination between MET-driven vs non-MET-driven patients, as would be expected given the mechanism. The confirmed response rate in MET driven patients was 57% (8/14) vs a calculated 15% (4/27) in non-MET driven. Median PFS (progression free survival) of MET-driven patients was 10.5 months vs 4.9 months across the study (n=41), with median OS (overall survival) of 27.4 months vs 14.1 months respectively. Overall trial data were previously published at ASCO GU in 2020.
These new data, coupled with the maturing data from the earlier Phase III SAVOIR study of savolitinib in 1L MET+ pRCC, support the planned SAMETA global Phase III study (first patient in expected Q321) in MET-driven PRCC. SAMETA will evaluate savolitinib + durvalumab vs sunitinib, and the study will resume the active development of savolitinib in PRCC, which had been discontinued as a single agent by AstraZeneca in 2019.
There were, however, no new data at this ASCO on savolitinib in NSCLC, which is the more commercially important indication for this product and its largest indication-based contributor in our valuation. HUTCHMED is pursuing a dual registration strategy for this asset: initially as monotherapy in China and in combination with AstraZeneca’s Tagrisso (osimertinib) globally.
The China NDA for savolitinib in NSCLC with MET exon 14 skipping mutations (MET ex14m) was granted conditional approval in June 2021, based on positive data from the 70-pt single arm, open-label Phase II registration study. Results from this study, which also included patients with the more aggressive pulmonary sarcomatoid carcinoma (PSC) subtype have been published in The Lancet Respiratory Medicine. This approval, the first for savolitinib in any geography, is conditional upon successful completion of a confirmatory Phase III study in NSCLC MET ex14. However, savolitinib will be branded Orpathys and is expected to be launched in China by AstraZeneca (with HUTCHMED responsible for manufacturing) later in 2021. We note that as this approval comes before the June 30 deadline, savolitinib should be eligible for entry into the next round of negotiations for inclusion in the NRDL (National Reimbursement Drug List).
Savolitinib’s first monotherapy indication in China is a specific NSCLC setting (NSCLC harbouring MET ex14m); however, HUTCHMED’s strategy is to target the combination with Tagrisso (osimertinib) in both 1L and 2L settings, in EGFRm NSCLC. Two China-focussed registrational studies are due to start in Q321. The Phase III SANOVO study will evaluate the savolitinib + osimertinib combination in 1L EFGRm+ NSCLC with MET overexpression, while the Phase III SACHI trial addresses 2L EGFR TKI refractory NSCLC with MET-amplification.
AstraZeneca is conducting a Phase II study (SAVANNAH) of the savolitinib + osimertinib combination in 2L or later, Tagrisso-refractory NSCLC with MET amplification. SAVANNAH has broad entry criteria with four cohorts: after first or second line Tagrisso; in MET amplification/over-expression; with no prior MET inhibitor therapy and no prior chemotherapy or immuno-oncology therapy. The SAVANNAH data will inform the design of a global Phase III in the same setting and are expected to be submitted for presentation at a scientific conference in H122. The design of this Phase III study is yet to be finalised, although the first patient in is expected in late 2021.
The China approval in MET ex14m NSCLC makes savolitinib the third approved MET inhibitor globally and the first in the important China market. HUTCHMED does not have an active study in this indication ex-China where Novartis/Incyte’s Tabrecta (capmatinib) and Merck KGaA’s Tepmetko (tepotinib) were approved in May 2020 and February 2021 for NSCLC with MET Ex14 skipping in 1L and 2L use. For 1L use, this would in practice be only for EGFR wild-type patients (EGFR mutants would be prescribed an anti-EGFR agent).
We believe that the clinical trials underway for the three lead MET inhibitors in NSCLC highlights a stronger competitive position for savolitinib than may be widely appreciated with respect to breadth of therapy lines and NSCLC settings. The savolitinib + osimertinib combination is also the most clinically advanced MET inhibitor + Tagrisso combination. Merck KGaA is running the registration-directed Phase II INSIGHT-2 trial or Tepmetko +/- Tagrisso, which should read out in Q322; while Novartis’s most recent pipeline update (Q121) only highlighted Tabrecta monotherapy studies although the Phase III GEOMETRY-E study of a Tagrisso combination should begin enrolling in the summer
Among the class competitors, Novartis presented updated results at ASCO 2021 on Tabrecta in MET Ex14 NSCLC, which appear to confirm earlier data used in registration. Both Novartis and Merck KGaA also presented data at ASCO 2021 showing better outcomes for their respective agents in patients where total MET suppression has been achieved, either as undetectable MET ex14 using next-generation sequencing or ctDNA depletion. Merck KGaA commented that this could be used to monitor response and/or represent a strategy for dose escalation/de-escalation.
MET amplification occurs in up to 20% of NSCLC patients with EGFR mutations who acquire resistance to EGFR inhibitors, such as Iressa (gefitinib), Tarceva (erlotinib) or Tagrisso. MET dependency can occur both de novo and at the time of EGFR TKI acquired resistance. Given AstraZeneca recently obtained approval for expanded use of Tagrisso in the adjuvant setting for EGFRm NSCLC, it is possible that it may at some point explore its combination with savolitinib in the subset of these patients with MET amplification/mutations.
Novartis is not pursuing registration-directed studies with Tabrecta in any other indication, while Merck KGaA does have a registration study underway with Tepmekto combined with its own EGFR-antibody Erbitux (cetuximab) in colorectal cancer, an area in which it has considerable experience.
Surufatinib is a targeted inhibitor of tyrosine kinases VEGFR1/2/3, FGFR1, and CSF-1R. It is approved in China as Sulanda for extra pancreatic neuroendocrine tumours (epNET) and for pancreatic NET (pNET). The NDA filing for advanced NETs has been accepted by the FDA and a 30 April 2022 PDUFA decision date assigned. MAA filing in the EU is imminent.
HUTCHMED reported updated efficacy data at ASCO 2021 in NETs although the more interesting new information to emerge was, in our view, promising results in two separate combination studies with the anti-PD-1 antibody Tuoyi (toripalimab, Shanghai Junshi). Tuoyi is already approved in China for melanoma and certain other indications, thus paving the way for a combination approach. The first of two combination studies is in advanced neuroendocrine carcinomas (NEC) – typically a poorly differentiated and more aggressive subset of neuroendocrine neoplasms, and hence related to the well-differentiated NETs representing a potential expansion of the approved/filed indication for Sulanda. The second is in gastric/gastroesophageal cancer, which is an approved indication in western markets for Keytruda and Opdivo. HUTCHMED is preparing to initiate a Phase III registration study with Sulanda + Tuoyi in ≥2L neuroendocrine carcinoma and is also planning the design of a gastric cancer registration study.
Several proof-of-concept studies are underway with Sulanda in combination Tuoyi in multiple indications, including NETs. There is evidence that anti-PD-1 agents have limited activity in NETs as a single agent (eg Merck & Co’s Keynote-158 study), although several agents are approved in Merkel cell carcinoma (a specific subset of NET but one that often has a different pathogenesis that results in a better response to immunotherapy). HUTCHMED also has studies underway with other anti-PD1s Tyvyt (sintilimab, Innovent Biologics) and tislelizumab (BeiGene) in solid tumours, the latter outside China. Details on the surufatinib clinical programmes are shown in Exhibit 3.
An ex-China study of Sulanda in combination with tislelizumab (BeiGene) began enrolment in March 2021, with potential to expand into five cohorts. The trial design is shown in Exhibit 4.
Fruquintinib is a tyrosine kinase inhibitor targeting VEGFR1/2/3, which has been approved and is marketed as Elunate in China for 3L mCRC. HUTCHMED is conducting two Phase 3 studies: FRESCO-2 (see ASCO-GI poster for design), which is designed to support registration in the same setting (≥3L mCRC) in the US, EU, and Japan, and FRUTIGA, which is being conducted in China in 2L gastric cancer. This latter study is expected to be fully enrolled around end-2021 and render top-line data in H222. Exhibit 5 outlines the clinical programme for fruquintinib.
Establishing Elunate as a combination with anti-PD-1 therapy is a strategic imperative, and several studies are underway with multiple locally developed agents. A Chinese investigator-sponsored study is also testing the combination with Jiangsu Hengui’s camrelizumab in non-MSI-H/dMMR refractory CRC. HUTCHMED presentations at ASCO 2021 included promising interim data from two CRC studies where fruquintinib is combined with anti-PD-1s. One study is examining the addition of Tyvyt (sintilimab, Innovent Biologics); the other, geptanolimab (Genor Biopharma).
Two basket trials are underway in China evaluating Elunate/Tyvyt in combination, in seven indications, as shown in Exhibit 6. HUTCHMED is planning a China registration study of this combination in endometrial cancer, which is likely to start in H221.
HUTCHMED also has two breast cancer studies underway with fruquintinib, one as monotherapy in various solid tumours with a focus breast cancer (either triple-negative or TNBC, HER2-negative, and HR-positive) and the other in combination with tislelizumab (BeiGene) in 2L TNBC. There is also a second basket study with this two-drug combination in three solid tumour types, gastric, colorectal and NSCLC, all of which are potentially important indications. Exhibit 7 outlines details on the design of the two fruquintinib/tislelizumab studies.
Approximately 12% of all breast cancers are triple negative (ie they are oestrogen-receptor (ER-), progesterone-receptor (PR-), and HER2-negative), which means that chemotherapy is the mainstay of treatment either as monotherapy or in emerging combinations. Roche’s Tecentriq is approved for use in combination with Abraxane (nab-paclitaxel) in PD-L1 positive (≥1%) TNBC, based on the IMpassion130 study. However, a subsequent trial, IMpassion131, showed no benefit from adding Tecentriq to paclitaxel in PD-1 positive TNBC patients. Merck & Co’s Keytruda gained approval in PD-1 positive TNBC, based on the Keynote-355 study, which added the PD-1 to any approved chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine/carboplatin). HUTCHMED is evaluating the fruquintinib + tislelizumab combination in both IO-naïve and IO-treated ≥2L TNBC patients.
Fruquintinib will likely face some formidable competition in the form of Lenvima (lenvatinib, Merck & Co/Eisai), a VEGFR1/2/3 inhibitor already approved in combination with Keytruda in endometrial cancer and under review in RCC. (Lenvima is approved as a single agent in thyroid cancer and hepatocellular carcinoma (HCC) and in combination with everolimus in RCC). Merck & Co is conducting 20 Phase III studies with Lenvima in combination with Keytruda in 14 tumour types. This includes studies in head and neck, urothelial carcinoma, melanoma, NSCLC, endometrial, gastroesophageal and colorectal cancer, as well as additional studies in RCC and HCC. Earlier this year, Merck and Eisai started a pivotal study (LEAP-017) of Lenvima + Keytruda in third line CRC (excluding MSI-High and mismatch repair deficient).
HUTCHMED summarised data on VEGFR TKI/anti-PD1 combinations in mCRC (Exhibit 8) at its pre-ASCO R&D presentation. Subsequently, at ASCO the data presented for the fruquintinib + sintilimab combination in ≥2L CRC (n =44; data cut off of April 7, 2021) showed an ORR of 22.7%, DCR of 86.4%, median PFS of 5.6 months (CI95%: 4.3-7.5) and a median OS of 11.8 months (CI95%: 8.2-N/A).
In addition to the usual caveats about cross-trial comparisons, there is a known difference in study populations shown in the exhibit, as the Merck/Eisai study excluded patients with microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) tumours, who respond well to Keytruda therapy (an approved indication in the US). A small study of Stivarga (regorafenib, Bayer), which has broader kinase inhibition that includes VEGFR2, combined with the anti-PD-L1 antibody Bavencio (avelumab, Pfizer/Merck KGaA) has shown PFS of 3.6 months (CI95%: [1.8-5.4]) and OS of 10.8 months (CI95%: [5.9-NA]) respectively (ASCO 2020). Stivarga is a third-line option in CRC.
Roche’s IMblaze 370 Phase III study of Tecentriq (atezolizumab) +/- cobimetinib (a MEK inhibitor) did not show a benefit versus Stivarga, a surprise result in CRC. There is also other potential competition, including from BMS which is conducting a Phase III study of Opdivo +/- Yervoy (ipilimumab) in combination with chemotherapy in the first line setting (Checkmate 8HW).
ASCO 2021 provided HUTCHMED with the opportunity to present early data on a number of its PD-1 combination studies. Two of these programmes are expected to enter registration trials later this year: surufatinib + toripalimab in 2L NEC, and fruquintinib + sintilimab in 2L EMC. The pace at which these late-stage trials are initiating suggests that further indications and/or combinations will also be rapidly progressed should proof of concept data merit further clinical development.
We have identified 16 combination studies currently underway, including six initiated by Chinese hospitals or academic organisations that combine one of HUTCHMED’s three lead compounds and an anti-PD-1 agent. These are summarised in Exhibit 10. We believe the breadth of these programmes will position HUTCHMED well if – as many now increasingly believe – the anti-PD-1 space could see greater price competition and substitution between what become considered effectively equivalent agents.
HUTCHMED’s R&D event also provided an update on plans for its haematology programmes, HMPL-689 (PI3Kδ inhibitor) and HMPL-523 (Syk inhibitor), and indicated that three IND filings are on track for 2021.
HMPL-689 has recently started a China registration intent Phase II monotherapy study (Exhibit 10) which should complete enrolment in relapsed/refractory follicular lymphoma H122 and r/r marginal zone lymphoma in H222. China NDA submission in these indications could be possible in late 2022/early 2023. Additional indications and combination approaches are also under consideration. The registration pathway in the US and EU could be clarified later this year, as the FDA end of Phase I meeting is anticipated in H221.
Initiation of a China Phase III study for HMPL-523 is also possible in H221, subject to an end of Phase II meeting with the China regulator. However, the lead indication for this asset will be in a immunology indication: ITP or immune thrombocytopenia. Timings are likely to be later in haematology as the registration strategy is yet to be outlined. The China/Australia Phase I in CLL/SLL post BTK-inhibitors is completed, and the expansion cohorts of the internation Phase I should begin in Q321.
Exhibit 11 summarises the clinical status of the next wave of assets. In addition, several assets in preclinical development have been disclosed by HUTCHMED, although due to their early stage we do not currently ascribe explicit value to these. Three programmes are targeting INDs in 2021: third-generation BTK (Bruton’s tyrosine kinase) inhibitor, HMPL-760; selective CSF-1R (Colony Stimulating Factor 1 Receptor) inhibitor, HMPL-653; and the company’s first biologic drug candidate, anti-CD47 monoclonal antibody, HMPL-A83.
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