Anlotinib + Sintilimab

NCT07398326 is a Phase 2, single-arm, 37-patient trial at Shanghai Changzheng Hospital testing anlotinib plus sintilimab as first-line treatment for advanced colorectal cancer in patients without liver metastases [1]. The unusually high NCT number (07XXXXXX) should be verified directly against ClinicalTrials.gov before this writeup is acted upon. Anlotinib is Chia Tai Tianqing's oral multi-target TKI (brand Fukewei / 福可维, NMPA-approved May 2018, with indications now covering NSCLC, soft tissue sarcoma, small cell lung cancer, and medullary thyroid cancer) [2] and sintilimab is Innovent Biologics' anti-PD-1 antibody (brand Tyvyt, partnered with Eli Lilly). The trial picks a specific subset of CRC patients - no liver metastases - because liver mets blunt PD-1 response by sequestering and killing tumor-reactive T cells (a tolerogenic environment that depletes systemic antitumor T cells), so excluding them is a calculated bet that an IO + anti-angiogenic combo can work in the microsatellite-stable (MSS) CRC population - the ~95% of metastatic CRCs that lack the mismatch-repair defects driving MSI-high tumors, and where almost every checkpoint inhibitor trial has failed.

Neither drug is FDA-approved, and this combination has no approval anywhere for CRC. Anlotinib is approved in China only, across NSCLC, soft tissue sarcoma, small cell lung cancer, and medullary thyroid cancer indications [2]. Sintilimab is approved in China for classical Hodgkin lymphoma, NSCLC, HCC, esophageal, and gastric cancer, but was rejected by the FDA in March 2022 when the ODAC voted 14-1 against the ORIENT-11 NSCLC filing due to single-country data and lack of US relevance [3]. This is therefore a Chinese investigator-initiated Phase 2 study with no FDA designations - no breakthrough therapy, no fast track, no orphan designation. The trial is currently recruiting per ClinicalTrials.gov, with no public timeline for primary completion or readout [1]. Because it's a single-center academic study with n=37 and ORR as the primary endpoint, this is signal-finding, not registration-enabling. Even a positive readout would require an industry partner to design a randomized Phase 3 versus current standard of care (FOLFOX/FOLFIRI plus bevacizumab) before any regulatory pathway opens. The realistic regulatory horizon for this exact combination in CRC is years away, contingent on whether the Phase 2 ORR signal justifies a sponsor stepping in.

Sintilimab blocks PD-1, a brake pedal on T cells that tumors press to shut down immune attack. Releasing the brake lets cytotoxic T cells kill tumor cells - when those T cells are present and primed. Anlotinib is a small molecule that blocks several blood-vessel-growth receptors (VEGFR2 and VEGFR3, which sense the signal tumors send to recruit new vessels) plus FGFR1, PDGFR, and c-Kit, starving tumors of new vasculature while also normalizing the chaotic vessels they already have [4]. The combination logic: anti-angiogenic treatment doesn't just cut blood supply, it also lowers the immunosuppressive pressure inside tumors (less VEGF means fewer regulatory T cells and fewer myeloid-derived suppressor cells), which can convert an immunologically cold tumor into one a PD-1 blocker can act on. This is the IMbrave150 paradigm - atezolizumab plus bevacizumab beat sorafenib in HCC [10] - extended to CRC. The catch: microsatellite-stable colorectal cancer (~95% of metastatic CRC) is the graveyard of checkpoint inhibitor trials. KEYNOTE-177 only worked because it was restricted to MSI-high patients - tumors with defective DNA mismatch repair that accumulate the mutational neoantigens checkpoint inhibitors need to mount a response [5]. The biological case for anti-angiogenic + IO converting MSS CRC into a responder population exists but remains unproven across multiple prior attempts.

NCT07398326 is a single-center, single-arm, open-label Phase 2 with a 37-patient enrollment target, sponsored by Shanghai Changzheng Hospital [1]. The primary endpoint is objective response rate (ORR) - the percentage of patients whose tumors shrink by RECIST criteria (a standardized measurement system that tracks the sum of target lesion diameters across serial scans to classify response as complete, partial, stable, or progressive disease). The patient population is treatment-naive advanced CRC without liver metastases, which is the biologically interesting selection: published data suggests liver mets create a tolerogenic environment that depletes systemic antitumor T cells, so non-liver-met patients are enriched for likely IO responders. Two critical stratification variables are not addressed in the publicly available trial record: (a) microsatellite status (MSS vs. MSI-H) is not specified as a formal enrollment criterion - given epidemiology, the enrolled population will be ~95% MSS by default, but the trial does not appear to require confirmation, which limits interpretability of any IO signal; and (b) RAS/BRAF mutational status, which governs first-line regimen choice in CRC (RAS wild-type tumors are EGFR-antibody candidates, BRAF V600E tumors are now treated with targeted triplets), is not mentioned as an enrollment criterion or stratification factor. Both gaps should be clarified before interpreting ORR results. The design problem is structural. Single-arm means no comparator, so even if ORR is 40%, you can't claim superiority over the historical 50-60% ORR seen with FOLFOX plus bevacizumab in first-line MSS CRC - a randomized trial would be needed to prove the combo beats standard of care. The 37-patient target is small enough that the ORR confidence interval will be wide (±15 percentage points typical), making interpretation noisy. Single-center recruitment from one Shanghai hospital also raises generalizability questions. The trial is best read as a proof-of-concept screen: if ORR clears 30-40% in MSS patients (which would be unusual), it justifies a randomized follow-on.

Our model gives this drug a 4% chance of eventually being approved. That number starts from the historical approval rate for Phase 2 drugs in this area, roughly 10%, then adjusts based on ten facts about the trial and sponsor. The biggest factors pulling the estimate down are the sponsor's weak approval record, few secondary endpoints, and limited earlier-phase results; the non-randomized trial design provides some lift. Most other facts fall near average for this stage, so they leave the estimate close to where the base rate set it.

Efficacy risk is the dominant concern. Microsatellite-stable CRC is where checkpoint inhibitor combos go to die - REGONIVO showed early Asian-population signal in regorafenib + nivolumab that failed to replicate, and LEAP-017 missed its primary endpoint in third-line MSS CRC [6]. The non-liver-met restriction is biologically defensible but unproven as a selection biomarker. Safety risk is on-mechanism and additive: anlotinib brings hypertension, hand-foot syndrome, proteinuria, and bleeding (VEGFR class effects); sintilimab brings the standard PD-1 immune-related adverse events - pneumonitis, colitis, hepatitis, endocrinopathies. Both have been combined with other agents previously, so the toxicity profile is understood, but a 37-patient single-arm gives limited safety resolution. Execution risk is moderate - academic sponsor, single Shanghai center, slow recruitment is plausible. Commercial risk is the biggest structural issue: even if ORR reads out positive, sintilimab failed the US regulatory bar in 2022 over single-country data [3], and anlotinib has never been filed with the FDA. Without a US-relevant Phase 3, this combination's commercial address is China-only, where pricing pressure from the National Reimbursement Drug List (NRDL) has compressed both anlotinib and sintilimab revenue substantially. Even commercial success looks modest.

Worth noting, not worth watching closely. The biology is reasonable, the patient selection (no liver mets) shows the investigators understand IO response determinants, and the combination has shown activity in adjacent indications - the same anlotinib + sintilimab pairing posted a Phase 2 signal in BRAF-wildtype anaplastic thyroid carcinoma in 2026 [7]. A separate TNBC neoadjuvant study (NCT04877821) is listed as completed in the registry but has no published efficacy data that could be located; it is not corroborating evidence [8]. This specific CRC trial is small, single-arm, single-center, and run by a sponsor with no clear path to a registrational Phase 3. The signal that would change the assessment: ORR above 35% in MSS-confirmed patients, which would be genuinely unusual and warrant a follow-on randomized study. Anything in the 15-25% range is consistent with chemotherapy comparators and tells you nothing new. Estimated readout 2027 given current recruiting status. The interesting commercial actor to watch is not Shanghai Changzheng Hospital but Innovent Biologics (sintilimab manufacturer, Hong Kong-listed 1801.HK) and Chia Tai Tianqing (anlotinib, subsidiary of Sino Biopharm 1177.HK) - neither has shown public interest in a registrational CRC combo program, and that absence is the most telling signal here.