Global Clinical Progress for Innovative Oncology Drugs Under the Spotlights in May 2021
Based on the incomplete statistics according to public information, as of May 31, 2021, a total of 11 recent major clinical developments in the field of oncology worldwide are under the spotlight. They are summarised as follows:

Lung cancer
(SUZHOU, China, May 28, 2021) CStone Pharmaceuticals ("CStone", HKEX: 2616) Announces the First-in-Class Registrational Clinical Trial of Sugemalimab Met its Primary Endpoint in Stage III NSCLC and Plans to Submit a New Drug Application.

A registrational clinical trial (GEMSTONE-301 study) of the anti-PD-L1 monoclonal antibody sugemalimab in patients with stage III NSCLC met its primary endpoint at a planned interim analysis reviewed by the independent Data Monitoring Committee (iDMC).

The findings showed that sugemalimab as a consolidation therapy brought statistically significant and clinically meaningful improvement in the Blinded Independent Central Review (BICR) assessed PFS in patients with locally advanced/unresectable NSCLC without disease progression after concurrent or sequential chemoradiotherapy. Investigator assessed PFS showed consistent results as those of the primary endpoint. Sugemalimab was well-tolerated with no new safety signals. Subgroup analyses demonstrated that sugemalimab was associated with clinical benefit regardless of whether patients received concurrent or sequential chemoradiotherapy prior to sugemalimab.

By report, Sugemalimab is the world's first anti-PD-1/PD-L1 monoclonal antibody to successfully improve progression-free survival (PFS) in patients with stage III non-small-cell lung cancer (NSCLC) without disease progression after concurrent or sequential chemoradiotherapy and the world's first anti-PD-1/PD-L1 monoclonal antibody covering both locally advanced/unresectable (stage III) and metastatic (stage IV) NSCLC patients.

As known by the medicine magic pharmago database, at present, 2 PD-L1 mAbs have been approved and listed in China, and 2 are in the declaration stage. As can be seen in the table below, the phase III NSCLC population for which AstraZeneca nivolumab was approved is for patients treated with concurrent chemoradiotherapy only, whereas cornerstone pharmaceuticals also enrolled patients treated with sequential chemoradiotherapy in the gemstone-301 study, covering a broader population. 

Breast cancer
On May 14th, when the neoadjuvant / adjuvant phase III study in early triple negative breast cancer by keytruda, merchedon, announced a positive outcome in the pivotal phase III study titled keynote-522, merchedon met its 2nd primary endpoint, event free survival (EFS).

According to an independent data monitoring committee (DMC) interim analysis, keytruda combined with chemotherapy as neoadjuvant therapy and continued single agent after surgery as adjuvant therapy resulted in a statistically and clinically meaningful improvement in EFS in high-risk early triple negative breast cancer (TNBC) patients compared with preoperative chemotherapy alone.Keytruda is the first PD-1 therapy to demonstrate statistically significant EFS benefit in the neoadjuvant / adjuvant setting for TNBC.

Data from the analysis of PCR (pathological complete response), the other primary endpoint of the study, was presented at the 2019 European Society for Medical Oncology (ESMO) Congress and presented at NEJM. The results showed that the addition of keytruda plus chemotherapy to neoadjuvant sequential keytruda adjuvant compared with placebo plus chemotherapy neoadjuvant sequential placebo adjuvant resulted in a significant improvement in PCR (64.8% vs. 51.2%, P = 0.00055), regardless of PD-L1 status.

Novel immune combination therapies
Bristol Myers Squibb Announces LAG-3-Blocking Antibody Relatlimab and Nivolumab Fixed-Dose Combination Significantly Improves Progression-Free Survival vs. Opdivo (nivolumab) in Patients with Previously Untreated Metastatic or Unresectable Melanoma

Bristol Myers Squibb (NYSE: BMY) today announced results from the Phase 2/3 RELATIVITY-047 trial, which showed that the fixed-dose combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, administered as a single infusion, demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit compared to Opdivo (nivolumab) alone in patients with previously untreated metastatic or unresectable melanoma. This is the first regimen to demonstrate a statistical benefit over anti-PD-1 monotherapy in metastatic melanoma.

Among patients treated with the combination, the median PFS (mPFS) was significantly longer at 10.12 months (95% Confidence Interval [CI]: 6.37-15.74) vs. 4.63 in those who received Opdivo (95% CI: 3.38–5.62); (Hazard Ratio [HR] 0.75; 95% CI: 0.62-0.92, p=0.0055). The safety profile of the fixed-dose combination of relatlimab and nivolumab was manageable and consistent with those previously reported for relatlimab and nivolumab. No new safety signals or new types of clinically important events were identified with the fixed-dose combination when compared to Opdivo monotherapy.Grade 3/4 drug-related adverse events were 18.9% in the combination arm compared to 9.7% in the Opdivo arm. Drug-related adverse events leading to discontinuation were 14.6% in the combination arm compared to 6.7% in the Opdivo arm.

Lymphocyte-activation gene 3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumor infiltrating lymphocytes (TILs) and contribute to tumor-mediated T-cell exhaustion. 
This is the first presentation of Phase 3 data from a trial evaluating a LAG-3-blocking antibody, meanwhile, the first regimen to demonstrate a statistical benefit over anti-PD-1 monotherapy in metastatic melanoma. Other detailed data to be featured in an oral presentation during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

It is worth mentioning that on May 14th, a clinical application for fixed dose compound injection consisting of LAG-3 mAb relatlimab and PD-1 mAb opdivo was received from CDE.

First Phase III trial to demonstrate overall survival benefit with tremelimumab Imfinzi plus chemotherapy demonstrated progression-free survival benefit, but a trend in overall survival did not achieve statistical significance.

On May 7, AstraZeneca released the final data for the Poseidon study.
POSEIDON was a Phase III trial of AstraZeneca’s Imfinzi (durvalumab) plus platinum-based chemotherapy or Imfinzi, tremelimumab and chemotherapy versus chemotherapy alone in the 1st-line treatment of patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC).

Positive high-level results from the final analysis of POSEIDON showed the combination of Imfinzi, tremelimumab and chemotherapy demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit versus chemotherapy alone. This immunotherapy combination also demonstrated a statistically significant improvement in progression-free survival (PFS) versus chemotherapy alone, as previously reported in October 2019. Patients in this arm were treated with a short course of tremelimumab, an anti-CTLA4 antibody, over a 16-week period in addition to Imfinzi and standard chemotherapy.

The Imfinzi plus chemotherapy arm demonstrated a statistically significant improvement in PFS versus chemotherapy in the previous analysis, but the OS trend observed in this analysis did not achieve statistical significance. Patients in the control arm were treated with up to six cycles of chemotherapy, while those in the experimental arms were treated with up to four cycles.

Each combination demonstrated an acceptable safety profile, and no new safety signals were identified. The combination with tremelimumab delivered a broadly similar safety profile to the Imfinzi and chemotherapy combination and did not lead to an increased discontinuation of treatment.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “We are pleased to see the POSEIDON Phase III trial demonstrate, for the first time, a significant and clinically meaningful overall survival benefit for Imfinzi plus tremelimumab with chemotherapy in metastatic non-small cell lung cancer. We were particularly pleased by the safety profile. We’ve seen encouraging uptake of novel combinations in this setting and believe this new approach will add a further option for patients with high unmet medical need. We look forward to discussing next steps with regulatory authorities.”

The data will be presented at a forthcoming medical meeting.

Imfinzi is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy and is the global standard of care based on the PACIFIC Phase III trial. Imfinzi is also approved in the US, the EU, Japan and many countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial.

Imfinzi is being further assessed across all stages of lung cancer as part of an extensive Immuno-Oncology programme across NSCLC and SCLC, as well as in other tumour types.

The combination of Imfinzi and tremelimumab is being tested in lung cancer, bladder cancer and liver cancer settings.

Early clinical progression milestones

2021-05-08:Datopotamab Deruxtecan Late-Breaking Data at ESMO Breast Shows Promising Preliminary Response and Disease Control in Patients with Metastatic Triple Negative Breast Cancer
The safety profile of datopotamab deruxtecan seen in the TNBC cohort is consistent with safety that has been previously reported in the non-small cell lung cancer (NSCLC) cohort of TROPION-PanTumor01. No patients discontinued treatment due to adverse events (AEs); however, dose reductions due to AEs occurred in six patients (25%) and were most commonly due to stomatitis (13%) and mucosal inflammation (8%). Grade 3 or higher treatment emergent adverse events (TEAEs) regardless of causality occurred in 33% of patients. TEAEs grade 3 or higher included stomatitis (13%), fatigue (4%) and anemia (4%) with no grade 3 or higher TEAEs of diarrhea or neutropenia. The most common TEAEs overall in ≥25% of patients were stomatitis, nausea, fatigue, vomiting, and alopecia. No cases adjudicated as drug-related interstitial lung disease (ILD) were observed.

Patients were treated with a median of four prior lines of therapy (range, 1-9, including prior lines of therapy in the [neo]adjuvant or metastatic setting) with a majority (88%) receiving more than two previous lines of treatment, including a taxane (83%), platinum-based chemotherapy (50%), immunotherapy (33%), sacituzumab govitecan (8%) and a PARP inhibitor (4%). As of data cut-off on January 8, 2021, 75% of patients remained on treatment with datopotamab deruxtecan.

TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicenter phase 1 trial designed to evaluate the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumors refractory to or relapsed from standard treatment or for whom no standard treatment is available, including NSCLC, TNBC and hormone receptor positive (HR+) breast cancer.

2021-05-12: Reports Updated Data in Two Abstracts for CA-4948 Accepted for Presentation at the European Hematology Association 2021 Virtual Congress
Updated clinical data from Phase 1/2 study of CA-4948 in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) from February data-cut includes reduction of marrow blasts in 8 out of 9 evaluable patients with elevated blast counts at baseline -
Four objective responses observed, including 1 complete response (CR), 1 complete remission with incomplete hematologic recovery (CRi) with negative minimal residual disease, and 2 bone marrow CRs -
All 3 patients with SF3B1 or U2AF1 spliceosome mutation achieved marrow CR or better -
CA-4948 demonstrated synergistic antileukemic activity in combination with venetoclax and azacitidine in AML cell lines -
Additional data to be presented in oral presentation and poster session at the European Hematology Association 2021 Virtual Congress (EHA); along with company-hosted virtual KOL event on June 11, 2021 

CA-4948 is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with AML and MDS. 

2021-05-19:Jasper Therapeutics Announces Updated 90-day Data from Phase 1 Clinical Trial of JSP191 as Targeted Stem Cell Conditioning Agent in Older Patients with Myelodysplastic Syndromes or Acute Myeloid Leukemia Undergoing Hematopoietic Cell Transplantation.
At 90 days after transplant, MRD as measured by cytogenetics, karyotype and next-generation sequencing was negative (undetected) in five patients and reduced in one patient, and full chimerism (greater than 95%) was observed in five of the six patients. One patient had secondary graft failure with no evidence of relapse at 90 days. JSP191, when added to low-dose radiation and fludarabine, was well tolerated in all six patients; the protocol allows for subjects to receive the conditioning regimen in an outpatient setting. No infusion reactions, treatment-related toxicities such as oral mucositis or evidence of acute graft versus host disease were reported. Pharmacokinetic data showed that serum levels of the JSP191 0.6 mg/kg dose were consistent among study participants as evaluated up to 14 days post-infusion. 
JSP191 is a first-in-class humanized monoclonal antibody in clinical development as a conditioning agent that blocks stem cell factor receptor signaling leading to clearance of hematopoietic stem cells from bone marrow, creating an empty space for donor or gene-corrected transplanted stem cells to engraft. 

2021-05-26:ADC Therapeutics Announces Online Publication of Camidanlumab Tesirine Phase 1 Results in The Lancet Haematology
The multicenter, open-label, single-arm, dose escalation and dose expansion Phase 1 clinical trial enrolled 133 adult patients, 77 (58%) with classical Hodgkin lymphoma and 56 (42%) with non-Hodgkin lymphoma. Enrolled patients were required to have pathologically confirmed relapsed or refractory Hodgkin lymphoma or non-Hodgkin lymphoma and no therapies with established clinical benefit for their disease stage available to them.
Camidanlumab tesirine (Cami, formerly ADCT-301) is an antibody drug conjugate (ADC) comprised of a monoclonal antibody that binds to CD25 (HuMax®-TAC, licensed from Genmab A/S), conjugated to the pyrrolobenzodiazepine (PBD) dimer payload, tesirine. Once bound to a CD25-expressing cell, Cami is internalized into the cell where enzymes release the PBD-based payload, killing the cell. 

2021-05-19:MacroGenics Announces Preliminary Clinical Results from Phase 1 Study of MGC018 to be Presented at ASCO Annual Meeting
As of the May 3, 2021 data cut-off, 28 of the 40 patients in the mCRPC cohort expansion had been enrolled, with disease classification available for 20 of these patients: seven had bone only, nine had mixed soft tissue and bone, and four had soft tissue only. Of the 28 mCRPC patients in cohort expansion, 22 had received at least one dose of MGC018 and had a post-baseline PSA. Eleven of these 22 patients (50%) had a PSA reduction of 50% or greater. All but three of these 22 patients were still on therapy as of the data cut-off. Of 13 patients who had measurable disease, six were not yet evaluable and seven had their first 9-week imaging, of which four had reductions in target lesion sums of 13%, 21%, 27% and 35% (unconfirmed partial response). Twelve of these 13 patients were still ongoing on MGC018.
MGC018 is an ADC comprised of an anti-B7-H3 humanized IgG1/kappa monoclonal antibody conjugated via a cleavable linker to the prodrug seco-DUocarmycin hydroxyBenzamide Azaindole (DUBA; licensed from Byondis, B.V.), with an average drug-to-antibody ratio (DAR) of ~2.7.


2021-05-19:Merus Announces Publication of Abstract on Zenocutuzumab in NRG1-fusion (NRG1+) Cancers at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting
As of January 12, 2021, 51 patients were treated with Zeno, of whom 33 were evaluable for response. Tumor regression was observed in 25 out of 33 patients, with confirmed partial responses in 9 of 33 (27% ORR), including 4 of 10 patients (40% ORR) with pancreatic cancer.
Zeno continues to be well tolerated with the majority of adverse events of mild or moderate (Grade 1 or 2) Zeno is an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced Biclonics® that utilizes the Merus Dock & Block® mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 gene fusions (NRG1+).severity, regardless of causality.


2021-05-20:PDS Biotech Announces Release of Abstract for PDS0101 in NCI-Led Phase 2 Clinical Study for Oral Presentation at 2021 ASCO Meeting
An overall objective response rate of 71% (10/14) in patients with refractory HPV16-associated cancers
1 complete response (anal cancer)
9 partial responses (3 cervical cancer, 2 vulvar/vaginal cancer, 2 anal cancer, 2 oropharyngeal cancer)
90% of these of these responses are ongoing after a median 5 months of follow up (9/10)
PDS Biotech’s lead candidate, PDS0101, combines the utility of the Versamune® platform with targeted antigens in HPV-expressing cancers. 
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