ASCO 2021: TOP10 New Opportunities

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The 2021 ASCO annual meeting is underway, and many international cutting-edge and highly-regarded clinical oncology research results and clinical data are also exciting.

The most noteworthy TOP10 new opportunities

MGC018 will be one of the most noteworthy Top10 new opportunities for everyone to explain and share in the live broadcast of Medical Rubik's Cube.

Source: AACR 2020

B7-H3 is a member of the B7 family of immunomodulatory molecules.

Image source: Macrogenics official website

At this ASCO meeting, MGC018 announced a dose escalation study that enrolled 29 patients covering multiple tumor types, including 3 patients with recurrent melanoma who had previously received ≥2 line checkpoint treatment.

Source: Macrogenics official website

Moreover, MGC018 also shows strong clinical activity against prostate cancer.

Source: ASCO2021

ASCO Focus-Listed Drugs

1.

On May 28, the FDA approved Lumakras (sotorasib) for the treatment of non-small cell lung cancer (NSCLC) with KRASG12C mutations, ushering in the first targeted drug milestone for the "undruggable" target KRAS.

Source: WCLC2020

With the approval to go public, Lumakras (sotorasib)'s attention may decrease.

Source: ASCO2021

However, in a sequencing analysis of nearly 80,000 people, it was once again confirmed that non-G12C mutations (G12D, G12V) accounted for more KRAS mutations.

Image source: ASCO2021

2.

On May 22, Amivantamab also received accelerated FDA approval, becoming the first treatment for adult non-small cell lung cancer (NSCLC) with an insertion mutation in exon 20 of EGFR.

Source: WCLC2020

In addition, the study of Amivantamab combined with EGFR-TKI third-generation drug lazertinib for the treatment of osimertinib recurrence and EGFR-mutant NSCLC that has not received chemotherapy may also be of interest.

Source: ASCO2021

However, through biomarker analysis, these corresponding patients are more based on the normal therapeutic effect of the drug mechanism.

Source: ASCO2021

Among 28 patients, 18 patients had unknown resistance mechanisms (8 PR), and 10 patients belonged to non-EGFR/MET resistance mechanisms (no response).

Source: ASCO2021

3.

As the second CDK4/6 inhibitor on the market in the world, Ribociclib updated the overall survival (OS) data for the first-line treatment of postmenopausal HR+/HER2-metastatic breast cancer at this meeting.

The data released this time is an exploratory analysis of the Phase III MONALEESA-3 study (NCT02422615).
Previous data has shown that Ribociclib combined with fulvestrant compared with placebo combined with fulvestrant, regardless of first-line or second-line treatment, significantly improved the HR+/HER2− OS of postmenopausal women with metastatic breast cancer (not up to vs 40.
0 months; HR, 0.
72; 95% CI, 0.
57-0.
92, P=.
00455).
The published data is an exploratory analysis of OS after an additional median follow-up of 16.
9 months.

The data showed that at the cut-off time (October 30, 2020), the median follow-up time was 56.
3 months.
68 patients (14.
0% vs.
8.
7%) are still receiving Ribociclib combined with Fulvestrant.
After this extended follow-up, Ribociclib combined with Fulvestrant continued to show OS benefit (mOS: 53.
7 vs 41.
5 m; HR, 0.
73; 95% CI, 0.
59-0.
90).
In addition, Ribociclib combined with fulvestrant in 1L (mOS, less than 51.
8m; HR, 0.
64; 95% CI, 0.
46-0.
88) and 2L subgroups (mOS, 39.
7 vs 33.
7 mo; HR, 0.
78; 95) Also shows longer OS benefits.

4.
Enhertu (DS-8201)

Enhertu (Trastuzumab deruxtecan, T-DXd; DS-8201), as a star drug in the ADC field, has attracted much attention.
Enhertu has not only expanded the field of multiple indications, but also walked on the journey of breaking the conventional "dogma" of ADC drugs.

Among them, Enhertu's randomized, multicenter treatment of HER2-positive advanced gastric or gastroesophageal junction (GEJ) clinical phase II study (DESTINY-Gastric01) final OS data was announced.
A total of 187 patients were enrolled, almost all of them were Asian patients (Japan: 79.
7%, South Korea: 20.
3%), 125 patients received T-DXd; the median of patients received the previous 2 lines and above, and 44.
4% were 3 lines or above.

Source: ASCO2021

At the time of the data cutoff (June 3, 2020), 8% of patients were still receiving T-DXd (median survival follow-up: 18.
5 months) treatment, while receiving the treatment control group (PC: irinotecan) selected by the doctor [I] or Paclitaxel [P]) is 0%.
Compared with PC, T-DXd has improved OS (mOS: 12.
5 vs 8.
9 m; HR: 0.
60); the 12-month OS was 52.
2% and 29.
7%, respectively.
The ORR of T-DXd treatment was 51.
3% (61/119; 11 CR, 50 PR), while PC was 14.
3% (8/56; all were PR), confirmed ORR (42.
0% vs 12.
5%), DCR ( 86.
6% vs 62.
5%), mDOR (12.
5 vs 3.
9 m), mPFS (5.
6 vs 3.
5 m; HR: 0.
47) were also significantly higher.

Source: ASCO2021

In addition to HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, Enhertu is also conducting research on HER2-negative gastric cancer.

5.
Toripalimab

As the first domestically-produced PD-1 product to be marketed, the internationalization process of tereprizumab is also at the forefront.
Teriplizumab is the first domestic PD-1 to submit a marketing application to the FDA, and it has obtained FDA BTD certification for nasopharyngeal carcinoma indications.
At this meeting, Tripril announced the results of an international multicenter, double-blind, placebo-controlled, phase III clinical registration study (JUPITER-02) for the first-line treatment of recurrent/metastatic nasopharyngeal carcinoma (r/m NPC), and It was included as a blockbuster research abstract (Late Breaking Abstract, LBA) by ASCO.

The JUPITER-02 study showed that compared with chemotherapy alone, the PFS of the teriprizumab combined chemotherapy group was significantly prolonged (HR = 0.
52), and the mPFS was 11.
7 vs 8.
0 months.
The 1-year PFS rates of teriprizumab plus chemotherapy group and placebo plus chemotherapy group were 49% and 28%, respectively.
In all relevant subgroups, including the subgroup of PD-L1 expression level, improvement in PFS of the teriprizumab combined with chemotherapy group was observed.
As of January 15, 2021, the OS is not yet mature.

In addition, the objective response rate (ORR) of the teriprizumab combined chemotherapy group and the placebo combined chemotherapy group were 77.
4% vs 66.
4% (P = 0.
033), and the median duration of response (DOR) was 10.
0 vs 5.
7 Months (HR=0.
50, 95% CI: 0.
33-0.
78).

ASCO focus-drugs under development

After watching the progress of marketed drugs, we turned our attention to drugs under development in the clinical research stage.

1.
First in class oral CD11b modulator GB1275

Although checkpoint immunotherapy has completely changed the treatment of cancer, not all types of tumors have achieved substantial benefits.
Pancreatic ductal adenocarcinoma (PDAC) is one of them.
As a highly lethal malignant tumor, the response to immunotherapy is very limited.

The extensive immunosuppressive bone marrow cell infiltration in PDAC is considered to be the main mechanism of immunotherapy resistance.
CD11b/CD18 is an integrin molecule that is highly expressed on the cell surface of these bone marrow cell subsets and plays an important role in the transport of inflammatory tissues and cell function.
GB1275 is a first-in-class oral CD11b modulator, which can reduce myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), and repolarize the M2 immunosuppressive TAM to the M1 phenotype, thereby increasing Activated tumor infiltration of CD8+ T cells and showed anti-tumor efficacy in preclinical models.

At the 2020ASCO meeting, GB1275 announced a single-agent and combined clinical study design (KEYNOTE-A36) and early in vivo PK characteristics of pembrolizumab.
This time, GB1275 brought early evidence of clinical activity.
As of January 8, 2021, 45 subjects have received treatment.
Among evaluable subjects, GB1275 single drug showed 31.
6% (6/19) SD, and combined drug reported 56.
3% (9/16) SD.
In the combination group (GB1275, 800 mg), 1 case of MSS-CRC received 263 days of treatment (a subtype with low levels of infiltrating lymphocytes in the tumor microenvironment, which often leads to immune checkpoint inhibitors that are almost ineffective) The subject reported PR, and 1 case of gastric cancer (GC) (because of disease progression was previously treated with pembrolizumab plus batuximab for less than 3 months) reported long-term SD (227 days); two cases were tested All are continuing to receive treatment.

Both GB1275 single-drug and combination-drugs have observed a decrease in peripheral MDSC and an increase in tumor infiltrating lymphocyte (TIL) counts.

2.
First-in-class RAD51 inhibitor CYT-0851

Homologous recombination (HR) is an essential high-fidelity mechanism for repairing DNA double-strand breaks (DSB).
The RAD51 protein is essential for repairing damaged DNA.
The RAD51 protein binds to the DNA at the break and wraps it in the protein sheath, completing the essential first step in the repair process.
In the nucleus of many normal cells, the RAD51 protein interacts with many other proteins, including BRCA1/BRCA2, to repair damaged DNA.

Source: ASCO2021

On the data cutoff date (DCO, December 8, 2020), 23 patients with advanced cancer (sarcoma: n=8; breast: n=4; non-Hodgkin's lymphoma: n=5; pancreas: n=3; Ovarian: n=2; mucoepidermoid carcinoma: n=1) was included in 6 cohorts (15 mg, 20 mg, 30 mg, and 45 mg BID; 90 mg and 130 mg QD), and dose-limiting toxicity has not been reported.
Before DCO, the response of 10 patients was assessable.
Two patients with DLBCL (-74%) and myxofibrosarcoma (-30%) who received 45 mg BID for more than 126 days and 250 days showed PR according to Lugano and RECISTv1.
1 standards.
In addition, 1 case of pancreatic cancer (-19%) and 1 case of follicular lymphoma (-42%) obtained SD when receiving 45mg BID treatment, and the tumor shrinkage continued for 111 days and 99 days or more.

Source: ASCO2021

CYT-0851 is a first-in-class RAD51 inhibitor with good tolerance.
Six patients (26.
1%) experienced CYT-0851-related adverse events, but only the number of patients with grade 1/2 nausea (n=3,13%) and constipation (n=2,8.
7%) was more than one.
CYT-0851 is the first DNA damage repair (DDR) therapeutic agent with clinical activity in both hematological malignancies and solid tumors.

3.
First-in-class humanized IgG4 monomer COM701

COM701 is a new type of First-in-class humanized IgG4 monoclonal antibody that can bind with high-affinity containing poliovirus receptor-associated immunoglobulin domain (PVRIG), blocking its interaction with its ligand PVRL2 effect.
Blocking PVRIG can enhance the activation of T/NK cells and inhibit tumor growth in mouse models.

Although COM701 has logged into ASCO many times, it is more of a clinical trial design and dynamic forecast.
This time, COM701 brings early clinical data for advanced solid malignant tumors.
Among the 51 DLT-evaluable patients recruited: Group A (COM701 single-dose escalation) 8 cohorts enrolled 16 patients (0.
01-20 mg/kg, IV Q3/4 wks); Group B (COM7010.
3-20 mg/ kg + nivolumab (NIVO) 360 mg/480 mg; IV Q3/Q4wks) 5 cohorts included a total of 15 patients.

No DLT was reported in group A or group B.
In terms of anti-tumor activity, in group A (cohort 8), 1 patient with platinum-resistant primary peritoneal cancer has confirmed PR and lasted for 14 months.
In group B (COM70110 mg/kg + NIVO 480 mg, IV Q4 wks), 1 case of anal squamous cell carcinoma (SCCA) who received NIVO last treatment confirmed CR and lasted for 18 months.
In addition, many patients with different tumor types obtained SD.

4.
The fastest-growing domestic ADC Widicitumumab

With the advancement of ADC technology, ADC drugs are constantly breaking through, and even subverting previous treatment concepts.
RC48, as a Her2 targeted ADC, continues to expand in Her2 positive tumors, and even advances to the low expression of Her.
At this meeting, RC48 also had a number of progress reports, including a pooled analysis of advanced or metastatic breast cancer with HER2 positive and HER2 low expression.
We might as well see from it, the therapeutic difference of RC48 at different expression levels of the target.

The analysis involved two studies, C001 CANCER (NCT02881138) and C003CANCER (NCT03052634).
On the data cut-off date (December 31, 2020), a total of 118 female breast cancer patients were enrolled and received RC48-ADC treatment.
70 patients (59.
3%) were HER2 positive, and 48 patients (40.
7%) were HER2 low expression.
In the HER2 low expression subgroup, ORR and mPFS were 39.
6% and 5.
7 months, respectively.
The ORR and mPFS of IHC 2+/FISH- (HER2 positive) patients were 42.
9% (15/35) and 5.
7 months, respectively.
For IHC 1+ patients (Her2 low expression), even if the COVID-19 pandemic caused some treatment delays, the ORR reached 30.
8% (4/13).

Source: ASCO2021

It can be seen that in the analysis of the HER2 positive and HER2 low expression subgroups of RC48-ADC, the ORR (42.
9% vs 39.
6%) and mPFS (5.
7 vs 5.
7 m) at the same therapeutic dose (2.
0 mg/kg) showed relative Consistent efficacy potential.

5.
PD-L1/CTLA-4 double anti-KN046 first-line treatment of NSCLC

KN046 is a new type of PD-L1/CTLA-4 bispecific antibody that can block the interaction of PD-L1 with PD-1/CD80, CTLA-4 with CD80/CD86.
At the ASCO meeting, continue to report on the efficacy and safety of newly treated stage IV NSCLC patients.
Eligible patients can receive KN046 combined with platinum-containing chemotherapy.

Source: ASCO2021

As of January 19, 2021, 87 patients were enrolled, of which 83 patients had tumor PD-L1 expression data (PD-L1 ≥1%: 55.
4%; PD-L1<1%: 44.
6%).
33.
3% of patients continued to receive study treatment, and 66.
7% of patients stopped treatment due to disease progression (27.
6%), TEAE (13.
8%), death (9.
2%) and other reasons (16%).
Among 81 patients with evaluable efficacy, ORR was 50.
6%, DCR was 87.
7%, mPFS was 5.
9, mOS was not achieved, and the OS rate at 12 months and 15 months was 74.
9%.
The ORR and DCR of patients with non-squamous NSCLC (n=8) were 45.
8% and 89.
6%, respectively.
The ORR and DCR of patients with squamous non-small cell lung cancer (n=33) were 57.
6% and 84.
8%, respectively.
In patients with PD-L1≥1%, mPFS was 6.
7 months (PD-L1≥1% patients with squamous non-small cell lung cancer was 10.
8 months).

Source: ASCO2021

Correspondingly, nivolumab combined with ipilimumab (PD-1+CTLA4) in the treatment of PD-L1≥1% phase IV or relapsed NSCLC study (CheckMate227), mOS was 17.
1 months; ati In the study of Linibizumab (PD-L1) monotherapy for IV non-squamous or squamous NSCLC (IMpower110), mOS reached 20.
2 months.
After most bispecific antibodies have advanced treatment mechanisms, whether they can show clinical benefits beyond monoclonal antibodies or combination therapy in the clinic still requires continuous attention.