In recent years, immune checkpoint inhibitors represented by anti-PD-1 monoclonal antibody have been approved for multiple tumor indications, and continue to impact the current standard treatment plan, thus bringing tumor treatment into the era of immunotherapy. At the same time, ADC (antibody-conjugated drugs) also ushered in a golden era of development. The products derived from the two different tracks have shown good prospects in multiple cancers. And in the field of recurrent/metastatic cervical cancer with limited treatment options, breakthroughs have been made. First, the ADC drug tisotumab vedotin was approved by the FDA. Then, the PD-1 /CTLA-4 dual anti-AK104 was officially launched on September 24 It was accepted by NMPA and was given priority review. People look forward to the iterative development of drugs on different tracks that can truly benefit clinical patients.
's first TF-targeted ADC drug
On September 20, Seattle Genetics (Seagen) and Genmab AinSpan announced that they were approved by the FDA for accelerated research , Used to treat recurrent or metastatic cervical cancer, becoming the first new cervical cancer drug targeting TF (tissue factor) and the 12th ADC drug approved globally.
Figure 1 The mechanism of action of tisotumab vedotin [1] _p11span vedotin is a new type of drug span
11pContains the part of the monoclonal antibody targeting tissue factor (TF), and the microtubule destroyer—methylmarendula E (MMAE). TF is abnormally expressed in a variety of solid tumors. Promote tumor growth, angiogenesis and accelerate tumor metastasis. After tisotumab vedotin is combined with tumor cell surface TF and internalized, it will release MMAE to induce cytotoxicity, thereby effectively killing tumor cells, and exhibiting very good therapeutic effects in the field of cervical cancer .
The approval of this indication is based on the good results of the innovaTV 204 study (NCT03438396) in the field of cervical cancer. This study is an open-label, multi-center, single-arm trial that is included in the group Among 101 patients with recurrent or metastatic cervical cancer, 69% of the patients had previously received bevacizumab treatment, the medication regimen was tisotumab vedotin 2 mg/kg Q3W, and the primary study endpoint was ORR (IRC) based on RESISITv1.1. The secondary endpoints were ORR, DOR, PFS , OS, safety and tolerability assessed by the investigator.
Figure 2 InnovaTV 204 study patient waterfall chart [1] _p11 br1p p4 95% span
p4 95%, good results for follow-up, CI = 5.9%, 33.3%), the median remission period was 8.3 months (95% CI: 4.2,not reached). TRAE (grade 1-2) is 65%, and TRAE (grade ≥3) is 28%, including decreased hemoglobin, fatigue, lymphopenia, diarrhea, and rash.
PD-1/CTLA-4 double antibody
In June 2021, Agenus announced that the FDA has accepted its anti-PD-1 monoclonal antibody Balstilimab (development code: AGEN2034) for the treatment of recurrent or metastatic cervical cancer, and has obtained accelerated review qualification .
Figure 3 Mechanism of action of AGEN2034
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The preliminary results of two independent phase II trials (NCT03104699 and NCT03495882) of combined use of Zalifrelimab (anti-CTLA-4 monoclonal antibody) in recurrent and metastatic cervical cancer,The overall response rate (ORR) of balstilimab monotherapy for cervical cancer was 14%, and the ORR of combined zalifrelimab was 22%. It is commendable that the dual immunization regimen is superior to Balstilimab single drug in ORR and DOR data, but there is no significant increase in adverse events.
Figure 4 Balstilimab and Zalifrelimab study results [2] _span4 _p11brp 4 In June 2020, Betta reached a cooperation with Agenus, an American company, and paid Agenus US$15 million as a down payment. At the same time, Betta Investment subscribed for the additional shares issued by Agenus with US$20 million in cash. Exclusive development and commercialization of Balstilimab and Zalifrelimab for all oncology and non-oncology indications except for intravesical administration.
Whether it is Amgen 's excellent performance in the field of cervical cancer, the double immunity plan of Balstilimab and Zalifrelimab, or + Yspan's double immunity plan approved For these tumor indications, one point of enlightenment to us is that blocking the two targets of PD-1 and CTLA-4 can significantly improve the therapeutic effect. But the side effects have always been criticized,There are also many domestic companies developing bispecific monoclonal antibodies, hoping to achieve better breakthroughs.
A double antibody based on the two targets of PD-1/CTLA -4. The fastest progress is the AK104 independently developed by Kangfang Bio (9926.HK), September 24, 2021. The National Medical Products Administration (NMPA) has officially accepted the company’s world’s first PD-1/CTLA-4 bispecific antibody Cadonilimab (Cadonilimab, development code: AK104) for the treatment of recurrent or metastatic cervical cancer. Apply and get priority review. This also makes Kadenizumab expected to become the world's first PD-1-based bispecific antibody drug that has submitted a marketing application and is approved for marketing.
Encouragingly, the objective remission rate in patients with recurrent or metastatic cervical squamous cell carcinoma reached 47.6%. The safety data of Cadonilimab is also gratifying. The incidence of grade 3 and above drug-related adverse events (TRAE) is only 12.9%, and the safety is equivalent to that of PD-1 single drug. It is worth mentioning that Cadonilimab not only achieved a higher response rate in PD-L1 positive populations, but also saw good results in PD-L1 negative populations, and the median progression-free survival was also significantly improved. Bringing better treatments to patients with advanced cervical cancer in China.
summary
2030 is the key to accelerate the elimination of cervical cancer in ChinaFor recurrent or metastatic cervical cancer, how to effectively improve the 5-year survival rate is particularly important. Tisotumab vedotin was approved by the FDA, and the new antibody drug represented by AK104 (PD-1/CTLA-4 double antibody) was accepted by the NMPA. It is hoped that it will be approved for marketing in China as soon as possible, and it will truly benefit clinical patients.
References:
span1 span1 span1 span1 2021 span1 _span 2 2021 span1 _span [1] Robert L Coleman 6092 _span _span 2 2021 span1. Congress; September 20, 2020; virtual.Abstract LBA34.
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