The birth of PD-1 inhibitors has brought a subversive therapeutic revolution to cancer patients. More and more patients are benefiting from this new trans-generational anti-cancer drug, realizing treatment benefits that were unimaginable in the past. Taking advanced non-small cell lung cancer as an example, PD-1 achieved a 5-year survival rate of 13.4% compared with chemotherapy. However, even this epoch-making “magic anticancer drug” still cannot escape the common problems of anticancer drugs: drugs Resistant. With the popularity of PD-1 inhibitors, more and more patients have encountered the problem of PD-1 resistance. For patients, how to solve PD-1 resistance The problem has become the most urgent expectation of patients. Taking melanoma patients as an example, apart from the primary drug-resistant patients who did not respond to treatment, about 20% to 30% of patients will start PD-1 inhibitor therapy. The drug resistance and progression of the tumor appeared after the response^[1]. With regard to immunotherapy resistance, the mechanisms are very complex and diverse. The decline in immune cell function or number, the loss of tumor antigen markers, and changes in the microenvironment may all cause immune resistance. medicine.

Once cancer patients develop resistance to immunotherapy, there is currently no clear and effective clinical treatment plan. How should we deal with such a situation?

Recently, a three-drug combination clinical study jointly conducted by Laikai and Innovent Biopharmaceuticals was conducted in West China University of Sichuan University. The second hospital completed the first patient administration, which brought us a brand new idea of breaking the problem: If the immunotherapy is resistant, we will restore its drug sensitivity!

The clinical program plans to combine the PD-1 inhibitor with the targeted drug AKT inhibitor, Coupled with the “immunity + targeting + chemotherapy triple regimen” of chemotherapeutic drugs, the treatment efficacy of PD-1-resistant patients can be reawakened and the patients can defeat cancer again. What are the advantages of this triple clinical trial program? Let’s start with its specific plan first. The full name of the clinical trial jointly submitted by Laikai and Innovent Biopharmaceuticals is: “Afuresertib + sintilimab + chemotherapy in the treatment of patients with specific solid tumors with anti-PD-1/PD-L1 resistance. /Phase II dose escalation and efficacy/safety study”(clinicaltrials.gov, NCT05383482) in patients with non-small cell lung cancer, gastric and gastroesophageal junction Adenocarcinoma, esophageal cancer, cervical cancer and endometrial cancer, covering a wide range of patient types. And this clinical trial sounds like a mouthful, but in fact we can see it very clearly when we separate the three drugs:

PD-1 inhibitor sintilimab

First of all, everyone Sintilimab, a well-known PD-1 inhibitor, is undoubtedly the “star drug” among domestic PD-1 inhibitors. Currently, 6 indications have been approved in China and 4 have been successfully incorporated into China National Health Insurance Directory. Sintilimab has achieved the end points of clinical trials in the first-line treatment of squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, esophageal cancer, liver cancer and gastric cancer, respectively (that is, with very good treatment data). It is the first PD-1 inhibitor approved for the first-line treatment of five major cancer types in China, which is of great significance to cancer patients in China. Taking lung cancer as an example, sintilimab has successively been approved for first-line treatment indications for non-squamous and squamous non-small cell lung cancer, solving the two most difficult problems in lung cancer. Among them, sintilimab combined with gemcitabine and platinum as first-line treatment for locally advanced or metastatic squamous cell carcinoma achieved a progression-free survival of 5.5 months, an objective response rate of 44.7% and a disease control rate of 86%. The treatment data are excellent.

chemotherapy drugs

and chemotherapy drugs don’t need much Said that the use of albumin-bound paclitaxel or docetaxel, which is the first-line/second-line recommended chemotherapy drug for non-small cell lung cancer, gastric and esophagogastric junction adenocarcinoma and other cancer types, is also one of the most suitable chemotherapy drugs .

Innovative targeted drug AKT inhibitor auresertib (LAE002) p>The key protagonist of this clinical trial, the key drug that plays the key role in reversing the efficacy of PD-1 inhibitors, is what we will focus on belowAKT inhibitor auresertib(LAE002). With the progress of targeted therapy research, AKT targets and AKT inhibitor auresertib(LAE002) have become one of the hotspots in clinical research on cancer treatment. Similar to popular therapeutic targets such as EGFR and HER2, the over-activation of AKT signaling pathway is an important cause of the occurrence and development of cancer; more importantly, researchers have found that AKT activation is associated with tumors. Drug resistance that occurs during treatment is closely related toIt brings a new idea to our cancer treatment: Can cancer patients be resensitized to drugs that have been resistant to drugs by using AKT inhibitors? Following this brand-new anti-cancer idea, several blockbuster drug companies have taken the step of exploration: For example, AstraZeneca’s AKT inhibitor Capivasertib and Roche’s AKT inhibitor The agent Ipatasertib has made some clinical progress. Among all AKT inhibitors, the highly selective ATP-competitive AKT inhibitor auresertib (hereafter referred to as A drug) )Clinical research and development progress is in the first echelon and is already in the key clinical trial stage(Phase II registration study). Nowadays, it is also the first drug A to open up the field of immunotherapy. Together with the PD-1 inhibitor sintilimab, the chemotherapy drug nab-paclitaxel or docetaxel, it is the first drug for PD-1/ New treatment options for PD-L1-resistant cancer patients. From the synergistic anti-cancer mechanism of the three drugs in the clinic, we have reason to expect the “triple” anti-cancer regimen of “Drug A” + sintilimab + chemotherapy, to give “no drug available” “Provides new hope for PD-1/PD-L1-resistant cancer patients. This clinical program, jointly developed by Laikai and Innovent, has been approved by the Center for Drug Evaluation of the State Drug Administration of China in January 2022. For cancer patients with PD-1/PD-L1 resistance, such a breakthrough clinical research program undoubtedly brings a lot of hope to them in the situation of “no drug available”. The completion of the first drug administration(the subject is a cervical cancer patient) is even more of a milestone. The principal investigator of the subject’s center, Professor Yin Rutie, director of the Department of Radiotherapy and Chemotherapy, West China Second Hospital, Sichuan Universitymeans:

“The incidence of cervical cancer ranks fourth among female malignant tumors in the world^[2].In 2020, there will be about 110,000 new cases of cervical cancer in China, and about 60,000 women will die of cervical cancer^[2]. Current standard treatment options Limited and poor prognosis^[3,4].Immunotherapy plays an increasingly important role in the treatment of recurrent/metastatic cervical cancer, with great potential for future The met therapeutic needs, with the launch of new immunosuppressive products, are used in the treatment of more tumor patients, and also play an important role in the treatment of cervical cancer patients.”“AKT inhibitors as a kind of Serine/threonine protein kinase is regarded as a potential new target for cancer therapy. Several preclinical studies have shown that inhibiting AKT can restore the sensitivity of cancer cells to tumor therapy. Looking forward to the clinical trial of this three-drug combination The progress of the trial has brought new breakthroughs and hope for the treatment of cervical cancer patients in China.”

The lead investigator of this clinical study is a top expert in digestive tract cancer in China,Peking University Cancer Hospital digestive tumor Professor Shen Lin, Director of Internal Medicine, served as the director. For this innovative clinical study, she believes:

“Innovation is the goal of oncology. New methods and new methods to treat cancer patients. Based on the results observed in preclinical studies and clinical studies, the combination of immune checkpoint inhibitors, AKT inhibitors and taxanes may be effective in patients who are refractory to immune checkpoint inhibitors A novel treatment strategy^[3-6].”“This innovative clinical trial of Laika and Innovent will help this new There is a huge clinical demand for digestive system tumors and gynecological tumors in China, and I am very much looking forward to seeing the strength of AKT inhibitors in solving the problem of tumor resistance.”

Currently, the clinical study of “Drug A” + sintilimab + chemotherapy is being actively carried out, and the registration of drug clinical trials is closely related to The registration number of the information publicity platform is: CTR20220746. The primary endpoints of the Phase I dose escalation study of this clinical study were MTD(maximum tolerated dose) and RP2D. The primary endpoint of Phase II is ORR(overall response rate), with planned expansion to MRCT in pivotal clinical phases (international multicenter clinical trial) .

Hope that this new targeted drug “A drug”, which we have high hopes for, can find a bright path for us in the fog of PD-1 inhibitor resistance and bring a new treatment plan to cancer patients.

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