PD-(L)1 Joint CTLA-4 is worth more to look forward to

CTLA-4 is located on the surface of T-cells, when T-cells are over-activated, CTLA-4 and CD28 competitive binding antigen sonizing the cell B7, so that T-cells are less active and unable to kill cancer cells; So, CTLA-4 and PD-1 antibody-like drugs, one that gives antigens to transmit cell signals to activate T-cells at an early stage, and one that prevents cancer cells from escaping from depleted T-cellsTherefore, the use of the two is expected to balance T-cell activity to obtain an improvement in efficacyNature recently announced 295 drug targets currently conducting clinical trials with the PD-1/PD-L1 antibody drug portfolio, the second largest number of CTLA-4-related drug clinical trials, after chemotherapythe number of clinical trials in which different drugs are used in conjunction with PD-(L)1 antibody drugs (Source: Nature Reviews Drug Discovery)CtLA-4-PD-(L)1 inhibitor combination indications are currently the most explored, with the fastest progress being of BMS's two major immunocheckpoint inhibitors, Ipilimum and Nivolabumum, first from Ipi-Nivo,approved for melanoma, kidney cells and hypercancercomprehensively occupy the advanced melanoma treatmentcombination therapy Nivo1mg / kg plus Ipi 3mg / kg Q3W, 4 cycles of medication, and then Nivo3mg / kg Q2W single-drug maintenance treatment until the disease progresses or the emergence of intolerable toxicity, has become a first-line treatment for adolescents and adults over 12 years of age regardless of BRAF mutationOn October 1, 2015, the FDA approved first-line treatment of BRAF V600 mutant wild metastatic melanoma (based on The CheckMate -069 trial results); For first-line treatment of both BRAF mutation-state metastatic melanoma (based on CheckMate -067 trial results);July 24, 2017, approved for first-line or above treatment of both BRAF mutation and metastatic melanoma in adolescents over 12 years of agethis year ESMO announced a new five-year survival breakthrough in the CheckMate-067 trial, with nivo-Ipi improving total survival (OS) compared to Ipi and Nivo, respectively, for patients with advanced metastatic melanoma, with a total survival rate of 26 in three groups of five-year survival, respectively%, 44% and 52%, which increased the five-year survival rate of late metastatic melanoma 10 years ago to an unprecedented 10 times, but 3/4 of the adverse reactions doubled in the joint group relative to Nivo and Ipi monosal, at 59%, 23% and 28%, respectivelyCheckMate -067 test 5-year follow-up survival curve
The efficacy of Ipi-Nivo in asymptomatic cerebral metastasis of advanced melanoma showed efficacy: more than one-third of patients with advanced melanoma had brain metastasis at the time of diagnosis, and up to 75% of melanoma patients died from brain metastasisThe CheckMate 204 trial included 101 patients with asymptomatic brain metastasis, consistent with first-line treatment, with a median follow-up of 20.6 months and an intracranial and intracranial response rate of 54% and 49%So for small volume, low number of metastasis, asymptomatic brain transfer patients may not need stereotactic radiation surgery or have the benefit of survivalIpi-Nivo was better as a new complementary effect for stage III melanoma: only Nivo and Pembro were approved for complementary treatment after surgery for topical melanoma, and the OpACIN trial first explored Ipi-Nivo as a new auxiliary or complementary treatment for patients with stage IIIB/C melanoma, with results showing that 30-month OS was 90% and 67% new and auxiliary, respectively immunotherapy has gradually become the mainstream of first-line treatment of renal cell cancer
Ipi-Nivo has been approved for first-line treatment of mid-high-risk advanced RCC on April 16, 2018, adding additional evidence that immunotherapy becomes the first-line treatment for advanced renal cell carcinoma The checkMate-214 trial reduced the risk of death by 37% compared to Shunitini, and the updated long-term survival follow-up results released in August were consistent, with the median follow-up of 32.4 months, the OS of Ipi-Nivo not reaching, and the Shunitini group at 26.6 months the effectiveness of primary treatment immunotherapy trial sepsis current lynome cell carcinoma first-line treatment drugs or VEGFR inhibitors, Ipi-Nivo is the only dual-immune combination therapy and survival advantage is obvious, but only for the middle-risk patient population, this part of the market is likely to eventually be available for the whole patient population Axitinib and Aveab or Pmebrozumab combination of replaced by many low-risk patients to advance front-line treatment of colorectal cancer with high MSI/MMR defects
Nivo- Low-dose Ipi was also approved for use in this highly unsatisfied population on 11 July 2018, following pembro and Nivo monosyllastes approved for secondary and third-line treatment of high microsatellite instability (MSI-H)/MMR defect solid tumors, respectively tumor types and stages containing MSI/MMR defects efficacy of immunotherapy trials for colorectal cancer with high MSI/MMR defects
given that high MSI/MMR defects are mainly present in less than 10% of colorectal cancer, endometrial and gastric adenocarcinoma, the population market is small, but Checkmate-142 updated the trial in 2018 in the first-line treatment population for one year of active survival data, the opportunity to advance NSCLC first-line therapy exploration road is a twist and fall
since Pembro combined chemotherapy was first approved for metastatic NSCLC first-line treatment, BMS also hope to enter the first line of treatment, this road is quite ups and downs, expect the final results to be announced October 22, 2019, BMS announced that Nivo plus low-dose Ipi were combined with two rounds of chemotherapy for the third stage of clinical research MateCheck-9LA for advanced NSCLC first-line therapy to reach the primary endpoint of total survival The trial design is similar to CheckMate-227part1, except that the Nivo-Ipi co-group also added two chemotherapy cycles 2,200 lung cancer patients, and three first-line treatments, Phase III, are in one Checkmate227 The Checkmate227 trial is too distressed from the results published so far: first, the nivo-chemotherapy in part2 does not show survival advantage; Extended, but in response to the EU review centre request to supplement the low TMB level population effectiveness data found that os in the TMB high and low level sedrifs no difference, and then BMS had to withdraw Nivi and Ipi in the high TMB level population NSCLC first-line treatment application high level of TMB tumors, representing the number of new antigens in tumor cells that can be recognized by the immune system, was once considered a more promising biomarker in I-O treatment, but from the current clinical evidence, TMB was poured cold water as a biomarker in lung cancer: first, AZ was incorporated into TMB 20 mut/Mb The population NEPTUNE trial failed, and then this year's ESMO conference announced tTMB in keynote-189 and 021 for metastatic NSCLC patientfirst-line research exploratory analysis showed that TMB can not predict the efficacy of pembro, and TMB and PD-L1 expression levels are not correlated comforting BMS is that part 1a part PD-L1-1% of the population Nivo-Ipi showed a survival advantage over chemotherapy, but Pembro-Plus chemotherapy has been approved in this population, and Nivo-Ipi is more toxic, unless the OS can be more obviously overtaken, it is more difficult to convince patients to choose NSCLC first-line immunotherapy trial effectiveness progress in small cell lung cancer Nivo-Ipi was lower than expected, CheckMate 032 trial Nivo-Ipi vs Nivo single-drug, although ORR improved: 21.9% vs 11.6%, but the two groups of OS no significant difference, and the joint group 3/4 treatment-related adverse events were three times as high as Nivo single drug early exploration shows advantages and requires larger validation trials
and many other indications in early exploration show tumor response advantages, and the following indications have recently been announced mesothelioma: Plesymmeloma is very aggressive, there is currently no standard therapy for advances after first-line pememes and platinum chemotherapy, Nivo-Ipi than Nivo single-drug show survival advantage, mOS is 15.9 and 11.9 months, respectively, which is a good omen, is currently in Phase III trial, progress faster gastroesophageal cancer: The CheckMate-032 trial explored two different dose combinations of Nivo monosylene and Nivo-Ipi for advanced gastroesophageal cancer patients who had at least 1 line of treatment, with 12 months of PFS up to 8% in the single-drug group, compared to 17% in the combined group, compared to Pembro was approved for second-line treatment of esophageal squamous cancer, Pembro monodrug compared to chemotherapy, and 15% and 9% of PFS in December, respectively prostate cancer: Metastatic prostate cancer expressing AR-V7 is an aggressive phenotype with a low survival rate AR-V7-positive tumors may be rich in DNA repair defects (DRDs), which may make them more sensitive to immune checkpoint blocking, and show initial efficacy in a Phase II trial of Nivo-Ipi with DRD-based AR-V7 metastatic prostate cancer sarcoma: In the Alliance A091401 trial, patients with metastatic sarcoma who had received at least one-line systematic treatment were found to have two different combination doses of Nivo-Ipi, and the results showed that ORR was superior to the single-drug group by 14% and 5%, respectively the increased safety problem is not to be underestimated
in the use of immunotherapy process, due to the off-target effect caused by the immune system overactivation of toxicity, known as immune-related adverse reactions irAE, from clinical trial data and drug warning database have found that CTLA-4 and PD-(L)1 antibody drug when using irAE is higher than single drug according to the WHO Drug Alert Database, the fatal irAE was used in CTLA-4-PD-(L)1 antibody, PD-(L)1 antibody and CTLA-4 antibody single drug were 1.23%, 1.08% and 0.36%, respectively, due to co-use caused by the death of the main irAE has colitis, myocarditis, hepatitis, pneumonia and myocarditis, in particular myocarditis and myocarditis Although the median time from the onset of symptoms to death is 32 days, there are no biomarkers that can reliably predict irAE, depending on the type of tumor and treatment, which can occur at any time during clinical treatment ipilimumab and PD-1 antibody drug irAE occurs 3/4 levels of irAE often requires the use of glucocorticoid injections or stronger immunosuppressants such as TNF-alpha inhibitors such as infliximab, at which time consideration is needed for other adverse reactions such as fatigue or weight gain that may result from combined medication At present, with the use of CTLA-4 plus PD-(L)1 antibody drugs in more and more patients with advanced tumors, the economic problems related to toxicity management are also worthy of attention there are some explorations for co-toxicity management, including adjustments to the method of administration, such as treatment of PD-1 antibodies directly after short-term CTLA-4 antibodies may have similar efficacy, but toxicity may be reduced, or the use of TNF inhibitors through preventive use can effectively alleviate the side effects of CTLA-4 and PD-1 antibody co-use, especially the degree of hepatitis and colitis disease, and even enhance the efficacy of anti-tumor other clinically researching products other CTLA-4-PD-(L)1 antibody combinations are AstraZeneca's Durvalumab and Tremelimab, Agenus Pharmaceuticals' AGEN1884 and AGEN2034, On CoImmune's CTLA-4 Antibody ONC-392-Pembrolizumab, Regenerative Element PD-1 Antibody Cemiplimab-Ipilimumab, and CTLA-4 Antibody REGN 4659-Cemiplimab there are other CTLA-4-PD-1 dual-target products, in which the progress of dual-resistance or fusion protein is faster, which by blocking the addition/synergy of two targets or connecting two receptors at the same time to achieve a single-specific antibody can not achieve the efficacy, has not yet been announced clinical results part of the clinical stage CTLA-4-PD-(L)1 double-target products