Drug therapy for advanced liver cancer yesterday, today and tomorrow
Returning to HIMALAYA research yesterday, it was A bit of A move, although the results may not top the A+T category.But there are many advantages to this combination, most simply that patients may have another treatment option in the future.Prior to this, the evolution of drugs for advanced liver cancer was reviewed with limited knowledge.Liver cancer disease burden In 2020, liver cancer was the sixth most common cancer worldwide and the third most fatal.There are about 90W new cases and 83W deaths in the world every year, of which HCC is the most important type, accounting for 75% to 85%.Unfortunately, many HCC patients are initially diagnosed with advanced stage, which means that treatment options are limited. If only supportive treatment is given, the median survival is less than one year.Only with the approval of sorafenib in 2007 did patients with advanced HCC have an effective systemic treatment for the first time.There is no doubt that sorafenib is an epoch-making and scientific leap for the drug treatment of advanced liver cancer…Over the next 10 years (2007-2016), the search for drugs for advanced liver cancer was once again Mired in failed candidates and failed clinical trials.In recent years, thanks to the boom in TKI and immune checkpoint inhibitors, the therapeutic landscape has changed dramatically.Moreover, based on the success of IMbrave-150, “A+T” once again makes drug therapy for advanced liver cancer stand up. People who were previously dismissed as “cold” by internal medicine teachers are favored again, because there were not many drug treatment options in the past.Sorafenib: an oral small molecule, multikinase inhibitor that inhibits vegFR1-3, PDGFR, and Raf-MEK-ERK pathways.The SHARP pivotal clinical study showed that sorafenib significantly extended median OS (10.7 vs 7.9, HR=0.69, P < 0.0001) compared to placebo, and median time to symptom progression was similar between the two groups (4.1 vs 4.9, HR=1.08, P < 0.77).Significantly longer median radiographic progression time (5.5 vs 2.8, P < 0.001) and higher DCR (43% vs32%, P =0.002).Based on this, FDA approved the first-line treatment indication for advanced liver cancer in 2007.2. Ramvaritinib: Oral small molecule, multikinase inhibitor, inhibiting VEGFR1-3, FGFR1-4, PDGFRα, KIT, RET.REFLECT key clinical study showed that ramvaritinib was not inferior to sorafenib in median OS (13.6 vs 12.3, HR=0.92, 95%CI,0.79-1.06), and other secondary end points were superior to sorafenib, significantly lengthening the median PFS (7.3 vs 3.6, HR=0.65,P < 0.0001), significantly longer median time to progression (mTTP) (7.4 vs 3.7, HR=0.61, P < 0.0001), and higher ORR of objective response (18.8% vs 6.5%, P < 0.0001).Based on this, FDA approved first-line treatment indication for advanced liver cancer in 2018.3. Regofinil: Oral small molecule, multikinase inhibitor, inhibiting VEGFR1-3, PDGFRβ, FGFR1, BRAF, RET, KIT.RESORCE Key clinical studies showed that Regofinib significantly extended median OS (10.6 vs 7.8, HR=0.63, P < 0.0001) and median PFS (3.1 vs 1.5, HR=0.46, P < 0.0001) compared with placebo. RESORCE key clinical studies showed that Regofinib significantly extended median OS (10.6 vs 7.8, HR=0.63, P < 0.0001) compared with placebo.The objective response rate was higher in ORR (11% vs 4%, P =0.0047) and DCR (65% vs 35%, P < 0.0001).Based on this, the FDA approved sorafenib as second-line therapy for advanced liver cancer in 2017.4. Caputinib: Oral small molecule, multikinase inhibitor, inhibits VEGFR1-3, MET, RET, KIT, AXL, FLT3.CELESTIAL Key Clinical studies show that carbotinib significantly lengthens median OS (10.2 vs 8.0, HR=0.76, P =0.005) and median PFS (5.2 vs 1.9, HR=0.44, P < 0.001) compared with placebo,The ORR of objective response rate was higher (4% vs 1%, P =0.009).Based on this, in 2019 FDA approved sorafenib for post-line therapy for advanced liver cancer.5. Ramuzumab: Selective VEGFR-2 inhibitor, IgG1 mab.The REACH pivotal clinical study showed no significant improvement in median OS compared with placebo (9.2 vs 7.6, HR=0.87, P =0.14), but a subgroup analysis showed a significantly longer median OS (7.8 vs4.2, p=0.14) in people with high BASELINE AFP (≥ 400 ng/mL).HR=0.674, P =0.006).Then, the first pivotal clinical study of REACH2 under the guidance of Biomarker in liver cancer was carried out. Regardless of the result, I think this is a milestone in liver cancer.Ramuzumab significantly prolonged median OS (8.5 vs 7.3, HR=0.71, P =0.0199) and median PFS (2.8 vs 1.6, HR=0.452) in advanced liver cancer at baseline with high AFP (≥ 400 ng/mL) compared with placebo.P < 0.0001), significantly prolonged median time to image progression (3.0 vs 1.6, HR=0.427, P < 0.0001), and higher DCR (59.9% vs 38.9%, P =0.0006).Based on this, IN 2019, FDA approved AFP≥400 ng/mL for second-line treatment of advanced liver cancer.Moved, for the first time in biomarker-driven drugs.It can be seen that compared with other targeted therapies for solid tumors, most of them are single-target drugs (precision attack and precision treatment), all the current approved targeted drugs for liver cancer are small-molecule multi-kinase inhibitors (excluding the anti-angiogenic drug of balm - ramuzumab).Why is that?1. Due to the heterogeneity of liver cancer itself, multi-target drugs may inhibit multi-pathway with better efficacy, but off-target toxicity may be greater;2. Liver cancer is the only solid tumor that can be diagnosed and treated only by imaging and clinical diagnosis, which means that tissue may not be available before treatment, let alone histochemistry and gene testing.Pathology, this is inconsistent with the concept of single target drugs, target can be used, but multi-target drugs do not involve this problem.Therefore, different tumor types of background is different, can not simply set the treatment model.For all approved first-line targeted drugs, ORR is no more than 20%, median OS is 9-14 months, and median PFS on imaging is 4-8 months.For all approved second-line targeted agents, ORR is no more than 15%, median OS is 8-11 months, and median PFS is 2-6 months.Later, these targeted drugs have hitched a ride on the immune drugs, play a big role.It also creates a new problem. All the targeted drugs currently approved, whether first-line or second-line, are based on the era of sorafenib: first-line drugs are compared head to head with sorafenib, and second-line drugs are treated with sorafenib or chemotherapy.When the first-line treatment pattern is overturned by Xinji Pharmaceutical, the back line evidence will no longer exist, and scientists have to explore the back line treatment step by step.When the tide goes out, who is still on the beach?Based on the results of two single-arm studies of Checkmate 040 and KeyNOTE-224, navurlizumab and Peberizumab were approved by FDA in 2017 and 2018 for second-line treatment of advanced liver cancer.Note that the earliest second-line targeted drug, Regofinib, was approved in 2017, mixed with navurliuzumab and paprizumab.This may partly explain the survival outcome of Keynote-224 over lumbar disc herniation (the patient was survived by regofinib after progression), but at the time this small stage II single-arm patient had the longest survival time ever for advanced liver cancer (12.9 months, before ramvaritinib was born).And that led to the overconfidence of the pharmaceutical companies, which led to the failure of the Phase III study Keynote-240, of course, failure is the mother of success, keynote-394 was adjusted in time and was successful.It is also fortunate that there is no standard second-line targeted drug before the two immunodrug studies begin, or they may have to go head to head. Not to mention the excellent effect, the cost and time consumption are huge.Of course, retrospectively, the OBJECTIVE response rate ORR of the two single-arm immunotherapies is really high, 15-20%, while the ORR of the second-line targeted drugs is less than 15%, and everyone has the same mPFS.We should know that immunotherapy is not dominant in the short-term effect of tumor reduction and PFS.There is no comparison between targeted drugs and immunodrugs. This is not the same root, so it is meaningless.Right person, right time, right medicine.Single exemption is willing to stop the second line?(median OS 16.4 vs 14.7, P =0.0752), after all, there will be so many first and second line targeted drugs approved in those years.But this at least tells us that immunotherapy should have a place in the first-line treatment.Combination therapy with immune checkpoint inhibitors 1. Navurliumab + ipilimumab:Checkmate 040 cohort 4 data showed that 50 subjects receiving 4 doses (1 mg/kg of Navurliumab + 3 mg/kg of ipilimumab, Q3W) followed by maintenance therapy with navurliumab (240 mg,Q2W) had good safety and ORR up to 32% (4 cases of CR,12 patients had PR, mDoR was 17.5 months, and DoR at 24 months was 31%.Based on this, the FDA obtained accelerated approval for second-line treatment of advanced liver cancer with sorafenib in 2020.After a follow-up of up to 44 months, 2021 ASCO GI updated the data set with a median OS of 22.2 months, an OS rate of 46% at 24 months, and an OS rate of 42% at 36 months. The ORR and DoR were consistent with previous results.2. Attilizumab + bevacizumab:Imbrove-150 pivotal clinical study showed that "A+T" significantly prolonged the median OS (NEvs 13.2, HR=0.58, P < 0.001) and the median PFS (6.8vs 4.3, HR=0.59,P < 0.001), the ORR of objective response rate was higher (27.3% vs 11.9%, p < 0.001, recist1.1).2021 ASCO update data showed that the median OS was as high as 19.2 months (vs sorafenib 13.4, HR=0.66).Based on this, FDA approved the first-line treatment indication for advanced liver cancer;At the same time, it is also the "gold standard" recommended by authoritative guides at home and abroad.Tremelimumab+durvalumab: HIMALAYA STRIDE combination This study has been repeatedly interpreted, without too much exposition, only put forward a little insight on the STRIDE combination.First, PD- (L) 1+CTLA-4 immunobinary star has been proved to be of clinical value in multiple tumor species. Further, O+Y showed good performance in the second line of liver cancer (ORR over 30%, DoR up to 17 months). Further, good results were shown in the "STRIDE" study of early liver cancer with the same type combination.Therefore, the STRIDE to first-line treatment for advanced liver cancer is reasonable (the mechanism is reasonable and the clinical evidence is solid).Second, although STRIDE is an immune binary star with classical mechanism, it innovatively explores the way of administration. A dose of high-dose CTLA-4 inhibitor combined with continuous PD-L1 inhibitor not only reduces the frequency of administration (conducive to compliance), but also may reduce economic toxicity (no need to pay continuously).Third, the efficacy data indeed cannot surpass "A+T", but the charm of the pure immune combination is that it is possible for some patients to achieve long survival. It can be seen that the STRIDE combination DoR is 22.34 months (vs 16.82 months for duvalisumab), which means that the efficacy of ORR patients is lasting.With longer follow-up, the OS KM curve may not fall downward.Fourth, bevacizumab may not be suitable for patients with high bleeding risk, severe proteinuria or uncontrolled hypertension, so STRIDE is a good supplement for this group of people.2. Other PD(L)-1+TKI: not to mention, the mechanism is similar to "A+T". Considering the small molecule multi-target targeted drugs, ORR will be much better.Advantages: oral administration, good compliance, strong tumor reduction, may be more suitable for conversion therapy.3. Other drugs: ADC, CAR-T, BiTE, Traditional Chinese medicine, etc.