2022 GI ASCO

2022年胃肠道美国临床肿瘤学会（GI ASCO）会议上个月结束，来自世界各地的研究人员聚集在一起，讨论胃肠道癌症的最新研究进展。我们请我们的临床试验冠军Maia和Manju解读2022年GI ASCO的一些最相关的研究，以帮助我们的社区了解进展和研究的方向。

如果你还没有见过Maia或Manju -- 你可以了解更多关于他们的信息 这里!

Here are the studies that Maia and Manju are most excited about from 2022 GI ASCO

马亚。

从2022年GI ASCO开始，首先是Ib/II期试验的 寰宇天下b (PCM-075，PLK1抑制剂)联合使用 FOLFIRI + 贝伐珠单抗 在二线治疗的 KRAS突变的 转移性结肠直肠癌（mCRC）。在对具有不同KRAS突变的mCRC患者进行二线治疗时，onvansertib和FOLFIRI-bev的组合具有良好的耐受性。有低级别的治疗突发不良事件，这些不良事件是可以容忍的，它显示了超过30%的总反应率（ORR）和超过9个月的无进展生存期，令人欣喜。研究显示，血浆中突变的KRAS存在的早期下降（即刚刚在第一个治疗周期后）与反应相关。这意味着它可能是未来探索的一个可行的生物标志物。(摘要 #100 审判 NCT03829410) 

In the trial, ongoing at the University of Colorado, five patients achieved a partial response, 24 patients reached stable disease, and 29 patients derived a clinical benefit at the first re-staging at two months. In the poster presented during the meeting, the authors concluded: “Toxicity from these three approved drugs is well-established and observed toxicity in this trial was as expected,” […]  “The combination…has promising activity in treatment-refractory mCRC with some patients achieving deep and durable responses and a majority of patients deriving clinical benefit at time of first disease re-staging.” (Abstract #118 审判 NCT03475004)

有几项临床试验将免疫疗法与已批准的、标准的mCRC疗法相结合，但没有取得良好的效果。虽然结果令人失望，但它们向我们展示了什么是无效的，或部分有效的，这是朝正确方向迈出的一步：有了更准确的信息，病人和医生就能更好地决定哪些治疗方法值得追求。作为倡导者，我们对所有结果的分享表示感谢!

其中一项试验是关于 "Melissa "的I/II期研究。 瑞戈非尼 (rego)和 pembrolizumab (pembro）治疗难治性微卫星稳定型（MSS）CRC。它没有达到II期的主要终点：无进展生存期（PFS）的明显改善。中位PFS为2.0个月，没有达到预设的2.85个月的PFS。中位总生存期（OS）为9.6个月。最常见的不良事件只是试验中使用的药物以及这些药物的剂量所产生的通常/典型的不良事件。鉴于其负面的结果，研究人员分析了超出试验设计中计划的数据（事后分析）：分析显示，没有肝转移的患者和之前接受过放疗的患者获得了更长的PFS。更多的研究将寻找生物标志物/特定的特征，以确定可能从这些治疗中受益的患者亚组。(摘要 #15 审判 NCT03657641) 

另一项没有达到预期的试验是 nivolumab 加 mFOLFOX6 和 贝瓦西单抗 用于mCRC的一线治疗。研究人员分享了这项II/III期临床试验CheckMate 9X8的结果，该试验调查了将免疫疗法nivolumab（Opdivo）加入mCRC一线标准护理（mFOLFOX6和贝伐珠单抗）的情况。与单独的SOC相比，该组合在PFS方面没有表现出统计学上的明显改善。即使没有达到PFS的主要终点，在一线治疗中，nivolumab + SOC显示了12个月后更高的PFS率，更高的反应率，以及与SOC相比更持久的反应，同时也有可接受的安全性。这表明，需要进一步研究，以确定在一线治疗中可能受益于该组合的mCRC亚组的患者特征。(摘要 #8 审判 NCT03414983)

曼珠。

一项惊人的、可能改变实践的研究，在局部晚期错配修复缺陷的实体瘤受试者中诱导PD-1阻断，其直肠癌的完全临床反应率为100%。(试验 NCT04165772)

这是2022年GI ASCO最令人兴奋的结果之一。早期或局部晚期（II期或III期）MSI-H直肠癌约占所有直肠癌的5%-10%。MSI-H型直肠癌的很大一部分是由林奇综合征患者构成的，他们可能相当年轻。目前，所有局部晚期直肠癌患者都得到化疗-RT、化疗和手术的综合治疗。对于MSS直肠癌患者来说，这种积极的治疗对治愈他们的癌症相当有效，但许多患者会因为放疗、化疗和手术而留下长期的、改变生活的副作用。患有MSI-H型直肠癌的患者可能对含有5FU的化疗反应不大。研究表明，免疫疗法对晚期（转移性）MSI-H型结肠直肠癌效果良好。

An amazing and potentially practice-changing study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Solid Tumors ha respond as well to 5FU containing chemotherapy. Studies have shown that immunotherapy works well in advanced (metastatic) MSI-H colorectal cancer. 

纪念斯隆-凯特琳癌症中心进行的这项小规模II期研究的想法是，看看免疫疗法在早期疾病中的效果如何，并使用它来代替化疗，治疗局部晚期MSI-H直肠癌患者。 Patients with a complete response to immunotherapy alone would have the option of omitting radiation and surgery and thus be spared side effects from both. In the study, patients with locally advanced deficient mismatch repair (dMMR) or MSI-H rectal cancer (stage II and stage III rectal cancer) were treated with a single agent PD-1 inhibitor, dostarlimab, for six months. Response was assessed at the end of treatment with PD-1 inhibitor. If the patients had a clinical complete response, they could undergo observation and forgo radiation and surgery. If they did not have a complete response, they would receive standard chemo-RT and then be evaluated again to potentially avoid surgery. 

会上介绍了对PD-1抑制剂的反应率。到目前为止，有16名患者入选，其中11人完成了6个月的PD-1抑制剂治疗。 所有11名患者都表现出完全的临床反应，因此不需要化疗或手术，目前正在进行观察跟踪。这些结果提示了一种治疗MSI-H型局部晚期直肠癌的新方法，单用PD-1抑制剂治疗可能有助于避免化疗-RT和手术，以及相关的长期副作用。 Further patient accrual is ongoing, and this trial is certainly on my list to watch closely. (Abstract #16)

恩科拉非尼、西妥昔单抗和尼沃鲁单抗治疗微卫星稳定、BRAFV600E突变的不可切除或转移性结直肠癌患者的I/II期试验也取得了令人鼓舞和期待的结果。(试验 NCT04017650)

Though the Beacon doublet (encorafenib+cetuximab, E+C) is a much welcome new treatment for MSS BRAF V600E mutated metastatic CRC, the response time is not as long as patients would like it to be. This E+C+N trial tests if targeting BRAF, EGFR, and PD-1 simultaneously, could result in more efficacy/ better treatment. In this single arm study done at MD Anderson Cancer Center as a phase I/II trial, MSS mCRC patients with tumors having a BRAFV600E mutation who have progressed on one or two previous lines of therapy, but have not yet had BRAF, EGFR or MEK inhibitor or immunotherapy, were enrolled. The trial looked at the best overall response and safety/tolerability of the combination. 

There were also promising and much awaited results for the phase I/II trial of Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRre efficacy/ better treatment. In this single arm study done at MD Anderson Cancer Center as a phase I/II trial, MSS mCRC patients with tumors having a BRAFV600E mutation who have progressed on one or two previous lines of therapy, but have not yet had BRAF, EGFR or MEK inhibitor or immunotherapy, were enrolled. The trial looked at the best overall response and safety/tolerability of the combination. 

So far, 26 patients have been enrolled, of which 22 were evaluable for response. No dose-limiting toxicities were seen, but grade 3-4 treatment-related adverse events occurred in four out of 22 patients, and a headache was the most commonly reported treatment-related side effect in all patients who had any side effects. 总反应率为50%（22人中有11人），疾病控制率为96%，中位PFS为7.4个月，中位OS为15.1个月，中位反应持续时间为7.7个月，这对于这部分生存不佳的患者来说是非常有希望的治疗组合。 Of the 11 patients who continue to remain on the study, two patients are now at 100 weeks of treatment. The follow-up randomized Phase II SWOG 2107 trial is coming soon where 75 patients will be randomized 2:1 to E+C+N vs. E+C. (Abstract #12)