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PD1/VEGF双抗随着康方数据爆出，PFS决定性胜出已是毫无争议的事实，对于OS还有很大不确定性，这是当下大多数人的疑虑。也是默沙东首席医学官质疑之处。Fierce做了相关的报道。

Ivonescimab与 Keytruda 相比，显著延长了肿瘤 PD-L1 表达阳性患者的无进展生存期 (PFS)。是本次引爆行业的关注热点。

默沙东首席医学官Eliav Barr 博士在 ASCO 2024 会议期间接受 Fierce Pharma 采访时表示：“这对患者来说是个好消息，或者可能是另一种 [治疗] 选择。”

“问题在于，”Eliav Barr继续说道，“已经有大量数据研究 VEGF 抑制剂在肺癌中的作用。而且我们已经对 [Keytruda] 的 VEGF 抑制进行了大量研究。在我们的许多研究中，PFS 呈阳性，包括肺癌。但 [总体生存率] 难以显示出优势。”

在针对一线 PD-L1 阳性 NSCLC 的 3 期 LEAP-007 临床试验中， Keytruda 和 Lenvima 联用，与 Keytruda单药相比，疾病进展或死亡风险显著降低了22%，但总体生存率下降了 10%。

但是在看待PD-L1低表达的患者的问题上，KEYNOTE-189/407临床试验中显示K药的治疗效果低表达差于高表达患者，Eliav Barr博士回答到：“他们（AK112）会（超过）吗？也许吧。我不知道。我们拭目以待。”这在一定程度上表示AK112在PD-L1低表达的情况下有超过K药的可能，当然还是要以数据说话。

与此同时，Tecentriq联用Bevacizumab在IMpower150临床试验中相比于Tecentriq单药也未展现出OS获益。

从目前的数据来看，无论PD1抗体联用VEGF抑制剂，还是PDL1抗体联用VEGF抑制剂在非基因驱动的非鳞状非小细胞肺癌，是无OS获益统计学意义。

AK112重点打的一张牌是鳞状非小细胞肺癌，因肺出血等VEGF抑制剂相关副作用，鳞状非小细胞肺癌成为VEGF抑制剂开发禁区。但从AK112的开发数据来看，AK112对于鳞癌和非鳞癌的安全性相当，并没有出现显著的差异。当然不排除筛选了入组条件。

同时再看OS获益程度，鳞状肺癌与非鳞状肺癌相比，获益明显，100多名患者参与的临床试验，可以进行初步参考。

贝伐珠在AVF0757g临床试验中，观察到初步疗效，然而在 13 名鳞状 NSCLC 患者中，有 4 例 (31%) 患有严重 PH（肺出血）。后续，又开展AVF3744g临床试验，选择没有PH基线风险因素的受试者，并推迟贝伐单抗用药时间，为经化疗后细胞恢复和上皮细胞愈合留出时间。但很不幸依然发生了一例3级肺出血事件，后来进展为4级肺出血，最后死于疾病进展。虽然发生一例，发生率较低，但是研究者认为样本也少，一旦样本加大也很难去避免这类情况的发生，这也致使鳞状非小细胞肺癌成为贝伐珠永远的禁区。

我们从以上两个临床来看，即便如何精选患者，依然有肺出血的可能，而从AK112的临床来看，这一副作用并未发生。当然还是要看其在美国临床的开发情况。不过，鳞状肺癌组咳血的情况还是稍重于非鳞癌组，SQ组任何级别咳血占9.5%（6/63），≥3级占1.6%（1/63），Non-SQ组任何级别咳血占4.2%（3/72），≥3级为0。后续临床仍需要继续观察。

AK112要想获得 FDA 在一线 NSCLC 治疗中的批准，很可能需要总体生存率的提高。毕竟有信达生物的前车之鉴，当然除了PFS以外，信达的另外一个点是不能反应美国人群。或者头对头进行非劣研究，这样也能够增加上市的可能性。

但从另一方面考虑，PD1/VEGF这样一个双抗，在一个PD1+ADC取代PD1+化疗的背景下，是一个可以去考虑的点。

从目前的数据来看，PD1+ADC已经取得不错的进展，但只要少数批准上市，如K药联合NECTIN4 ADC，大多数仍未上市，更未成为标准疗法，把PD1单抗替换成PD1/VEGF双抗，两者联用势必在未来大有前景。不可否认的是PD1/VEGF双抗，大多数情况下，PFS要优于PD1单抗。

在实际人群中，有一部分是VEGF抑制剂敏感人群，或者说VEGF抑制剂敏感肿瘤，而非PD1抑制剂敏感，其实在临床前的研究中也是如此，有些肿瘤是VEGF抑制剂敏感型，具有良好的抑瘤效果，而对PD1相应不佳。但相比于单纯的VEGF抑制剂，多了的PD1抗体能够对于系统性转移肿瘤有一定抑制效果。比如说结直肠癌，肝转移患者，从理论来看，用PD1/VEGF这样的双抗其实再合适不过。

在临床前的研究中，能够明确发现VEGF抗体能够增加T细胞的浸润效果。

如果未来仍旧是以免疫治疗为基础肿瘤治疗场景下，PD1/VEGF联用ADC可以替代PD1+化疗的现有治疗，从而从K药的地盘里分一杯羹。毫无疑问的是，目前AK112已在国内获批，当然以国内支付能力来说，目前的价格还是相当大的负担。

原报道：

On the eve of the American Society of Clinical Oncology’s annual meeting last week, a piece of news set off vigorous discussions. A bispecific antibody from China appears to have done the unthinkable: beating Merck & Co.’s PD-1 inhibitor Keytruda, the world’s best-selling medicine, in a head-to-head phase 3 trial in non-small cell lung cancer.  

The drug is ivonescimab, a PD-1 x VEGF bispecific developed by Chinese biotech Akeso and out-licensed to Summit Therapeutics in the U.S. in late 2022 in a deal worth up to $5 billion. The China-only trial, coded HARMONi-2, found that ivonescimab significantly extended patients' progression-free survival (PFS) time compared with Keytruda those whose tumors have positive PD-L1 expression, Summit said in release Thursday.

Before this result, no single drug had ever beaten Keytruda in a head-to-head phase 3 NSCLC trial.

Summit CEO Bob Duggan went as far as calling the readout “the beginning of a paradigm change” in the treatment of cancer in general. Analysts are doing their best to sort out the financial ramifications, and biopharma insiders are eager to see the exact data. But what does Merck think?

“Good news for patients or maybe another [treatment] option,” Eliav Barr, M.D., chief medical officer at Merck Research Laboratories, said in an interview with Fierce Pharma at the ASCO 2024 meeting.

“The issue,” Barr continued, is that “there’s been a lot of data looking at VEGF inhibitors in lung cancer. And we’ve done, God knows, a lot of studies of VEGF inhibition with [Keytruda]. In many of our studies, PFS was positive, including in lung. But [overall survival] was a little more difficult to show.”

“Patients, regulators, payers […] will focus on OS,” Barr continued. “So, we’ll see. It’s possible that this is going to be something interesting.”

Indeed, in the phase 3 LEAP-007 trial in first-line PD-L1-positive NSCLC, Merck and partner Eisai’s combination of Keytruda and Lenvima led to a statistically significant 22% reduction in the risk of disease progression or death but a negative 10% trend in overall survival compared with Keytruda alone. Lenvima is a kinase inhibitor targeting VEGF receptors and many other proteins involved in cancer.

As Barr indicated, an overall survival win would likely be needed for the Akeso/Summit drug to win an approval from the FDA in first-line NSCLC.

Trouncing Keytruda in its home turf would be a huge deal, considering the drug’s $25 billion in sales across numerous indications in 2023.

“I think everyone’s curious about what the Summit data is going to show—that’s so explosive a couple days ago,” P.K. Morrow, Takeda’s newly installed head of the oncology therapeutic area unit, said during an interview on the sidelines of ASCO 2024.

Keytruda won its FDA approval as a monotherapy to treat PD-L1-positive NSCLC in 2016. But Barr noted that most doctors today only use Keytruda monotherapy in PD-L1-high disease, where the single agent’s effect is bigger.

As for cases with a lower PD-L1 expression below a TPS score of 50%, Keytruda’s various combinations with chemotherapy represent the current practice. That means in those patients, an ivonescimab regimen will need to beat Keytruda and chemo.

“Will they? Maybe. I don’t know. We’ll have to see,” Barr said.

Meanwhile, it’s a common understanding in the oncology world that a China-only study such as HARMONi-2, or a trial conducted predominantly in one country outside the U.S., alone likely couldn’t support a U.S. filing, especially in a large indication such as NSCLC. The FDA’s oncology chief, Richard Pazdur, M.D., reiterated that position on the sidelines of the ASCO 2024 meeting.

When reviewing a clinical dataset, the FDA typically performs its analysis across different trial sites to look for differences and consistencies, Pazdur explained in response to a question about the ivonescimab readout during a Stat event Friday.

“This builds confidence in a system,” Pazdur said. “And when you’re bringing in data where we don’t have confidence, we need that confidence here.”

In addition, a trial conducted in China wouldn’t reflect the ethnic diversity of a U.S. population, the FDA official added.

Akeso’s HARMONi-2 readout might have benefited from its Chinese population, Jefferies analysts argued in a Friday note, pointing to past trial experiences where anti-VEGF treatments did better in Asian patients than for non-Asian populations.

According to Summit, ivonescimab’s PFS benefit was seen across patient subgroups, including in PD-L1-low, PD-L1 high, squamous, nonsquamous and high-risk patients. Detailed results will be shared at a future medical meeting.