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Pedro Barata: Hello, everyone. I'm Pedro Barata. I'm a GU oncologist at Case Western Reserve University in Cleveland, Ohio. I'm happy to be here today, joined by Dr. Wen Kong.

Dr. Kong is affiliated with the Department of Urology in Renji Hospital that's in Shanghai, China. Welcome, Dr. Kong.

Wen Kong: Thank you for having me here. It's a great honor for me to discuss with you guys. Thank you.

Pedro Barata: Of course. So thank you for taking the time to sit down with us. And the reason why we're here is hopefully we'll get an update for the today audience on a novel combination that you explore and present at ASCO GU on this combination of TKI lenvatinib that we know, along with a PD-1 inhibitor tislelizumab for first-line FH-deficient RCC.

So we all know that non-clear cell RCC is far less frequent. You look for FH mutations if you will. And it's an interesting study and interesting data with this kind of IO-TKI combination.

But perhaps I would suggest it's not everybody is aware of the design and the specifics of the data. So, Dr. Kong, would you be able to in kind to walk us through the data pretty quick with the highlights?

Wen Kong: Hello, everyone. I'm very happy to be here to share with you about our study, lenvatinib plus tislelizumab as the first-line therapy for the advanced fumarate hydratase-deficient renal cell carcinoma. Actually it's a very small study from our center.

We know that the FH-deficient RCC is a rare disease, but it's an aggressive malignancy with a dismal prognosis. And in the NCCN guideline, we have the bevacizumab plus erlotinib combination, actually. But this kind of combination actually is recommended for about 10 years. And during this time actually the landscape of the RCC treatment are dramatically changed for the adding of novel therapies.

So in 2023, we did a retrospective study across China from 15 centers in China. We found that for the FH-deficient RCC, the combination of TKI plus IO therapy actually showed comparable response rates with bevacizumab plus erlotinib. But the TKI plus IO combination showed better survival.

To clarify this, we designed this study. Actually, the study design is very simple. We planned to enroll 20 patients with pathologically confirmed FH-deficient RCC. They have the advanced unresectable or metastatic disease and have at least one measurable lesion according to the RECIST criteria and good performance status. So we give lenvatinib plus tislelizumab.

Actually, the treatment scheme is more or less similar with the KEYNOTE-B61 study. The only difference is we used the anti-PD-1 antibody from a Chinese company, which is tislelizumab.

So the primary endpoint is the ORR, and the secondary endpoints include PFS, OS, DOR, and safety.

As the time cutoff, we enrolled 20 patients. We can see here according to the IMDC risk classification, the majority of patients is classified as the intermediate or poor risk groups. And three quarters of the patients have the history of nephrectomy. And the median number of metastatic sites is three.

We can see actually the recurrence or metastasis is a little bit different from ccRCC patients. Most of the patients have recurrence in lymph nodes, and the next is bone metastasis and the retroperitoneal space or renal fossa recurrence.

And we know that for FH-deficient RCC, most patients are carrying the germline mutation. So we found that 75% of our patients were confirmed to carry the germline mutation of the FH gene, and 20% of the patients were confirmed to have the somatic biallelic alteration of the FH gene, and the remaining one patient was unevaluable.

So we can see our results of the efficacy as time cutoff. Right now in our 20 patients, 18 patients have the objective response, including four patients achieving complete response and 14 patients having partial response. The disease control rate is actually 100%, and the clinical benefit rate is 85%. We observed that it looks like the somatic mutation patients and the germline mutant patients both can benefit from the therapy.

And very interestingly, all the patients got some degree of tumor shrinkage as the treatment started. We did not observe the primary progression in our cohort. You can see from the spider curve here.

About the safety, most of the patients experienced adverse events. Grade ≥ 3 events actually occurred in 45% of patients. The lenvatinib dose reduction occurred in 45% of patients. And we had three patients developing immune-related adverse events and discontinuing the tislelizumab.

I have two cases here. We can show that there was a huge tumor in the right kidney with the IVC thrombus and enlarged lymph nodes and also pulmonary metastasis. As the treatment went on, we can see the metastasis in the bilateral lungs actually disappeared, and we see the dramatic shrinkage of the right kidney tumor and also the retroperitoneal lymph nodes.

And for this patient, we can see the lymph nodes shrinkage very dramatically as the treatment started. And this patient actually developed immune-related pneumonitis, and his treatment was discontinued for 3 and 1/2 months. But it's very interesting that at this point, after the treatment was discontinued for over three months, the patient actually achieved a CR. We did not find any lesion in his imaging. So it's very interesting.

So, in conclusion, we found that lenvatinib plus tislelizumab showed encouraging anti-tumor efficacy and an acceptable toxicity profile. The ORR actually is 90%, with 20% of patients achieving complete response. No primary progression was observed. All patients achieved disease control. And the adverse event profile is similar to previous reports.

TKI plus IO therapy might become a promising alternative option for the first-line treatment for advanced FH-deficient RCC. However, the follow-up duration of our study is limited. The data is immature, and the sample size actually is very small, and it's a single-center, single-arm design. Expanded validation is needed.

We also have some very interesting exploratory endpoints which we didn't show in this ASCO GU meeting. Maybe we can show those results in the future. Thank you.

Pedro Barata: Thank you, Dr. Kong. This is super helpful data. And it's quite impressive to see very high response rates, no progressive disease as best response. It's a relatively small cohort, as you mentioned, 20 patients with FH-mutated RCC, most with hereditary leiomyomatosis. But it's still quite remarkable to get those patients in a year time frame.

Wen Kong: Yeah.

Pedro Barata: So can you please tell us a little bit about how did you get so many patients? And how is the testing being done, genetic testing being done in China, in Shanghai?

Wen Kong: Actually, the incidence of this disease is extremely low, about one patient per about 2 million people. But in China, there are a lot of social media. And there are a lot of patient groups. They can spread the information from patient to patient.

So when we initiate this study, patient A got this new information and then will tell B, and then the information just spread very quickly. China actually we have a very large population. Any kind of rare disease in China, if you can use a lot of work to find the patient, you can find a lot of patients.

Pedro Barata: That's very interesting.

Wen Kong: Yeah.

Pedro Barata: What about genetic testing?

Wen Kong: Actually, the genetic testing is very popular for cancer patients right now in China. So a lot of the patients, if they are diagnosed as this kind of very rare disease, the physician will recommend them to undergo genetic testing. And they get the results, oh, they say, I have FH-deficient RCC.

So they will Google. And actually in China it's Baidu. They will do a lot of work on the internet. And they find, oh, in Renji Hospital, there are a group of doctors who did a lot of work in this disease. So they will come to us with the report.

Pedro Barata: I see. Well, that's very good to know and an amazing job getting these patients in such a short period of time. So, Dr. Kong, I agree with you. I mean, this combination of lenvatinib at 20 milligrams, which is similar to what we see here in the US when we use pembrolizumab—actually it's the same dose—and for tislelizumab it's 200 milligrams, comparable to pembro.

And at least here in the US, when we had data for non-clear cell with lenvatinib and pembrolizumab, which Laurence Albiges was the first author on, the guidelines did include this combination and expanded that we have an expansion of the label for non-clear cell. So in other words, for patients with non-clear cell subtype, including hereditary leiomyomatosis, they can get access to an IO-TKI combination.

Tell me a little bit about data like this, the one you just developed. If it continues to be positive with longer follow-up, as you said, does it happen in a similar way in China? Meaning, do you have a similar regulatory structure where you can have the combination of lenvatinib and tislelizumab available there, and then patients can start getting treated? How does that work?

Wen Kong: Actually, the situation in China is quite different from the US. From last month, we have the first anti-PD-1 antibody approved by the Chinese FDA to be used in RCC patients, just starting from this year.

So in the past, we had to talk a lot with the patient about how to choose treatments, because all these immune therapies in China for RCC patients in the past years were not approved by the FDA, and actually were off-label uses, and then could not be covered by insurance. So it's quite different.

Pedro Barata: I see. So obviously data like this might help. Great. So, Dr. Kong, I'm assuming—I actually have a question because I agree with you. With a median follow-up of seven months, it gives you a good preliminary efficacy signal. No PDs as best response is quite impressive.

And so I'm interested, and I think a lot of us will be interested, to look at the median progression-free survival with longer follow-up, and maybe overall survival. As you said, you're going to prepare to get updated data with a new data cut. If you've seen this continues to be the case, meaning most patients continue to be on or off treatment without progression, of course we're looking forward to see the manuscript as well and the updated analysis, perhaps with longer follow-up.

Wen Kong: Yeah. We'll keep following these patients. Right now we have four patients actually who got PD, including one patient who died of disease progression.

Pedro Barata: I see. And I guess one last question, Dr. Kong, before I let you go. You are absolutely right, the data from the NCI on bevacizumab erlotinib was very compelling. For these patients who got an IO-TKI up front, is that what you're recommending in second line if they progress? Or how is the management for patients with hereditary leiomyomatosis progressing on IO-TKI? What are you all recommending as second-line strategy? Is that bevacizumab plus erlotinib? Or is there TKI monotherapy? How are you approaching those patients who progress?

Wen Kong: So your question is when the patient got progression after the TKI plus IO therapy, what do we recommend, right? It's very interesting, and it's reality. It's a challenge we face right now. From my own point, I will suggest patients to take bevacizumab plus erlotinib as the second-line therapy. But from my own experience for the second-line treatments, the bevacizumab plus erlotinib only gave the patients half to one year of PFS. That is my own experience.

So right now actually, a lot of patients face the challenge to choose the third-line or the fourth-line treatments. So that is what we are working on. Actually we are working on some novel therapy for this disease. Maybe we can show the results in ASCO or ESMO in the next two or three years.

Pedro Barata: Well, that sounds exciting. That's awesome. Happy to hear. We do need novel therapeutics in RCC, particularly non-clear cell, right, as you said. So this is fantastic, Dr. Kong—super helpful.

Congratulations on a fantastic presentation. We're looking forward to seeing the updated results, and hopefully the manuscript as well. I'm sure it will come. And congratulations on the good job.

Wen Kong: Thank you.