Bob Underwood, M.D. (Host): Phase I clinical trials are the foundation for how we develop new cancer drugs. They are the first time an experimental drug is being tested on human beings. Welcome to the Cancerwise podcast from The University of Texas MD Anderson Cancer Center. Hi, I'm Dr. Bob Underwood, and in this episode, our guest today is the vice president, head of Clinical Development, Therapeutics Discovery Division, and professor, department of Investigational Cancer Therapeutics Phase I Program from The University of Texas MD Anderson Cancer Center, Dr. Timothy Yap. Dr. Yap, welcome, and thanks for being on the podcast today.

Timothy Yap, M.B.B.S, Ph.D.: Thanks very much, Dr. Underwood. Thanks for having me here.

Bob Underwood, M.D. (Host): You bet. So, there's some exciting research in the Phase I space around DNA damage repair being represented at the 2024 American Society of Clinical Oncology, or ASCO, annual meeting. Particularly two studies that you are going to be presenting. The first is Abstract 3005. Can you tell us about that study and why the findings are so significant? And for those not familiar, can you explain how the drug works and why it is so novel?

Timothy Yap, M.B.B.S., Ph.D.: Absolutely. Thanks very much for that question. So, DNA damage response, or DDR inhibition, is a very exciting area of cancer research. And with these new data being presented at ASCO, you know, we're beginning to gain insights into how we may begin to really build on the success of the first generation of PARP inhibitors with other DDR agents in combinations that may actually help to overcome drug resistance and ultimately enhance outcomes for all of our patients. The first study I will be presenting is a Phase I clinical trial of a first-in-class USP1 inhibitor RO7623066. USP1 actually stands for ubiquitin specific peptidase one and USP1 regulates the DNA translesion synthesis and Fanconi anemia repair pathways by removing ubiquitin from a variety of different substrates, such as PCNA, FANCI, FANCD2, so and so forth that are crucially involved in DNA damage response. And therefore, coming in with RO7623066, which is a novel first-in-class small molecule with excellent selectivity, it is felt to have anti-tumor activity. And in particular, USP1 inhibitor combination strategies are expected to synergize with and to overcome resistance to PARP inhibitors and other DDR agents in homologous recombination repair-deficient tumors such as those with BRCA1 mutations. And it's already been shown that RO7623066 has very strong synergistic activity with PARP inhibitors and also platinum chemotherapy in BRCA1-mutated, patient-derived xenograft models from preclinical testing. For example, the combination with olaparib in a lab leads to durable tumor control in PARP inhibitor-resistant, patient-derived xenograft models, therefore really supporting the combination of this USP1 inhibitor with the PARP inhibitor olaparib.Host: So, you kind of talked about how you use the models, is that what led you and other research to consider USP1 inhibitors as a potential treatment for patients who have advanced solid tumors with homologous recombination repair mutations?

Timothy Yap, M.B.B.S., Ph.D.: That’s correct. So, the models actually helped us in informing which patients we should actually be recruiting onto the study. So, during this particular trial, we mandated during the expansion cohorts that patients were required to have tumors with homologous recombination defects, for example, those patients with BRCA1 and BRCA2 mutations and other ones such as PALB2, RAD51C and D mutations as well. In the study, we actually allowed patients who had previously received platinum-based chemotherapy and also PARP inhibitors as well to try and provide that proof of concept that we could actually benefit patients who had already received the standard of care treatments.

Host: Yeah, absolutely. And I think you may have already answered this question: so, you’re using this in combination with olaparib or carboplatin. So, what was the full rationale behind picking these two drugs for combination studies?

Timothy Yap, M.B.B.S., Ph.D.: Well, it was really based on a strong preclinical rationale showing strong synergistic activity with both PARP inhibitors and also platinum-based chemotherapy, really showing durable tumor control, tumor regression and different patient-derived xenograft models, including breast cancer models, ovarian cancer models, so on and so forth. And also, in combination with platinum chemotherapy, it was shown the combination has actually shown to improve the durability of the anti-tumor response in platinum-sensitive triple negative breast cancer patient-derived xenograft models as well.

Host: Right. So, what other treatments do we currently have for patients with advanced solid tumors that are enriched for homologous recombination repair mutations? And how do these preliminary disease control rates compare to those of existing treatments?

Timothy Yap, M.B.B.S., Ph.D.: Yeah, so, currently PARP inhibitors are approved for patients who have BRCA-mutated cancers, and that includes tumor types such as ovarian, breast, pancreas and also prostate cancers. And they are approved in different settings, either in a maintenance setting and also in a relapse setting. So, what we're trying to do here is to really try and improve on the durability of the responses that we're already seeing with these approved PARP inhibitors. We currently have four approved drugs — rucaparib, talazoparib, olaparib, and niraparib —  that are approved in different settings and different tumor types. And so, the idea here with this clinical trial is to combine the USP1 inhibitor RO7623066 with the PARP inhibitor olaparib to see if we could actually observe, number one, safety and tolerability in patients with this combination. And most importantly as well, anti-tumor activity in patients, meaning either stability of disease or shrinkage of the disease, as well as tumor marker responses in these patients with these different alterations.

Host: So, since you mentioned it, you talked about tolerable dose, and my understanding is that maximum tolerable dose was not actually reached in any of the arms of the Part 1 escalation portion of the study. So, what does that mean for the next steps in Part 2, both for determining the recommended doses for expansion and for assessing the efficacy and safety of the combinations?

Timothy Yap, M.B.B.S., Ph.D.: Yeah, that's a great question. So, during the trial whilst we didn't observe or establish an MTD, you know, what we did see was anemia as one of the adverse events with this combination. Importantly, the anemia observed was reversible and manageable. There were no adverse events of anemia that were greater than grade 3, and none of these anemia events actually led to study treatment discontinuation, and only one of these actually led to a dose reduction with RO7623066. And, you know, we believe that a lot of this grade 3 anemia was probably driven through the exposure of olaparib rather than the USP1 inhibitor. And in fact, when we tested the USP1 inhibitor as a single agent, the rates of anemia were pretty low at about 5 percent of grade 3 or greater rates of anemia. So, the USP1 inhibitor by itself is very well tolerated, but we do see some increased anemia with the combination. So, what we're going to do in the upcoming cohorts with this combination is to really address the hematological toxicity by changing and altering the eligibility criteria to make them more in line with what we currently have for the olaparib label, meaning that we would mandate patients actually have a hemoglobin level of at least 10 grams per deciliter at baseline. And we believe that that will help in terms of minimizing the anemia that was observed with this particular combination.

Host: That’s awesome. Okay, so, let’s switch over to one of the other studies. So, let’s talk about the Abstract 301a. Can you start by summarizing the second study for us?

Timothy Yap, M.B.B.S., Ph.D.: Yeah, so, this second study is a novel dose-finding study of the ATR inhibitor tuvusertib, in combination with a PARP inhibitor that’s already approved called niraparib. So, this was a dose-finding Phase I clinical trial set out to really establish the optimal dose of both of these drugs in combination. What we found was that intermittent schedules of both drugs showed manageable safety profiles, and we actually were able to select two different regimens at the recommended dose for expansion cohorts that we're now analyzing. And so, we were able to establish two regimens, one at 90 milligrams once daily of tuvusertib in combination with 200 milligrams once daily of niraparib given on a one week on, one week off schedule. And the other regimen was tuvusertib at 180 milligrams QD in combination with niraparib at 100 milligrams once daily both given on a one week on, one week off schedule. And during this trial, we observed that myelosuppression, mainly anemia, was the most frequent side effect. There were no surprising or new safety signals observed. And overall, in terms of the pharmacokinetics, the exposures of both drugs, in combination, were very consistent with their respective monotherapy drug exposures, suggesting a lack of any mutual drug-drug interactions, which is a good thing. And importantly, we observed encouraging anti-tumor activity in very heavily pre-treated patients with an overall response rate of 19 percent and a molecular response rate of 47%. And in of interest, you know, the anti-tumor activity was especially pronounced in patients with ovarian cancer, where the overall response rate was 38%, molecular response rate at 60%, you know, despite 12 out of 13 patients having had prior PARP inhibitors. And so, currently, this combination is being explored further in patients who have PARP inhibitor-resistant ovarian cancer.

Host: Right. So, what led you to consider ATR and PARP inhibitors for patients with solid tumors?

Timothy Yap, M.B.B.S., Ph.D.: A great question. So, ATR and PARP protein kinases we know are critical and crucial components of the DNA damage response. And importantly, PARP inhibitors have shown synergism with ATR inhibitors both in vitro and also in vivo. And what we showed in preclinical models was that this combination of these two drugs, tuvusertib and also niraparib, showed greater anti-tumor activity than either drug alone. And we know that tuvusertib is a potent oral selective ATR inhibitor with a very manageable safety profile, and therefore combining the ATR inhibitor tuvusertib with the PARP inhibitor niraparib may actually result in what we call synthetic lethality and really triggering replication fork collapse, mitotic catastrophe, and really driving cancer cells to cell death. And that was really the reason for proceeding to this Phase I clinical trial of this particular combination.

Host: Right, and so, this study may not have shown the entire synergy that was actually expected or hoped for, so, how does that change the future thinking about this?

Timothy Yap, M.B.B.S., Ph.D.: Well, I think we did observe encouraging anti-tumor activity in a range of different cancer types in a very heavily pre-treated patient population. You know, despite all of that, across the board, across different cancer types, we saw an overall response rate of 19% and a molecular response rate of nearly 50%. And when we look specifically at patients with ovarian cancer who have heavily pre treated and a majority of them had already received a prior PARP inhibitor; the overall response rate was very promising at nearly 40 percent and the molecular response rate was 60 percent. And so what we're going to do now is to really do a deeper dive to explore this signal, this anti tumor signal of this combination in PARP inhibitor resistant patients who have advanced ovarian cancer.

Host: So, why was or how was epithelial ovarian cancer selected as the disease type for this combination study? And what's the rationale or expected benefit of continuing to give PARP inhibitor resistant patients PARP inhibitors in combination with other treatments?

Timothy Yap, MD, PhD: Great question. So, we do see that a good proportion of patients with ovarian cancer have BRCA there. So, they either have germline or somatic DDR alterations, particularly BRCA1 and BRCA2 mutations, also other alterations, including homologous recombination deficiency. And so, it's certainly a rational approach to treat patients with ovarian cancer where we already have PARP inhibitors approved in this particular tumor type. And a real challenge for us currently is what to do for patients in the post-PARP inhibitor setting. Once patients have developed resistance to a PARP inhibitor, what next? And what we have found is through this clinical trial and other similar studies, that the combination is synergistic. This combination can potentially overcome that resistance. And as evidenced in this particular trial, 12 out of the 13 patients with ovarian cancer had already progressed on prior PARP inhibitors. And despite that, we actually saw an overall response rate of nearly 40 percent and a molecular response rate of 60%. Obviously, these are small numbers, and that's the reason and rationale for why we're now exploring this combination in a much larger population of patients with PARP inhibitor-resistant ovarian cancer.

Host: All right, now let's move on the last one. You're the senior author on abstract 2507. Let's talk about that before we close out today.

Timothy Yap, M.B.B.S., Ph.D.: Yeah, so, this abstract really describes the Phase I trial called the DRAGON trial of a drug called SRK-181, which is a latent TGFβ1 inhibitor, where we combine that, that particular drug with pembrolizumab, the PD1 inhibitor. And in particular, we studied this in patients who had PD1 or PDL1 resistance in patients with advanced solid tumors. So, the whole rationale behind this is that we know that TGFβ1 actually drives tumor immune escape that enables tumor survival, and it's also a key driver of tumor resistance to immune checkpoint inhibitors, and is also present in multiple compartments of the tumor microenvironment. And so, coming in with SRK-181, which is a very selective anti-TGFβ1 antibody, it was really shown to overcome immune suppression and to also enhance tumor cell killing, and in particular, it targets latent TGFβ1, and it inhibits the growth factor before it actually gets activated. And importantly, from a safety perspective, it was highly selective to TGFβ1 versus TGFβ2 and 3, and that increases the therapeutic window, and it also helped to demonstrate an improved safety profile in our preclinical models, particularly the toxicology studies. And there was certainly no concerning toxicities, such as cardiac toxicities. But all of that provided the rationale to proceed to this particular trial where we first assessed SRK-181 as a single agent and then combined it with the PD1 inhibitor pembrolizumab. And in this particular combination presentation, we presented data on different cohorts of patients treated in the expansion cohorts and the expansion phase, including patients with clear cell renal cell cancer, head and neck squamous cell cancer and also advanced melanoma.

Host: Wow, so, what are the next steps to move this treatment forward?

Timothy Yap, M.B.B.S., Ph.D.: Yeah, so, what we saw in this particular trial was an overall response rate of about 23 percent in patients with clear cell renal cell cancer, 18 percent in head and neck squamous cell cancer, 27 percent in melanoma, including one complete response, and also saw a response rate of about 9.1 percent in other cancers as well, such as urothelial cancers. The plan now will be to move on into Phase II clinical trials of this particular combination in these selected tumor types.

Host: So, as we close out today, is there anything else you'd like to add about the upcoming ASCO meeting?

Timothy Yap, M.B.B.S., Ph.D.: No, thank you very much for your time and uh, thanks for having me on this podcast. Thank you very much.

Host: No, thanks for joining us. We've reached the end of this episode of the Cancerwise podcast from The University of Texas MD Anderson Cancer Center, and it really sounds like the 2024 ASCO meeting is going to have some great information presented. If you'd like more information, please visit MDAnderson.org/ASCO. That's MDAnderson.org/ASCO. Thank you, Dr. Yap, for being with us today. I'm your host, Dr. Bob Underwood.