The first-in-class p53 Y220C reactivator rezatapopt (formerly PC14586) has the potential to turn the

 Y220C mutation, which had previously been termed undruggable, into a tumor-agnostic target for patients with advanced solid tumors. The agent is currently under evaluation in the phase 1/2 PYNNACLE study (NCT04585750).

“p53 has a variety of different hotspot mutations that cause a loss of function, it’s a tumor suppressor gene,” Tom Karasic, MD, explained in an interview with 

. “Y220C is found in [approximately] 1% of all cancers and it’s more common in ovarian cancer, [occurring in approximately] 3% [of patients]. It’s important not because it is any different in terms of its usual cancer behavior, but because it can be targeted [with a] small molecule inhibitor. Targeting it and reactivating it provides p53 function again; it generally loses function and that leads to growth or proliferation of the cancer.”

Karasic is the director of the Developmental Therapeutics Program at Abramson Cancer Center, as well as an assistant professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania, in Philadelphia.

Rezatapopt is an orally available small molecule that is designed to bind selectively to the pocket within the 

 Y220C mutant protein. In preclinical study, rezatapopt has shown the ability to inhibit tumor proliferation across all Y220C-expressing cell lines. Notably, increased sensitivity to the agent has been correlated with the absence of a 

“This is the first time that we’ve been able to inhibit a particular 

-mutant allele,” Aparna Parikh, MD, an oncologist at Massachusetts General Hospital in Boston, Massachusetts, said in a separate interview with 

. “There have been a lot of different approaches that have tried to indirectly target p53, [such as] MDM2 inhibitors. [Rezatapopt] binds to a pocket that is only [present] in the 

 Y220C alteration. It stabilizes [the protein] in the wild type, not the mutant form, and by keeping it in the wild-type conformation [the agent] restores p53 activity.”

PYNNACLE is an open-label, multicenter study that is examining the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of rezatapopt in patients with locally advanced or metastatic solid tumors harboring with a 

 Y220C mutation. To be eligible for the trial, patients must be at least 18 years old, or 12 to 17 years old with safety review committee approval, have an ECOG performance status of 1 or less, have experienced disease progression following 1 prior line of therapy, have adequate organ function, and measurable disease per RECIST v1.1. There will also be a phase 1b cohort that will receive the agent in combination with pembrolizumab (Keytruda); patients in this group need to be anti–PD-1/PD-L1 inhibitor naive or have experienced disease progression on treatment.

During phase 1, rezatapopt will be administered orally at multiple dose levels given daily to establish the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) and pembrolizumab will be given intravenously every 3 weeks at a dose of 200 mg in the combination group. Phase 2 will include ovarian cancer, lung cancer, breast cancer, endometrial cancer, and other solid tumors cohorts who will all be treated with daily oral rezatapopt at the RP2D.

The coprimary end points in phase 1 are safety, establishing the RP2D and the MTD of rezatapopt, both as monotherapy and a combination component; the primary end point in phase 2 is overall response rate (ORR) per RECIST v1.1 by independent review. Secondary end points include pharmacokinetics, disease control rate, progression-free survival, overall survival, and duration of response (DOR).

“As the study moves into phase 2, there are more and more sites that are open that hopefully are closer to patients than when [the trial] was only in phase 1,” Karasic noted. “The bigger challenge is making sure that clinicians are aware that this is a targetable alteration. As data have emerged, it hasn’t necessarily made it to everyone. We think of p53 as something that can sometimes [indicate] a poor prognosis, but [not as something that is] necessarily targetable. Having clinicians recognize that this specific mutation is targetable is important.”

Rezatapopt Displays Early Signals of Efficacy, Tolerability

During the 2023 AACR-NCI-EORTC International Congress on Molecular Targets and Cancer Therapeutics, investigators presented updated findings from the phase 1 portion of PYNNACLE. The results included 67 patients treated with rezatapopt monotherapy in the efficacious dose range of 1150 mg daily to 1500 mg twice daily. The median age was 63 years (range, 32-84); most patients were White (76%), had an ECOG performance status of 1 (67%), had received at least 3 prior therapies (55%), and were 

 wild type (75%). The update included data from patients with ovarian (n = 22), pancreatic (n = 12), breast (n = 9), colon (n = 5), prostate (n = 6), head and neck (n = 2), small cell lung (n = 2), endometrial (n = 1), and other (n = 8) cancers.

At the September 5, 2023, data cutoff, efficacy-evaluable patients who were treated at a dose of 1150 mg daily to 1500 mg twice daily (n = 38) achieved an ORR of 34%. The ORRs among patients with ovarian (n = 7), breast (n = 3), small cell lung (n = 1), endometrial (n = 1), and other (n = 1) cancers were 47%, 38%, 50%, 100%, and 8%, respectively.

Efficacy-evaluable patients treated at the 2000-mg daily dose level achieved an ORR of 38%. The ORRs among patients with ovarian (n = 2), breast (n = 2), endometrial (n = 1), and other (n = 1) cancers were 40%, 67%, 100%, and 17%, respectively.

In terms of safety, treatment-related adverse effects (TRAEs) were mostly grade 1 or 2 in severity, with the most common any-grade TRAEs being nausea (50.7%), vomiting (43.3%), and increased blood creatine (26.9%). Investigators noted that administering rezatapopt with food improved the gastrointestinal toxicities that were observed. Only 1 patient experienced a grade 4 TRAE and 3% of patients were forced to discontinue treatment due to a TRAE.

Study authors concluded that rezatapopt monotherapy displayed a favorable safety profile and displayed clinical efficacy across multiple tumor types. The RP2D was determined to be 2000 mg daily.

“The numbers are relatively small, as they often are in these studies, but certainly [rezatapopt] has notable activity in patients with generally refractory cancers and limited treatment options,” Karasic said. “The ongoing phase 2 expansion of the study will help clarify what the expected response rate is and will [help us] gain additional information about what diseases and what genetic phenotypes it [is effective] in. It seems to have enough activity that it seems likely to become an available agent for patients.”

In March 2024, during the SGO Annual Meeting on Women’s Cancer, a phase 1 analysis from PYNNACLE was presented which encompassed a subgroup of patients with advanced ovarian cancer harboring a 

 Y220C mutation. The analysis consisted of efficacy and safety findings from 22 patients with a median age of 66 years (range, 49-81). Most patients included in the analysis were White (68%), had an ECOG performance status of 1 (73%), were platinum resistant (86%), had high-grade serous histology (91%), had measurable disease at baseline (91%), and did not have germline 

mutations (59%). The median number of prior lines of therapy was 4 (range, 1-9) with most patients receiving at least 3 (64%); all patients were negative for germline 

Among 15 efficacy-evaluable patients treated with rezatapopt across the efficacious dose range, 7 patients achieved a partial response (PR). Seven patients experienced stable disease and 1 patient had disease progression. Additionally, 5 patients with a radiographic PR and 1 patient with stable disease achieved a CA-125 response. The median DOR was 7 months and treatment was ongoing in 4 patients at the data cutoff.

Later in March 2024, PMV Pharmaceuticals, Inc. announced that the first patient had been dosed in the phase 2 portion of PYNNACLE.

“If [the findings in phase 2] are promising, as what we saw with the initial dose escalation, I am optimistic around a path of approval––whether that’s an accelerated approval based on phase 2 will be a conversation with the FDA,” Parikh said in conclusion. “[There have been] certainly encouraging results to date and I am optimistic to potentially have another option for these Y220C patients. Hopefully it opens the door for other p53-targeting strategies that are being explored.”

The evaluation of PC14586 in patients with advanced solid tumors harboring a TP53 Y220C mutation (PYNNACLE). ClinicalTrials.gov. Updated July 3, 2024. Accessed July 17, 2024. https://clinicaltrials.gov/study/NCT04585750

KOL webinar for phase 1/2 PYNNACLE study of PC14586 from the 2023 AACR-NCI-EORTC International Conference. PMV Pharma. October 12, 2023. Accessed July 17, 2024. bit.ly/4bMNtb9

Schram AM, Shapiro GI, Johnson ML, et al. Updated phase 1 results from the PYNNACLE phase 1/2 study of PC14586, a selective p53 reactivator, in patients with advanced solid tumors harboring a 

. 2023;22(suppl 12):LBA_A25. doi:10.1158/1535-7163.TARG-23-LB_A25

Schram AM, Shapiro GI, Thompson JA, et al. Phase 1 analysis from the PYNNACLE phase 1/2 study of PC14586 in the subgroup of patients with advanced ovarian cancer harboring a 

Y220C mutation. Presented at: 2024 SGO Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.

PMV Pharmaceuticals announces first patient dosed in global tumor-agnostic phase 2 PYNNACLE trial for rezatapopt in TP53 Y220C-positive solid tumors. News release. PMV Pharmaceuticals, Inc. March 27, 2024. Accessed July 18, 2024.bit.ly/3WuPowJ

Articles

Rezatapopt has displayed early signals of efficacy and tolerability in p53 Y220C-mutated solid tumors.

Rezatapopt Takes Aim at Previously Untargetable p53 Allele to Treat Advanced Solid Tumors

! I’m your host today, Courtney Flaherty.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, sponsored by PMV Pharmaceuticals, we had the pleasure of speaking with Shivaani Kummar, MBBS, FACP, about the ongoing investigation of the first-in-class p53 reactivator rezatapopt (PC14586) for patients with 

 Y220C–mutated advanced solid tumors. Dr Kummar is the Margaret and Lester DeArmond Endowed Chair of Cancer Research, professor, and division head in the Division of Hematology/Medical Oncology at the Oregon Health & Science University School of Medicine in Portland. She is also the codirector of the Center for Experimental Therapeutics and the co-deputy director of the Knight Cancer Institute.

The development of tumor-agnostic agents, such as rezatapopt, is revolutionizing cancer treatment by focusing on specific molecular targets across different tumor types rather than histologic classification. Rezatapopt has activity in advanced solid tumors harboring this mutation, particularly ovarian, breast, lung, and endometrial cancers, with notable response rates and manageable adverse effects.

Updated results from the phase 1/2 PYNNACLE trial (NCT04585750) revealed a 38% confirmed overall response rate (ORR) with rezatapopt monotherapy administered at the recommended phase 2 dose (RP2D) of 2000 mg daily in patients with 

 wild-type tumors (n = 16). Within the ovarian cancer cohort, partial responses were achieved by 7 of the 15 patients with measurable disease at baseline, and 7 patients achieved stable disease. These early data support further investigation of rezatapopt in the phase 2 segment of the trial, which is currently assessing the efficacy of rezatapopt at the RP2D across various cohorts of patients with 

In our exclusive interview, Dr Kummar discussed the significance of targeting 

 Y220C in solid tumors, early efficacy and safety data reported with rezatapopt in 

 Y220C–mutant solid tumors, and directions for future development of TP53-directed drugs both alone and in combination regimens.

That’s all we have for today! Thank you for listening to this episode of 

, sponsored by PMV Pharmaceuticals. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

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Dr Kummar discusses the significance of targeting TP53 Y220C in solid tumors and early data reported with rezatapopt in TP53 Y220C–mutant solid tumors.

Kummar on the Investigation of Rezatapopt in TP53 Y220C–Mutated Advanced Solid Tumors

Phase 1 data with rezatapopt (PC14586) in patients with 

 Y220C–mutated advanced solid tumors have demonstrated early signals of clinical efficacy with this agent and support the continued investigation of rezatapopt in this patient population, according to Shivaani Kummar, MBBS, FACP.

“TP53 is a tumor suppressor gene and mutations in TP53 that result in p53 inactivation have been contribute to oncogenesis. Rezatapopt is a first-in-class p53 reactivator that binds to the pocket created by the 

 Y220C mutation, restoring p53 function,” Kummar said in an interview with 

®. “That’s the rationale behind testing [this agent] in patients with advanced solid tumors that carry this mutation in the 

The phase 1/2 PYNNACLE trial (NCT04585750) is investigating rezatapopt in patients with 

 Y220C–mutated advanced solid tumors.1 The primary end point of the phase 1 portion of the trial was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of rezatapopt monotherapy. Updated phase 1 findings demonstrated that the agent elicited a 38% confirmed overall response rate (ORR) when administered at the RP2D of 2000 mg daily in patients with 

 Additionally, findings from the PYNNACLE ovarian cancer patient cohort showed that of the 15 patients with baseline measurable disease, 7 patients achieved a partial response (PR) and 7 patients had stable disease (SD).

The ongoing phase 2 portion of the trial is evaluating the efficacy of rezatapopt at the RP2D across cohorts of patients with 

 wild-type solid tumors, including a cohort of patients with ovarian cancer.

In the interview, Kummar discussed the mechanism of action of rezatapopt; early efficacy data observed with this agent across solid tumors, including in patients with ovarian cancer; and potential next steps for the future evaluation of TP53-directed drugs in solid tumors.

Kummar is the Margaret and Lester DeArmond Endowed Chair of Cancer Research, professor and division head in the Division of Hematology/Medical Oncology at the Oregon Health & Science University School of Medicine in Portland, where she is also the codirector of the Center for Experimental Therapeutics and the co-deputy director of the Knight Cancer Institute.

: What is the value of investigating tumor-agnostic agents across solid tumors?

: The reason we are approaching cancer not just with the traditional histology-based classification, but more based on the presence of a target, is because now we understand specific molecular targets can be present across histologic types and we can design drugs against these targets. We are trying to evaluate whether [directing agents at targets that are present] across [tumor types] will result in clinical benefit for patients. Clinical trial designs now include basket trials where we enroll patients with tumors carrying the molecular target of interest and evaluate a therapeutic agent.

 Y220C in solid tumors, and what is known about its mechanism of action?

 is a tumor suppressor gene. Mutations within this gene lead to inactivation of p53, which has been demonstrated to be a key step in oncogenesis. 

 Y220C is a hotspot mutation found in approximately 1% of solid tumors. In ovarian cancer, it has the highest incidence. In approximately 2.9% of tested [ovarian cancer] samples, we demonstrated the presence of this mutation.

 Y220C mutation is present, it destabilizes the p53 protein, leading to its inactivation. Rezatapopt is a first-in-class p53 reactivator that has been designed to specifically bind to the pocket that’s created when 

 gene. This binding results in restoration of p53 activity, at least based on preclinical data.

In what advanced solid tumors has rezatapopt begun to show activity?

Data from the [PYNNACLE] trial were reported at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Data from the first 67 patients who were evaluable for safety and the first 51 patients who were evaluable for efficacy were reported. Of these patients, in the subset that had the 

 Y220C mutation but did not have a mutation in 

[n = 38], there were a total of 13 confirmed responses, [translating to] an ORR of 34%. This ORR was observed across multiple tumor types, such as ovarian cancer, breast cancer, small cell lung cancer, and endometrial cancer.

As we went through the dose-escalation [portion of the trial], we established the [rezatapopt] dose of 2000 mg a day [as the RP2D], which is [the dose level of the drug that the ongoing] phase 2 part of the trial [is investigating]. [In the] patients who were treated at this dose in the dose-escalation portion of the trial who had a 

In just the patients with ovarian cancer, data were reported at the 

. Of the 15 patients with measurable disease at baseline who had at least 1 post-baseline tumor assessment, 7 patients achieved a confirmed PR, and an additional 7 patients had SD. The median duration of response was 7 months.

We are seeing encouraging activity in the phase 1 portion of the study. As proof-of-mechanism and proof-of-concept, reduction in the variant allele frequency was observed, especially in responders. Now, we are excited about the phase 2 portion, which is adding more patients at this RP2D, to see whether we can continue to find patients who derive clinical benefit from this agent.

What is the safety profile of rezatapopt?

Some of the most common [adverse effects (AEs) associated with rezatapopt] have been nausea and gastrointestinal [GI] toxicities. We found as the trial progressed that if we administer rezatapopt following food, we can reduce the associated GI AEs. The administration of food before patients take the agent has helped with that AE profile.

We have seen elevations in creatinine levels in certain patients, and there have been some increases in liver enzymes. Overall, rezatapopt has been well tolerated, and some of the AEs have been managed by dose modifications. There has been a low rate of drug discontinuation due to treatment-related AEs, [at 3%].

What are the next steps for evaluating rezatapopt in patients with solid tumors? Will combination regimens using this agent be investigated?

[Next steps] depend on what we see in the phase 2 part of the trial. The phase 1b component of the trial evaluated [rezatapopt in combination with] immunotherapy. Those data are still in evolution, and we’ll find out more as we get experience [with rezatapopt]. However, in general, the response rates and promising activity we’re seeing are with rezatapopt as monotherapy. The phase 2 component is what I’m excited about to see whether we can induce durable clinical responses with an oral agent that is relatively well tolerated for this patient population.

What other TP53-targeted agents are in development for patients with solid tumors?

[Rezatapopt] is the first-in-class agent that is the furthest along [in development]. There are ongoing efforts to target other mutations in p53. There are multiple mutations that have different consequences, but most of them lead to increased oncogenesis. Targeting those [will] be important, but we need to develop specific agents that are designed to target those specific mutations, such as [rezatapopt] for 

 Y220C mutations. I’m excited to see those ongoing efforts come into the clinical space.

What is your main message for community and academic colleagues based on this research with rezatapopt?

There are different levels of excitement. I’ve been doing drug development for over 20 years. I find that at this point, we are at one of the most exciting times in this field, as we can now design molecules against molecular targets within cancer cells, and we have a slew of different types of agents that target the tumor microenvironment and immune cells.

However, the old paradigm of [conducting] phase 1 trials just for safety and finding a dose is no longer completely true. We do find the dose and look for safety for these new drugs [in phase 1 trials]. However, we are seeing response rates and clinical benefits more often when we can develop drugs such as rezatapopt. Considering clinical trials for patients earlier on in their treatment for metastatic cancers, as well as educating patients along the way about participation in clinical trials, even in the neoadjuvant and adjuvant settings, will help deliver good care to individual patients and move the needle as we try to expedite anticancer drug development.

The evaluation of PC14586 in patients with advanced solid tumors harboring a TP53 Y220C mutation (PYNNACLE). ClinicalTrials.gov. Updated February 9, 2024. Accessed March 27, 2024. 

https://classic.clinicaltrials.gov/ct2/show/NCT04585750

PMV Pharmaceuticals updated PC14586 phase 1 data demonstrated anti-tumor activity across multiple solid tumor types with a TP53 Y220C mutation. News release. PMV Pharmaceuticals, Inc. October 12, 2023. Accessed March 27, 2024. 

https://ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-updated-pc14586-phase-1-data-demonstrated

Schram AM, Shapiro GI, Thompson JA, et al. Phase 1 analysis from the PYNNACLE phase 1/2 study of PC14586 in the subgroup of patients with advanced ovarian cancer harboring a

 Y220C mutation. Presented at: 2024 SGO Annual Meeting; March 16-18, 2024; San Diego, California.

Shivaani Kummar, MBBS, FACP, discusses the mechanism of action of the TP53-directed agent rezatapopt and efficacy data with this agent in solid tumors.

Rezatapopt Revolutionizes Research Directions in TP53-Mutated Solid Tumors

Dr Kummar on the Evaluation of Rezatapopt in Advanced Solid Tumors

Shivaani Kummar, MBBS, FACP, Margaret and Lester DeArmond Endowed Chair of Cancer Research, Professor and Division Head, Division of Hematology/Medical Oncology, Oregon Health & Science University School of Medicine; co-director, Center for Experimental Therapeutics, co-deputy director, Knight Cancer Institute, discusses the evaluation of rezatapopt (PC14586) in patients with advanced solid tumors.

Rezatapopt is a first-in-class p53 reactivator that binds to the mutated 

 Y220C protein in solid tumors, thereby restoring wild-type p53 function, Kummar says. The phase 1/2 PYNNACLE trial (NCT04585750) is evaluating this agent in patients with 

Y220C–mutated advanced solid tumors. Data from the phase 1 portion of the trial were presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics and included findings from the first 67 safety-evaluable patients. In the subset of evaluable patients with 

 wild-type disease who received rezatapopt in the efficacious dose range (n = 38), the confirmed overall response rate (ORR) was 34% (n = 13). Additionally, the ORR was 38% (n = 6) in evaluable patients with 

 wild-type disease who received the agent at the recommended phase 2 dose (RP2D) of 2000 mg daily (n = 16). Responses were observed across several tumor types, including ovarian cancer, small cell lung cancer, breast cancer, and endometrial cancer, Kummar notes.

 Y220C mutations occur at a higher frequency in ovarian cancer than in other solid tumors, at approximately 2.9% vs 1%, Kummar explains. Data with rezatapopt in the ovarian cancer patient cohort were presented at the 

 and showed that among the 15 patients with measurable disease at baseline who underwent 1 or more post-baseline tumor assessments, 7 experienced a radiographic partial response, and 7 had stable disease. The median duration of response was 7 months.

Variant allele frequency decreases in patients who responded to rezatapopt were also observed in the phase 1 proof-of-concept portion of the trial, Kummar emphasizes. The phase 2 portion of the trial has launched and is enrolling patients to receive rezatapopt at the RP2D. The study aims to determine which patients will benefit most from treatment with this agent, Kummar concludes.

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Shivaani Kummar, MD, FACP, discusses the evaluation of rezatapopt in patients with advanced solid tumors.

Rezatapopt (PC14586) elicited responses with a favorable toxicity profile in heavily pretreated patients with advanced ovarian cancer harboring 

 Y220C mutations, according to data from the phase 1/2 PYNNACLE study (NCT04585750) presented at the 

2024 SGO Annual Meeting on Women’s Cancer

When given at an efficacious dose range from 1150 mg once daily to 1500 mg twice daily, rezatapopt evoked an objective response rate (ORR) of 47% in evaluable patients who had measurable disease at baseline and had at least 1 post-baseline assessment (n = 15). Specifically, 7 patients had a partial response (PR), and 7 had stable disease (SD). A total of 6 patients had a CA125 response, which included 5 patients with a radiographic PR and 1 with SD. The median duration of response (DOR) was 7 months.

 showed promising efficacy in heavily pretreated patients with 

 Y220C–mutant ovarian cancer,” Alison Schram, MD, a gynecologic oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York, said in a late-breaking presentation during the meeting. “[The agent] had a favorable safety profile in the overall population and in [patients with] ovarian cancer.”

Seventy percent of patients with ovarian cancer have 

 mutations; the incidence of this mutation is even higher in the subset of patients with high-grade serous disease (>96%). Moreover, the hotspot mutation 

 Y220C is most prevalent in ovarian cancer, occurring in 2.9% of these patients.

 Y220C protein and restores wild-type activity,” Schram noted.

PYNNACLE enrolled patients with locally advanced or metastatic solid tumors harboring 

 Y220C mutations, which were identified utilizing local next-generation sequencing. To be eligible, patients needed to be at least 12 years of age.

In the study, rezatapopt was evaluated at doses ranging from 1150 mg once daily (n = 5), 1500 mg once daily (n = 10), 2000 mg once daily (n = 29), 2500 mg once daily (n = 13), and 1500 mg twice daily (n = 10).

The primary objectives of the study were to identify the maximum tolerated dose, determine the recommended phase 2 dose (RP2D), and to assess the safety and tolerability of the agent. Secondary objectives included evaluating the pharmacokinetic profile of the agent and to examine the preliminary efficacy in the form of ORR. Exploratory objectives included biomarker analysis and evaluating pharmacodynamics.

As of the data cutoff date of September 5, 2023, a total of 67 patients were enrolled in the efficacious dose range; this included 22 patients with ovarian cancer. In this subset, investigators examined ORR by investigator assessment per RECIST v1.1 criteria and serum CA-125 response defined as a greater than 50% decrease at 2 separate time points, 4 weeks apart. Safety was examined across tumor types and in the efficacious dose range for the overall population and in the subset of patients with ovarian cancer.

Earlier data from the PYNNACLE study were previously presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

 Results showed that when rezatapopt was given at the RP2D of 2000 mg daily, it led to an ORR of 38% per RECIST v1.1 criteria in evaluable patients with 

 Y220C–mutated solid tumors (n = 16), including ovarian, breast, prostate, small cell lung, and endometrial cancers. When given in the efficacious dose range, the ORR achieved with the agent was 34% (n = 13) in evaluable patients (n = 38). The median DOR was 7 months.

At the SGO Annual Meeting, Schram shared data from the ovarian cancer subset. In these 22 patients, the median age was 66 years (range, 49-81). More than half of the patients were White (68%) and had an ECOG performance status of 1 (73%). The majority of patients had high-grade serous ovarian cancer (91%), and the remaining 9% had endometroid histology. Ninety-one percent of patients had measurable disease at baseline.

 Y220C alteration. About one-third of patients [who] had homologous recombination deficiency–positive disease, including 2 patients with somatic 

 mutations,” Schram reported. “No patients had a 

The median number of prior systemic therapies received was 4 (range, 1-9), with 64% of patients receiving at least 3 or more lines of treatment. Moreover, 86% of patients had platinum-resistant disease, and 5% had platinum-refractory disease; 9% of patients were platinum sensitive.

Schram noted that most patients experienced some degree of tumor shrinkage, and several patients remained on treatment at the time of data cutoff.

Rezatapopt had a favorable safety profile. In the overall population (n = 67), any-grade treatment-related adverse effects (TRAEs) occurred in 89.6% of patients. Grade 1, 2, 3, and 4 TRAEs occurred in 23.9%, 40.3%, 23.9%, and 1.5% of patients, respectively.

The most common TRAEs experienced by patients who received the agent were nausea (grade 1, 32.8%; grade 2, 16.4%; grade 3, 1.5%; grade 4, 0%), vomiting (23.9%; 17.9%; 1.5%; 0%), increased blood creatinine (14.9%; 11.9%; 0%; 0%), diarrhea (17.9%; 0%; 1.5%; 0%), fatigue (11.9%; 7.5%; 0%; 0%), increased alanine aminotransferase (6.0%; 7.5%; 4.5%; 0%), increased aspartate aminotransferase (10.4%; 3.0%; 3.0%; 0%), anemia (1.5%; 9.0%; 4.5%; 0%), decreased appetite (3.0%; 6.0%; 1.5%; 0%), proteinuria (1.5%; 7.5%; 0%; 0%), maculopapular rash (1.5%; 4.5%; 3.0%; 0%), headache (6.0%; 1.5%; 0%; 0%), increased lipase (6.0%; 0%; 1.5%; 0%), decreased platelet count (1.5%; 1.5%; 3.0%; 0%), increased amylase (4.5%; 1.5%; 0%; 0%), and dehydration (0%; 6.0%; 0%; 0%).

“The pivotal global PYNNACLE phase 2 trial is ongoing and will assess rezatapopt as monotherapy in patients with 

 wild-type advanced solid tumors, including ovarian cancer,” Schram concluded.

Editor’s Note: Dr Schram disclosed serving on advisory boards for Relay Therapeutics, Mersana, Merus, and PMV Pharma; having a consulting role with Blueprint Bio, Flagship Pioneering, and Redona Therapeutics; and being a steering committee member with Merus and Pfizer. Research funding to institution was provided by AstraZeneca, ArQule, BeiGene/SpringWorks, Black Diamond Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay Therapeutics, Revolution Medicine, and Surface Oncology.

 Y220C mutation. Presented at: 2024 SGO Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, California.

PMV Pharmaceuticals updated PC14586 phase 1 data demonstrated anti-tumor activity across multiple solid tumor types with a TP53 Y220C mutation. News release. PMV Pharmaceuticals, Inc. October 12, 2023. Accessed March 18, 2024. https://ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-updated-pc14586-phase-1-data-demonstrated

Rezatapopt induced responses with acceptable toxicity in heavily pretreated patients with advanced ovarian cancer harboring TP53 Y220C mutations.

Rezatapopt Shows Preliminary Efficacy in TP53 Y220C–Mutated Advanced Ovarian Cancer

Despite previous unsuccessful attempts to target 

, investigators have continued to try to develop novel therapeutics directed at the tumor suppressor gene with the goal of restoring 

 wild-type activity. With the initiation of the phase 1/2 PYNNACLE (NCT04585750) trial, investigators hope to crack the code in order to overcome previous challenges in targeting 

 and add the first-in-class agent PC14586 to the treatment armamentarium for multiple types of advanced solid tumors.

“Mutations in TP53 result in loss of its antitumor activity, creating an oncogenic environment that promotes tumor proliferation, invasion, and drug resistance,” Ecaterina E. Dumbrava, MD, assistant professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with 

. “[Approximately] half of all cancers have a TP53 mutation, and the specific TP53Y220C [mutation] is one of the hot spot mutations that is present in 1% of all solid tumors. Historically, 

 has been undruggable; we did not have any drug that [directly targets] 

. PC14586 is a first-in-class small molecule that reactivates 

. It binds selectively to this protein and stabilizes it in a wild-type configuration and restores its activity. This is the first time that we [have been] able to target 

 YY20C mutation in which tyrosine is substituted by cysteine at amino acid 220 of the protein. This modification causes a small gap to form in 

, causing it to become thermally unstable and incapable of interacting with DNA effectively.

In October 2020, the FDA granted fast track designation to PC14586 for the treatment of patients with locally advanced or metastatic solid tumors that have a TP53 Y220C mutation and the agency noted that there are currently no FDA-approved agents directed at the mutation.

PYNNACLE is an open-label multicenter trial enrolling patients with advanced solid tumors with a TP53 Y220C mutation. The phase 1 and 2 portions of the study will assess PC14586 monotherapy, and the phase 1b portion will examine the agent in combination with the PD-1 inhibitor pembrolizumab (Keytruda; 

The study is aiming to enroll approximately 181 patients aged at least 18 years or patients aged 12 to 17 years after adequate safety findings are collected. Patients must also have an ECOG performance status of 1 or less, adequate organ function, and experienced disease progression after previously receiving at least 1 line of anticancer therapy. In phase 1b, patients must also be anti-PD-1/L1 inhibitor naive or have experienced disease progression on treatment.

Patients who received anticancer therapy within 21 days of treatment with PC14586, those who received radiotherapy within 28 days of treatment, and those with unstable brain metastases are not eligible for enrollment. In the combination phase, those who received prior therapy with an agent directed at another stimulatory or coinhibitory T-cell receptor and were forced to discontinue treatment due to grade 3 or higher immune-related adverse effects (AEs) are also excluded.

Patients in the phase 1 dose-escalation portion will receive PC14586 daily in an escalating manner to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The phase 1b dose-escalation portion will evaluate multiple dose levels of PC14586 plus intravenous pembrolizumab 200 mg every 3 weeks to determine the MTD and RP2D of PC14586 with the combination. In the phase 1b dose expansion, patients who are PD-1/PD-L1 inhibitor-naive and have relapsed/refractory disease will be divided into 2 cohorts to receive the RP2D of PC14586 in combination with pembrolizumab.

Phase 2 will consist of 2 dose expansion cohorts. Cohort A will include patients who meet all eligibility criteria and have measurable disease per RECIST 1.1 criteria, and cohort B will consist of patients who did not meet all eligibility criteria, such as those with primary central nervous system tumors, and those who do not have measurable disease.

The coprimary end points in phases 1 and 2 are characterizing the safety of PC14586 by determining the type and number of AEs and overall response rate (ORR) via RECIST 1.1 criteria per independent review. Investigators will also aim to establish the MTD and RP2D of PC14586 both as monotherapy and in combination with pembrolizumab.

Early PYNNACLE Data Display Efficacy, Tolerability

During the American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics, which took place from October 11 to 15, 2023, in Boston, Massachusetts, investigators presented updated findings from PYNNACLE. At the September 5, 2023, data cutoff 77 patients had been treated with PC14586 monotherapy, including 67 in the efficacious dose range of 1150 mg daily to 1500 mg twice daily.

Patients included in the analysis were 12 years or older and received PC14586 monotherapy at a daily dose of 1150 mg (n = 5), 1500 mg (n = 10), 2000 mg (n = 29), and 2500 mg (n = 13). There was also a cohort of 10 patients who received the agent twice daily at a dose of 1500 mg.4

The median patient age across cohorts was 63 years (range, 32-84). Most patients were White (76%), female (61%), had an ECOG performance status of 1 (67%), and had 

 wild-type disease (75%). Patients were heavily pretreated; the median number of prior lines of therapy was 3 (range, 1-9), and 55% of patients received at least 3 prior lines of systemic therapy, 28% received 2 lines, and 9% received 1 line. The analysis included patients with ovarian (33%), pancreatic (18%), breast (13%), prostate (9%), colon (7%), head and neck (3%), endometrial (1%), small cell lung (3%), and other (12%) cancer.

Fifty-one patients were evaluable for efficacy; 13 patients had TP53 Y220C and 

wild-type TP53 Y220C–mutated disease. Reduction of target lesions was seen in both groups of patients; however, confirmed responses were only reported in the group of patients who had 

 wild-type and TP53 Y220C–mutated disease.

 wild-type and TP53 Y220C–mutated disease population, the ORR was 34%, all partial responses (PRs), with 20 patients achieving stable disease (SD) and 5 experiencing disease progression. Patients treated at the 2000-mg daily dose level (n = 16) achieved an ORR of 38%, with 8 patients experiencing SD and 2 experiencing progression. All responses were also PRs in the 2000-mg cohort. The median time to response among all responders was 1.5 months, and the median duration of response was 7 months.

Patients with ovarian (n = 2), breast (n = 2), small cell lung (n = 0), endometrial (n = 1), and other (n = 1) cancer in the 2000-mg daily dosing cohort experienced ORRs of 40%, 67%, 0%, 100%, and 17%, respectively.

“PC14586 showed preliminary efficacy in multiple advanced cancers,” Dumbrava said. “This brings hope that 

 is now considered a targetable gene and no [longer] undruggable. And if the phase 2 [findings] of the study are positive, I believe that PC14586 would be a valuable addition to the arsenal of tumor-agnostic targeted therapies that would bring hope for patients and improve their outcomes.”

In terms of safety, patients treated in the efficacious dose range experienced any-grade treatment-related AEs (TRAEs) at a rate of 89.6% and the most common included nausea (50.7%), vomiting (43.3%), increased blood creatine level (26.9%), diarrhea (19.4%), and fatigue (19.4%). Grade 3 TRAEs occurred in 23.9% of patients, and there was 1 grade 4 TRAE of immune thrombocytopenia. No grade 5 TRAEs were reported.

“PC14586 has a favorable safety profile; patients are tolerating treatment well,” Dumbrava said. “Nausea, vomiting, and diarrhea improved with administration with food. Also, the study had a low discontinuation rate of 3% because of TRAEs.”

Study authors concluded that PC14586 displayed clinical efficacy as a single agent in heavily pretreated patients across multiple tumor types. The RP2D of the agent as a monotherapy was determined to be 2000 mg daily. Dumbrava noted that the phase 1b portion of PYNNACLE is still enrolling patients and the phase 2 portion will open soon.

PMV Pharmaceuticals, the manufacturer of PC14586, announced plans to initiate a registrational phase 2 trial examining the agent in early 2024.

PMV pipeline. PMV Pharma. Accessed November 20, 2023. bit.ly/3G67AUn

PMV Pharma granted FDA fast track designation of PC14586 for the treatment of advanced cancer patients that have tumors with a p53 Y220C mutation. News release. PMV Pharma. October 13, 2020. Accessed November 20, 2023. bit.ly/3G5UUfY

The evaluation of PC14586 in patients with advanced solid tumors harboring a p53 Y220C mutation (PYNNACLE). ClinicalTrials.gov. Updated September 7, 2023. Accessed November 17, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04585750

Schram AM, Shapiro GI, Johnson ML, et al. Updated phase 1 results from the PYNNACLE phase 1/2 study of PC14586, a selective p53 reactivator, in patients with advanced solid tumors harboring a TP53 Y220C mutation. Presented at: American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics; October 11-15, 2023; Boston, MA.

PMV Pharmaceuticals updated PC14586 phase 1 data demonstrated anti-tumor activity across multiple solid tumor types with a TP53 Y220C mutation. News release. PMV Pharmaceuticals. October 12, 2023. bit.ly/40FXq6p

Despite previous unsuccessful attempts to target p53, investigators have continued to try to develop novel therapeutics directed at the tumor suppressor gene with the goal of restoring p53 wild-type activity. 

PC14586 Targets Previously “Undruggable” p53 in Treatment of Solid Tumors

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In today’s episode, sponsored by PMV Pharmaceuticals, we had the pleasure of speaking with Ecaterina E. Dumbrava, MD, about the phase 1/2 PYNNACLE trial (NCT04585750) of PC14586 in patients with 

 Y220C–mutated advanced solid tumors. Dr Dumbrava is an assistant professor in the Department of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

At the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, investigators presented phase 1 data from PYNNACLE. At a data cutoff of September 5, 2023, data showed that 67 patients included in the safety analysis who were treated with an efficacious dose of the agent, defined as 1150 mg daily and above, had a median age of 63 years (range, 32-84), and patients had received a median of 3 prior lines of therapy (range, 1-9). In this trial, PC14586 elicited an overall response rate per RECIST v1.1 criteria of 38% at the recommended phase 2 dose of 2000 mg daily.

In our exclusive interview, Dr Dumbrava discussed the rationale and design of the PYNNACLE trial; phase 1 efficacy and safety findings with PC14586 in patients with 

 Y220C–mutated advanced solid tumors; and the next steps for this research.

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Dr Dumbrava discusses the rationale and design of the PYNNACLE trial; phase 1 efficacy and safety findings with PC14586 in patients with p53 Y220C–mutated advanced solid tumors; and the next steps for this research. 