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Adjusting clinical trial designs to examine the benefit from phase of treatment will be a focus in the future, as data from the phase 3 AEGEAN trial (NCT03800134) have sparked conversations on where the efficacy of a perioperative regimen is coming from in patients with resectable non– small cell lung cancer (NSCLC). Findings from the trial did not clearly show whether the positive event-free survival (EFS) outcomes seen with neoadjuvant durvalumab (Imfinzi) plus chemotherapy followed by adjuvant durvalumab were a result of the PD-L1 inhibitor’s use in the neoadjuvant phase of therapy, adjuvant phase, or both.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 that the FDA should require that new trial design proposals for perioperative regimens in resectable NSCLC include adequate within-trial assessment of contribution of treatment phase (

“It’s important to note that the FDA’s question that was voted [on during the meeting] was specifically for future trials. They explicitly said this doesn’t apply to AEGEAN or current studies. There was a separate nonvoting question about whether additional studies were needed [regarding] AEGEAN, and the consensus of the panel was that additional studies were not needed,” John V. Heymach, MD, PhD, said in an interview with 

Following the ODAC meeting held on July 25, 2024, durvalumab received FDA approval in combination with platinum-containing chemotherapy as neoadjuvant treatment and then as single-agent adjuvant treatment for adult patients with resectable NSCLC with no known EGFR mutations or ALK rearrangements. The August 15, 2024, approval was based on findings from AEGEAN, and resectable disease was defined as tumors 4 cm or larger and/or node-positive disease.

“For future studies, the concern is that over-treatment is a possibility,” Heymach added. "All patients may not require both the neoadjuvant phase and the adjuvant phase [of therapy], and [further] treatment may incur toxicity, additional inconvenience, and cost. It may not bring [patients] adequate benefit to justify that.”

Unpacking the First ODAC Discussion Question: AEGEAN Trial Data

The first of 2 discussion topics focused on the adequacy of efficacy and safety data from the AEGEAN trial, which supported the then-proproposed perioperative indication. In addition to concerns about the potential for overtreatment of patients with perioperative immune checkpoint inhibitor regimens, the FDA noted that AEGEAN was unable to determine whether the efficacy seen with durvalumab in patients with resectable NSCLC was a result of the agent’s administration in the neoadjuvant, adjuvant, or perioperative phases of treatment.

“The best we can do is post hoc analyses or exploratory analyses that give us some hints [on efficacy],” Heymach said. “Post hoc analyses suggest that there is benefit from the adjuvant phase, but that’s not the same as a study designed specifically to address that question.”

Findings from AEGEAN revealed that patients with previously untreated stage IIA to IIIB resectable NSCLC with no EGFR/ALK alterations achieved a median EFS that was not reached (NR; 95% CI, 31.9-NR) in the durvalumab plus chemotherapy arm (n=366) vs 25.9 months (95% CI, 18.9-NR) in the chemotherapy alone arm (n=374; HR, 0.68; 95% CI, 0.53-0.88; P=.0039).

The FDA acknowledged that the trial met its primary end point with a statistically significant and clinically meaningful improvement in EFS seen, but the design of the trial did not allow for a within-trial assessment of the individual contributions of durvalumab in combination with chemotherapy in the neoadjuvant phase and durvalumab in the adjuvant phase.

Additionally, there was not a statistically significant difference in disease-free survival, a key secondary end point at the first interim analysis, which was required to formally test overall survival (OS). However, a descriptive analysis showed that there was no clear detriment from treatment.

“It’s important that the FDA specified that the OS [data] were not enough to decide that there was a contribution of phase [of treatment]. I believe that OS is the most important end point in these trials, and only 1 trial for the time being reached an OS [end point],” Marina Chiara Garassino, MD, said in the dual interview with OncologyLive. “For the FDA, the OS data were not enough to say that the perioperative trials were superior to the neoadjuvant only [phase 3 CheckMate 816 (NCT02998528) trial].”

A 4-year data update from CheckMate 816 presented at the 2024 American Society of Clinical Oncology Annual Meeting showed an OS benefit for patients with stage IB to IIIA resectable NSCLC and no 

 alterations who received neoadjuvant nivolumab (Opdivo) plus chemotherapy vs chemotherapy alone. The median OS was NR in the nivolumab plus chemotherapy arm (n=179) vs NR in the chemotherapy arm (n=179; HR, 0.71; 98.36% CI, 0.47-1.07; P=.0451). Four-year OS rates were 71% vs 58%, respectively. Investigators noted that this reinforces the doublet as a standard of care for patients with resectable disease.

“Findings from the CheckMate 816 trial with 358 patients [who received neoadjuvant therapy] showed a HR very similar to findings from a perioperative trial accounting for [a large amount of] patients. We all would like to know if the adjuvant component [of treatment] is helping patients or if we can select patients for an adjuvant part [of therapy],” Garassino said. “Trials in the perioperative settings didn’t answer this question, and now we are at an impasse of having a short regimen that showed very similar results to a longer [regimen].”

Voting Question: Adjusting Clinical Trial Criteria Has Several Implications

The ODAC vote, which centered on the need for adequate within-trial assessment of contribution of treatment phase in the design of new trial proposals for perioperative regimens in resectable NSCLC, also highlighted a few concerns regarding time taken to conduct trials.

“The FDA raised concerns that they were going to make [the process of] trials much slower, which may not be beneficial, and they raised the possibility of novel designs or using other markers as potential end points, which is a wonderful suggestion,” Heymach said. “If we’re mandating that studies require understanding of the contribution of phase [of treatment] but we’re potentially accelerating research using biomarkers such as pathologic complete response, then it may not delay development so much. It may give us more information.”

He noted that perioperative studies may take 5 to 8 years to read data out and that pros and cons should be weighed when designing future trials. Although focusing on contribution of phase of therapy studies would help answer the question of whether certain phases are benefiting patients, Heymach suggested that newer regimens may then miss the opportunity for investigation.

“Given that at least 60% of this population [will experience] recurrence and that PD-1 inhibitors are generally well tolerated in the adjuvant setting, that makes this a cost/benefit question,” he noted. “Is the field better off investing resources in figuring out the optimum duration of a drug that’s relatively well tolerated or trying to move forward with new combinations that will increase cure rates?”

Garassino added that she agrees, noting that “taking advantage of liquid biopsy, radiomics, patients’ conditions, and many other things [is important so that] it’s possible that we [can] personalize the adjuvant component of therapy more in the future. I have been in Italy for most of my life, [and] I believe that it will be very difficult for European countries and socialized countries like Canada where there are full reimbursements to accept continuously adding clinical trials. These kinds of trials will help a lot, particularly [for] those countries where it is possible [that they won’t have access to perioperative regimens].”

Where Does Durvalumab Stand Based on This Approval and Discussion?

The only other currently FDA-approved perioperative regimen in resectable NSCLC is pembrolizumab (Keytruda) plus platinum-containing chemotherapy as neoadjuvant treatment followed by adjuvant single-agent pembrolizumab.

Data from the pivotal phase 3 KEYNOTE-671 trial (NCT03425643), upon which the approval was based, revealed that at a median follow-up of 29.8 months (range, 0.4-62.0), the median OS was NR (95% CI, NR-NR) in the pembrolizumab arm (n = 397) vs 52.4 months (95% CI, 45.7-NR) in the chemo- therapy/placebo arm (n = 400; HR, 0.72; 95% CI, 0.56-0.93; 1-sided 

 = .00517). Median EFS was also improved with the pembrolizumab regimen vs chemotherapy alone arm, as the risk of disease recurrence, progression, or death was reduced by 41% (HR, 0.59; 95% CI, 0.48-0.72).

“In the case of the AEGEAN and KEYNOTE-671 [regimens], at this point the KEYNOTE-671 [data] are a bit more mature, [showing improvement in both EFS and OS], which is wonderful that we have a regimen that has done that for patients. [However,] we also have a lot of experience [using] the phase 3 PACIFIC trial [NCT02125461] regimen with 1 year of adjuvant durvalumab. That’s also something that we have developed a significant degree of comfort with... Choice of multiple effective regimens is good, and as always, physicians and patients will review those data and select the regimen accordingly.”

FDA. July 25, 2024 meeting of the Oncologic Drugs Advisory Committee (ODAC). YouTube. Accessed August 19, 2024. bit.ly/4dRLWCb

FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed August 15, 2024. bit.ly/3MbKzlT

 Oncologic Drugs Advisory Committee (ODAC) Meeting: Combined FDA and Applicant ODAC Briefing Document. FDA. July 25, 2024. Accessed August 19, 2024. bit.ly/3ArzZVo

 Imfinzi. Prescribing information. AstraZeneca; 2024. Accessed August 19, 2024. bit.ly/4cx8Ltu

Spicer JD, Girard N, Pulla MP, et al. Neoadjuvant nivolumab (NIVO)+chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: four-year update from CheckMate 816. J Clin Oncol. 2024;42(suppl 17):LBA8010. doi:10.1200/ JCO.2024.42.17_suppl.LBA8010

FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed August 19, 2024. bit.ly/3YRPZtQ

European Commission approves Merck’s Keytruda (pembrolizumab) plus chemotherapy as neoadjuvant treatment, then continued as monotherapy as adjuvant treatment, for resectable non-small cell lung cancer (NSCLC) at high risk of recurrence in adults. News release. Merck. March 28, 2024. Accessed August 19, 2024. bit.ly/4cx9gnm

Articles

The AEGEAN trial has prompted discussions on the efficacy of perioperative regimens in resectable NSCLC, leading to an FDA advisory committee's recommendation for future trials to assess treatment phase contributions. The trial showed improved event-free survival with durvalumab plus chemotherapy, but it was unclear which treatment phase was most beneficial. The FDA approved durvalumab for neoadjuvant and adjuvant use, despite concerns about potential overtreatment. The CheckMate 816 trial showed similar outcomes with a shorter regimen, highlighting the need for personalized treatment approaches and efficient trial designs.

Clinical Perspectives 

John V. Heymach, MD, PhD, and Marina Chiara Garassino, MD, detail the 11-0 ODAC vote that new trial designs for perioperative regimens in resectable NSCLC should include within-trial assessment of each treatment phase's contribution.

ODAC Weighs In on the Future of Perioperative Trial Designs in Resectable NSCLC

PARP1-selective inhibitors could represent the next frontier and generation of PARP inhibitors in oncology, potentially reducing the hematologic toxicity demonstrated in both preclinical and clinical research with first-generation dual inhibitors of PARP1 and PARP2.

“PARP is an enzyme that repairs single-strand breaks on DNA; this is one of the first defense mechanisms that allows cells to repair DNA and survive,” Neeraj Agarwal, MD, FASCO, said in an interview with 

. “If an [individual has] deficient…BRCA1 or BRCA2 or has a germline mutation, they are not able to repair a double-strand break in the [DNA of] their tumor.”

Agarwal added that inhibiting PARP causes the accumulation of single-strand DNA breaks, which eventually become double-strand breaks during cell division, noting that without the homologous recombination repair (HRR) mechanism intact, the cells will die (

 Agarwal is the Presidential Endowed Chair of Cancer Research, director of the Genitourinary Oncology Program and the Center of Investigational Therapeutics, and professor of medicine at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

Presently, there are 4 FDA-approved PARP inhibitors in ovarian, breast, prostate, and pancreatic cancer. Three PARP inhibitors are approved in the maintenance setting in ovarian cancer: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca). Olaparib is also approved in breast cancer, as is talazoparib (Talzenna). Olaparib and rucaparib are also approved by the FDA for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC), and olaparib is FDA approved in the maintenance setting in pancreatic cancer.

“All PARP inhibitors as a class can cause anemia, thrombocytopenia, and neutropenia; they’re considered [to be like] an oral form of chemotherapy because of their marrow suppression,” Andrew J. Armstrong, MD, MSc, professor of medicine in the Department of Medical Oncology, professor of pharmacology and cancer biology in the Department of Pharmacology & Cancer Biology, and professor of urology at Duke Cancer Center in Durham, North Carolina, said in an interview with 

. “There are concerns about any drug that is DNA damaging, potentially causing bone marrow toxicity and myelodysplastic syndrome. That’s something we’re looking out for, particularly as we move these drugs into earlier settings where patients have longer life expectancy.”

Saruparib Leads the Way for the Next Generation of PARP Inhibitors

Saruparib (formerly AZD5305) is a first-in-class, next-generation PARP inhibitor that selectively inhibits PARP1. Investigators hypothesized that inhibition of PARP1 alone could maintain and potentially improve the therapeutic benefit seen with PARP1/2 inhibitors with a lessened potential for hematologic and other toxicities. In findings from preclinical study, saruparib demonstrated a high level of potent selectivity for PARP1 and limited drug-drug interactions.

“All the approved first-generation PARP inhibitors are dual PARP1/2 inhibitors,” Timothy A. Yap, MBBS, PhD, FRCP, said in an interview with 

. “However, only PARP1 trapping is required for synthetic lethality in homologous recombination deficiency settings. Therefore, the rationale is that saruparib could be developed through rational design to be highly selective for PARP1 with increased potency and improved physiochemical properties vs all the first-generation [FDA]-approved PARP inhibitors.” Yap is vice president and head of clinical development in the Therapeutics Discovery Division, and professor in the Department for Investigational Cancer Therapeutics (Phase I Program) in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Saruparib is being evaluated in patients with advanced/metastatic solid tumors, including HER2-negative breast, ovarian, pancreatic, and prostate cancer, in the ongoing phase 1/2 PETRA trial (NCT04644068). The open-label, multicenter study is evaluating saruparib monotherapy in adult patients with advanced solid malignant tumors harboring 

mutations. The study also contains combination arms examining the agent in combination with paclitaxel, carboplatin with or without paclitaxel, fam-trastuzumab deruxtecan-nxki (Enhertu), datopotamab deruxtecan, and camizestrant.

The primary end point is safety and tolerability. Secondary end points include objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to response.

During the American Association for Cancer Research Annual Meeting 2024 in San Diego, California, Yap presented preliminary findings from patients with molecularly selected ovarian, pancreatic, prostate, and HER2-negative breast cancer treated in the dose escalation portion (part A) and patients with HER2-negative breast cancer treated in the dose expansion portion (part B) of PETRA. Patients who received saruparib in part B (n = 31) achieved an ORR of 48.4% (95% CI, 35.7%-61.3%), a median DOR of 7.3 months (95% CI, 5.6-7.6), and a median PFS of 9.1 months (95% CI, 5.7-9.3).

Patients treated at the 60-mg daily dose level in parts A and B (n = 141) experienced infrequent dose reductions (14.2%) and dose discontinuations (3.5%). The rates of grade 3 or higher anemia (11.3%), neutropenia (10.6%), and thrombocytopenia (5.7%) at this dose level in this group were all below 15%. The recommended phase 2 dose (RP2D) of saruparib was determined to be 60 mg once daily.

“Saruparib demonstrated a very favorable safety and tolerability profile, with no unexpected safety findings,” Yap said. “The adverse effects [AEs] were mainly grade 1 to 2, and AEs leading to dose reductions or discontinuations were highly infrequent. Importantly, the saruparib pharmacokinetics were linear, and it was able to achieve much higher target pharmacokinetic coverage vs all the approved PARP inhibitors.”

Investigators are also examining saruparib as a combination component in multiple clinical trials. Building on the positive results reported in PETRA, investigators have initiated the phase 3 EvoPAR-Prostate01 trial (NCT06120491), the trial design of which was presented during the 2024 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

EvoPAR-Prostate01 is a double-blind, placebo-controlled, multicenter global trial that is enrolling adult patients with metastatic castration-sensitive prostate cancer (CSPC) that is either de novo or recurrent. Patients must also have low- or high-volume disease with an ECOG performance status of 1 or less. Patients must also be receiving androgen deprivation therapy in combination with a gonadotropin-releasing hormone analogue through the duration of the trial or have undergone bilateral orchiectomy and be suitable for treatment with next-generation hormonal agents.

The study includes 2 cohorts, with 1 encompassing patients with HRR mutations and 1 containing patients without. In the cohort with HRR mutations, which will enroll approximately 550 patients, patients must have mutations in at least 1 of the following genes: 

. The cohort without HRR mutations will enroll approximately 1250 patients.

The primary end point is radiographic PFS per RECIST v1.1 criteria and/or Prostate Cancer Working Group 3 criteria in patients with 

- and HRR-mutated disease as well as in those with no HRR mutations. Overall survival is a key secondary end point; other secondary end points include time to second progression, health-related quality of life, pharmacokinetics, and safety and tolerability.

In both cohorts, patients will be randomly assigned 1:1 to receive saruparib at the RP2D in combination with physician’s choice of a next-generation hormonal agent or placebo plus a next-generation hormonal agent. Hormonal agents available for selection in the study consist of abiraterone acetate (Zytiga), darolutamide (Nubeqa), or enzalutamide (Xtandi). Enrollment in EvoPAR-Prostate01 began in November 2023 and is ongoing. “The hope is that by having a wide therapeutic index but at the same time achieving much higher pharmacokinetic drug exposures, we’ll be able to combine saruparib more optimally with other drugs,” Yap explained.

Beyond EvoPAR-Prostate01, saruparib is also being investigated in combination with androgen receptor (AR) pathway inhibitors in patients with either metastatic CRPC or CSPC in the phase 1/2 PETRANHA study (NCT05367440). PETRANHA is enrolling adult patients irrespective of HRR mutation status; patients must also have an ECOG performance status of 1 or less. The primary end point is safety and tolerability; secondary end points include pharmacokinetics and preliminary antitumor activity.

Patients in arm A (n = 11) received daily oral enzalutamide at a dose of 160 mg, those in arm B (n = 19) received daily oral abiraterone at a dose of 1000 mg plus prednisone at a dose of 5 mg, and those in arm C (n = 18) received darolutamide at a dose of 600 mg twice daily. All patients were also treated with saruparib at the RP2D.

Interim safety findings from PETRANHA, presented during the 2024 Genitourinary Cancers Symposium in San Francisco, California, demonstrated that at the data cutoff of July 10, 2023, patients with metastatic CRPC (n = 32) and metastatic CSPC (n = 16) experienced serious AEs at rates of 25% and 6.3%, respectively, with 3.1% and 6.3% of these being related to treatment, respectively. Patients in both arms experienced grade 3 or higher treatment-emergent AEs (28.1% vs 31.3%) and grade 3 or higher treatment-related AEs (15.6% vs 31.3%). No dose-limiting toxicities or deaths due to AEs were reported, although 1 patient in each group was forced to discontinue treatment with saruparib due to an AE.

Notably, no significant drug-drug interactions were reported with any of the combinations. Study authors concluded that the initial data from PETRANHA showed that saruparib can be safely combined with enzalutamide, abiraterone, or darolutamide.

“There’s interest in expanding the PARP-AR combination successes into other settings, [such as] nonmetastatic CRPC and even nonmetastatic high-risk hormone-sensitive prostate cancer,” Armstrong said. “There’s a lot of discussion and ongoing study design around earlier disease settings—even neoadjuvant studies that are being explored to eradicate prostate cancer before it spreads.”

Illuzzi G, Staniszewska AD, Gill SJ, et al. Preclinical characterization of AZD5305, a next-generation, highly selective PARP1 inhibitor and trapper. 

. 2022;28(21):4724-4736. doi:10.1158/1078-0432.CCR-22-0301

LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL. Exploring and comparing adverse events between PARP inhibitors. 

. 2019;20(1):e15-e28. doi:10.1016/S1470-2045(18)30786-1

Cortesi L, Rugo HS, Jackisch C. An overview of PARP inhibitors for the treatment of breast cancer. 

. 2021;16(3):255-282. doi:10.1007/s11523-021-00796-4

Smith AJB, Apple A, Hugo A, Haggerty A, Ko EM. Prior authorization for FDA-approved PARP inhibitors in ovarian cancer. 

. 2024;52:101335. doi:10.1016/j.gore.2024.101335

Daly GR, AlRawashdeh MM, McGrath J, et al. PARP inhibitors in breast cancer: a short communication. 

. 2024;26(2):103-113. doi:10.1007/s11912-023-01488-0

Taylor AK, Kosoff D, Emamekhoo H, Lang JM, Kyriakopoulos CE. PARP inhibitors in metastatic prostate cancer. 

. 2023;13:1159557. doi:10.3389/fonc.2023.1159557

FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma. FDA. December 30, 2019. Accessed August 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-gbrcam-metastatic-pancreatic-adenocarcinoma

Yap TA, Schram AM, Balmaña J, et al. PETRA: first-in-human phase 1/2a trial of the first-in-class new generation poly(ADP-ribose) polymerase-1 selective inhibitor (PARP1i) saruparib (AZD5305) in patients with advanced solid tumors with 

 mutations. Abstract presented at: American Association for Cancer Research Annual Meeting 2024; April 5-10, 2024; San Diego, CA. Abstract CT014.

Study of AZD5305 as monotherapy and in combination with anti-cancer agents in patients with advanced solid malignancies (PETRA). ClinicalTrials.gov. Updated June 25, 2024. Accessed August 16, 2024. https://clinicaltrials.gov/study/NCT04644068

Chi KN, Agarwal N, Armstrong AJ, et al. Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with new hormonal agents in patients with metastatic castration-sensitive prostate cancer with and without homologous recombination repair mutation (EvoPAR-Prostate01).

. 2024;42(suppl 16):TPS5123. doi:10.1200/JCO.2024.42.16_suppl.TPS5123

Azad A, Voskoboynik M, Joshua AM, et al. PETRANHA: phase 1/2 study of AZD5305 + novel hormonal agents in patients with metastatic prostate cancer–interim safety and pharmacokinetic results

. 2024;42(suppl 4):123. doi:10.1200/JCO.2024.42.4_suppl.123

PARP1-selective inhibitors, such as saruparib, are emerging as a promising advancement in oncology, potentially reducing hematologic toxicity associated with first-generation PARP inhibitors. Saruparib, a next-generation PARP1 inhibitor, has shown potent selectivity and limited drug-drug interactions in preclinical studies. Clinical trials, including the PETRA and EvoPAR-Prostate01 studies, are evaluating saruparib's efficacy and safety in various cancers. Preliminary results indicate favorable safety profiles and promising efficacy, with ongoing research exploring its combination with other therapies to enhance treatment outcomes in prostate cancer and other malignancies.

Pathways

Neeraj Agarwal, MD, FASCO; Andrew J. Armstrong, MD, MSc; and Timothy A. Yap, MBBS, PhD, FRCP, detail the latest research on PARP1-selective inhibitors in oncology.  

PARP1-Selective Inhibitors Generate Excitement in Solid Tumors

The next generation of CDK inhibitors have hit the ground running, with recent data in advanced solid tumors demonstrating the early efficacy of inhibitors such as BLU-222 targeting CDK2 as well as PF-07220060 targeting CDK4.

The first-in-class next-generation CDK4-selective inhibitor, PF-07220060, in combination with endocrine therapy (ET), showed encouraging clinical efficacy and a favorable safety profile in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, according to data from a phase 1/2a trial (NCT04557449) presented at the 2024 European Society for Medical Oncology Breast Cancer Annual Congress. Treatment with the novel oral inhibitor, which has a significant sparing of CDK6, plus ET elicited a median progression-free survival of 8.1 months (95% CI, 5.3-10.9) in patients treated in parts 1B and 1C of the study (n = 33); patients in part 1B received PF-07220060 at 300 or 400 mg twice daily in combination with letrozole and in part 1C in combination with fulvestrant (Faslodex). The disease control rate was 81.8%, and 21.2% of patients experienced partial responses and 1 patient (3%) had a complete response.

“There’s a new generation of CDK4 and CDK6 inhibitors being developed that may have better antitumor activity and may be more selective for targeting CDK4, which is believed to be mediating most of the antitumor effect of CDK4/6 inhibitors,” Joseph A. Sparano, MD, said in an interview with 

. Sparano is the Ezra M. Greenspan, M.D. Professor in Clinical Cancer Therapeutics, chief of the Division of Hematology Oncology, and deputy director of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York, New York. He is also the 2024 Giants of Cancer Care® recipient in the Breast Cancer category.

The data from the phase 1/2 study support an ongoing phase 3 trial (NCT06105632) evaluating PF-07220060 plus fulvestrant vs investigator’s choice of therapy in patients with HR-positive, HER2-negative advanced or metastatic breast cancer who experienced disease progression on prior CDK4/6 inhibitor–based therapy.

Findings from the trial also revealed that patients with 

 mutations (n = 15) experienced an objective response rate (ORR) of 26.7% (95% CI, 7.8%-55.1%) compared with 40.0% (95% CI, 12.2%-73.8%) among those without

 mutations (n = 10) when treated with the CDK4 inhibitor plus ET. Patients with at least 1 

 mutation (n = 10) achieved an ORR of 40.0% (95% CI, 12.2%-73.8%) compared with 26.7% (95% CI, 7.8%-55.1%) among those without one of the aforementioned mutations (n = 15). The treatment was well tolerated overall, with no grade 4 or higher treatment-related treatment-emergent adverse effects (TEAEs) observed. A serious treatment-related TEAE of nausea also occurred in 1 patient.

CDK2 Plus CDK4/6 Inhibition Shows Potential

As data suggest that the overexpression of cyclin A/E-CDK2 complex disrupts normal cell cycle regulation, which leads to uncontrolled proliferation of cancer cells, agents targeting CDK2 are of particular interest with the new wave of CDK inhibitors. Investigators have also noted that research should focus on the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors as well as proteolysis-targeting chimeras (PROTACs).

Findings from the phase 1/2 VELA trial (NCT05252416) presented at the 2024 American Society of Clinical Oncology Annual Meeting were the first to show the successful combination of a selective CDK2 inhibitor with an approved CDK4/6 inhibitor. Safety data revealed BLU-222—an oral, potent, highly selective CDK2 inhibitor—was well tolerated as monotherapy in patients with heavily pretreated advanced solid tumors as well as in combination with ribociclib (Kisqali) with fulvestrant in patients with HR-positive, HER2-negative breast cancer. No dose-limiting toxicities were seen with the combination in patients with breast cancer, and there were no BLU-222–related dose discontinuations in this patient population.

An ongoing dose escalation and optimization portion of the trial is currently enrolling patients to receive BLU-222 in combination with 400 or 600 mg of ribociclib with fulvestrant. Dose confirmation cohorts for the regimen with ribociclib and letrozole are also planned (

Looking to the Future With PROTAC-Based Therapy

“Promising therapeutic strategies include a host of new antiestrogenic therapies based on different mechanisms of action such as PROTACs, estrogen receptor antagonists, and other agents that can more effectively target tumors that have developed acquired resistance to antiestrogen therapy,” Sparano explained.

The novel PROTAC protein degrader vepdegestrant (ARV-471) received fast track designation in February 2024 from the FDA for the treatment of patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine-based therapy, and the ongoing phase 3 VERITAC-2 trial (NCT05654623) will examine the agent vs fulvestrant in patients who previously received ET-based therapy.

The oral PROTAC agent has a unique mechanism of action that harnesses the ubiquitin-proteasome system to induce degradation of the ER.4 In the phase 1b portion of a phase 1/2 study (NCT04072952), treatment with vepdegestrant plus the CDK4/6 inhibitor palbociclib (Ibrance) resulted in a 63.0% (95% CI, 47.5%-76.8%) clinical benefit rate for patients (n = 46) with ER-positive, HER2-negative advanced breast cancer who had previously received ET with or without a CDK4/6 inhibitor. Patients (n = 31) achieved an ORR of 41.9% (95% CI, 24.5%-60.9%).

Vepdegestrant will be combined with the investigational CDK4-selective inhibitor PF-07220060 in the phase 1b/2 TACTIVE-K study (NCT06206837), which is currently enrolling patients. Preclinical models examining the combination showed it effectively suppressed tumor growth at a greater extent than either agent did as monotherapy.

Another novel development surrounding biomarkers centers on prognostic tools, according to Sparano. “We’re now beginning to see prognostic tools developed that integrate both the prognostic and predictive information provided by biomarkers, with clinical pathologic features that provide prognostic information for distant recurrence,” he explained. “[This] can help [us] make more informed decisions regarding adjuvant therapy recommendations.”

Examining What’s New but Focusing on What’s Available Now

As therapies such as novel CDK inhibitors are generating excitement, “Predictive Biomarker Testing,” “Biology of Breast Pathogenesis and Key Molecular Pathways,” and “Germline Mutations and Management Issues” will be sessions of interest at the upcoming 22nd Annual School of Breast Oncology meeting held by Physicians’ Education Resource from November 6 to 9, 2024, in Atlanta, Georgia.

Physicians including Sparano will gather to discuss not only exciting agents under development but also treatment approaches for available therapies and best practices.

In his presentation “The Art and Science of Managing Metastatic Breast Cancer,” Sparano will review the mechanistic basis for the efficacy of agents that have established clinical activity so that “clinicians have a much better understanding of why these drugs are benefiting patients and are associated with their [particular] clinical benefits and AEs.” He also noted that he will focus on the evolving evidence supporting the use of immunotherapy for the treatment of patients with localized triple-negative breast cancer in his second presentation “Considerations in Systemic Therapy for Early-Stage Triple-Negative Breast Cancer.”

Sparano added that this is especially relevant now as there are “emerging [data] from the phase 3 KEYNOTE-522 trial [NCT03036488] that pembrolizumab [Keytruda] added to chemotherapy can improve not only event-free survival but overall survival. The key challenge for the use of these agents in early-stage localized disease is the spectrum of immune-related AEs that develop, some of which can occur early and be potentially life-threatening, others of which can occur later and be chronic and require lifelong therapeutic interventions to address.”

In addition to immunotherapy in triple-negative disease, in the breast cancer treatment landscape, he’s keeping his eye on “broadly, the next generation of CDK4/6 inhibitors, antiestrogenic agents, and agents targeting the PI3K/AKT/mTOR pathway as well as antibody-drug conjugates targeting a variety of therapeutic targets.”

Yap TA, Sharma MR, Hamilton EP, et al. First-in-human phase I/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors (CDK4/6i): safety and efficacy update. Abstract presented at: 2024 European Society for Medical Oncology Breast Cancer Annual Congress; May 15-17, 2024; Berlin, Germany. Abstract 184MO.

Zeng Y, Ren X, Jin P, et al. Inhibitors and PROTACs of CDK2: challenges and opportunities. 

. Published online July 12, 2024. doi:10.1080/17460441.2024.2376655

Juric D, Patel MR, Duska LR, et al. BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2i), as monotherapy in patients (pts) with advanced solid tumors and in combination with ribociclib (RIBO) and fulvestrant (FUL) in HR+/HER2− breast cancer (BC). 

. 2024;42(suppl 16):1056. doi:10.1200/JCO.2024.42.16_suppl.1056

Telli ML, Gawryletz CD, Wei M, et al. TACTIVE-K: phase 1b/2 study of vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in combination with PF-07220060, a cyclin-dependent kinase (CDK)4 inhibitor, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. 

. 2024;42(suppl 16):TPS1131. doi:10.1200/JCO.2024.42.16_suppl.TPS1131

Arvinas and Pfizer’s vepdegestrant (ARV-471) receives FDA fast track designation for the treatment of patients with ER+/HER2- metastatic breast cancer. News release. Arvinas Inc. February 6, 2024. Accessed August 2, 2024.

Hamilton E, Hurvitz SA, McAndrew NP, et al. Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib (palbo) in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: updated phase Ib cohort results. Abstract presented at: 2024 European Society for Medical Oncology Breast Cancer Annual Congress; May 15-17, 2024; Berlin, Germany. Abstract 218P.

Twenty-Second Annual School of Breast Oncology. Physicians’ Education Resource. Accessed August 2, 2024. bit.ly/4fvHoml

Recent advancements in CDK inhibitors, particularly targeting CDK2 and CDK4, show promising efficacy in treating advanced solid tumors. PF-07220060, a CDK4-selective inhibitor, combined with endocrine therapy, demonstrated significant clinical efficacy in HR-positive, HER2-negative metastatic breast cancer. The VELA trial highlighted the potential of combining CDK2 and CDK4/6 inhibitors. Additionally, PROTAC-based therapies, like vepdegestrant, are emerging as effective treatments for ER-positive, HER2-negative breast cancer. These developments underscore the evolving landscape of breast cancer treatment, focusing on novel therapeutic strategies and biomarker-driven approaches.

Cover Story

Joseph A. Sparano, MD, details the next generation of CDK inhibitors such as BLU-222 targeting CDK2 and PF-07220060 targeting CDK4.

Next Generation of CDK Inhibitors Are Breaking Ground in HER2– Breast Cancer

We are at an interesting, even paradigm-changing juncture in the academic exercise of scientific peer-reviewed publications. This long-standing process has served society well in establishing criteria for an objective evaluation of observations from the laboratory or clinic, including claims and conclusions made following the completion of clinical trials.

There is an unofficial ladder of scientific journals, just as in the realm of the academic world, with many referring to the “impact factor” (or a similar measure of how other investigators cite previously published works) as a guide to a publication’s place within this hierarchy. As a card-carrying academic for several decades, this commentator is well aware of the influence of an article published, for example, in 

 vs other quite excellent journals that might be considered by some to be somewhat or even substantially lower in the recognized continuum of scientific publications. Although clinical oncology will have its own listing of premier vs nonpremier journals, the unofficial lists clearly exist. The effect of the publication venue is relevant not only for the scientific community and society at large but may have a major influence on the process of academic advancement as well as subsequent recruitment and job retention, among other potential personal benefits.

Unfortunately, a number of disquieting events have shown how much this rather idealized view of the academic peer-reviewed publi- cation process does not represent an objectively adequate view of the current state of affairs, raising a vexing challenge for the scientific community. Who would have thought even a decade ago that a scientific superstar a now ex-president of Stanford University in California, would be forced to resign because of question- able publications?

Yes, the claim is that others under his leadership were responsible for the multiple documented concerning issues, but he was ultimately responsible for the submitted and subsequently published manuscripts. Similarly, in the oncology realm, could one imagine that multiple senior investigators at Dana-Farber Cancer Institute in Boston, Massachusetts, would be embroiled in serious controversy regarding the quality of their research publications, with a final “to-be-determined” number of peer-reviewed publications required to be withdrawn?

To be clear, the academic commu- nity has witnessed in the more distant past the need for withdrawal of manuscripts following publica- tion after they had undergone what was declared to be appropriate peer review. Consider, for example, the extremely seriously flawed research paper by Andrew Wakefield in 

that inappropriately claimed an association between measles, mumps, and rubella vaccination and the subsequent development of autism,

which was finally with- drawn 12 years after publication.

Although there is absolutely no intent in this discussion to equate the Wakefield scandal to the previously noted reports of withdrawal of scientific publications, news reports highlighting these incidences have the legitimate potential to undermine, perhaps seriously, the faith of many in the scientific stablishment.

Further, these events seem to be far from isolated. Recent reports have noted “egregious conduct” in Alzheimer studies,

 data manipulation by a prominent Harvard “honesty researcher,”

 required retractions of multiple publications dealing with sports-related concussions from the former editor in chief of a sports medicine journal,

 the retractions of several papers by a physicist studying superconductivity,

 and the ongoing investigation of manuscripts coauthored by a Nobel Prize–winning neuroscientist.

In addition to these reports of questionable publications from high-profile scientists appearing in the peer-reviewed literature, other issues raise more general concerns. There has been an explosion of journals over recent years, many unfortunately of quite dubious quality. The term predatory journals has been coined to help identify publication efforts that “do not provide scientifically rigorous peer review; their feedback is rubbish. They also have dishonest business practices.”

Unfortunately, even when a publication of this nature is identified, the company may simply rebrand itself under a different name and be back in business.

If what has already been noted is not enough, there is increasing evidence of rather large-scale fraud in certain publications, which, when discovered, has required the withdrawal of hundreds or even thousands of papers

; unabashed bribery of editors to ensure publication

; and the direct selling of coauthorship,

 including to individuals from foreign countries attempting to improve their chances to obtain a medical residency in the United States.

Naomi Oreskes notes the massive expansion of scientific publication over the past several decades.

She highlights a study finding that there are currently more than 7 million such publications each year, whereas that number in 1980 was less than 1 million. Further, she comments on “[results from] another study that found 265 academic authors—two-thirds of whom were in the medical and life sciences—who published a paper every 5 days on average.”

Who is providing the peer review for this massive number of manuscripts? Do we need to wait for the limited group of “science sleuths” to discover the errors (inadvertent or intentional) that make it through this increasingly porous process?

The concerns being emphasized here are the multiple challenges facing what has been traditionally considered the gold standard for the objective evaluation of scientific efforts, including clinical investigation: rigorously undertaken and adequately overseen peer review. 

In the opinion of this commentator, it is critical that now, and even more so in the future, the scientific community be able to effectively communicate observations from investigative efforts as well as their relevance for our individual and societal welfare, both internally and with the public. Unfortunately, if the academic peer review process is unable to be fully trusted, it is not difficult to contemplate the possible ramifications.

Kaiser J. ‘I should have done better’: Stanford head steps down. 

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Horton R. A statement by the editors of The Lancet. 

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Eggertson L. Lancet retracts 12-year-old article linking autism to MMR vaccines. 

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Subbaraman N. Harvard hospital seeks study retractions. 

Subbaraman N. Scientist engaged in misconduct, probe finds. 

Piller C. Probe of Alzheimer’s studies finds ‘egregious misconduct’. 

. 2023;382(6668):251-252.doi:10.1126/science.adl4276

O’Grady C. Embattled Harvard honesty professor accused of plagiarism. 

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Garisto D. Third retraction looms for superconductivity physicist. 

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Else H. Journals investigating Nobel winner’s papers. 

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Moher D, Moher E. Stop predatory publishers now: act collaboratively. 

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Subbaraman N. Counterfeit studies are infecting scientific journals. 

Joelving F; Retraction Watch. Paper trail. 

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Chawla DS. How a site peddles author slots in reputable publishers’ journals. 

2022;376(6590):231-232. doi:10.1126/science.abq4276

Joelving F; Retraction Watch. Prescription for controversy. 

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Oreskes N. Trouble in the fast lane: scientific research needs to slow down, not speed up. 

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Subbaraman N. Science sleuth says papers use copied images. 

From the Editor

Maurie Markman, MD, discusses concerns regarding the scientific validity of peer-reviewed publications in oncology and their ramifications for the field.  

The Scientific Validity of Peer-Reviewed Publications: A Concerning Situation With Implications for Oncology

Antibody-drug conjugates (ADCs) targeting HER2 are rapidly being established as standard-of-care therapies across breast, gynecologic, gastrointestinal (GI), lung, and genitourinary (GU) cancers, but the paradigm is far from homogeneous with current and potential future indications spanning distinct categorizations including HER2-positive, -mutated, and -amplified disease.

“HER2 can mean many different things [in the realm of cancer care]; when it’s amplified it’s a driver and contributing to the cancer’s biology,” 

, said. “Another way these proteins can contribute to the cancer’s biology is if there’s an activating mutation in the tyrosine kinase domain. Through next-generation sequencing, fluorescence in situ hybridization, and protein immunohistochemistry [IHC], we can identify these [aspects] in many different cancers. More recently, [HER2 has become] a target of convenience. Sometimes you can have a skosh of this protein present on a cancer and still have it be actionable because some of these monoclonal antibodies attached to chemotherapy warheads can still [kill] using that target.”

“[The consensus] is rapidly evolving in terms of what HER2 overexpression means. There are some data that [indicate potentially] 50% of all solid tumors have some [level of] HER2 [expression]. If you’re using it as your anchor to get your warhead in, there may be many possibilities in terms of expanding [our use of these agents to] other cancers that may not be conventionally HER2-high,” 

®, a panel of expert clinicians who specialize in various tumor types took stock of the current standing of HER2-directed ADCs in solid tumors, including breast, gynecologic, GI, lung, and GU cancers. They summarized findings that led to the FDA approvals of several ADCs across disease settings in recent years, discussed updated data from clinical trials examining HER2-directed ADCs in solid tumors presented during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, and tried to discern the agents’ current and future standing in the treatment paradigm of these disease settings.

HER2-Directed ADCs in Breast Cancer Set the Precedent for Solid Tumors

There are 2 FDA-approved HER2-targeted ADCs for the treatment of patients with breast cancer: ado-trastuzumab emtansine (T-DM1; Kadcyla) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). In 2013, the FDA first approved T-DM1 for the treatment of patients with HER2-positive metastatic breast cancer who have received prior treatment with trastuzumab (Herceptin) and taxane-based chemotherapy.

 Subsequently T-DXd was approved by the FDA for patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen in the metastatic setting or in the neoadjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. The approvals were supported by findings from the phase 3 EMILIA (NCT00829166) and DESTINY-Breast03 (NCT03529110) trials, respectively.

T-DXd later earned another indication for patients with HER2-low IHC1+ or IHC2+/in situ hybridization–negative disease who had received chemotherapy in the metastatic setting or experienced disease recurrence during or within 6 months of completing adjuvant chemotherapy based on positive data from the phase 3 DESTINY-Breast04 trial (NCT03734029). The agent is also indicated for the adjuvant treatment of patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant taxane and trastuzumab-based treatment. The 2019 regulatory decision was supported by findings from the phase 3 KATHERINE trial (NCT01772472).

“ADCs in solid tumors began with T-DM1 in the EMILIA trial,” Gadi said. “The standard of care at the time in the second line was lapatinib [Tykerb] plus capecitabine [Xeloda]. T-DM1 was both more effective and more tolerable [than that combination], with a progression-free survival [PFS] difference of several months. It had an overall survival [OS] benefit as well. This led to the approval [of T-DM1] and a renaissance of [asking], ‘What else can we do with ADCs?’”

During the 2024 ASCO Annual Meeting, investigators presented updated exploratory findings from the phase 3 DESTINY-Breast03 study, which compared T-DXd to T-DM1 in patients with HER2- positive metastatic breast cancer who had received at least 1 prior anti-HER2 regimen. The primary end point was blinded independent centrally reviewed PFS; secondary end points included OS, objective response rate (ORR), duration of response (DOR), and safety.

At the November 20, 2023, data cutoff, patients in the T-DXd (n = 261) and T-DM1 (n = 263) arms experienced a median investigator-assessed PFS of 29.0 months (95% CI, 23.7-40.0) vs 7.2 months (95% CI, 6.8-8.3), respectively (HR, 0.30; 95% CI, 0.24- 0.38). The confirmed investigator-assessed ORRs were 78.9% (95% CI, 73.5%-83.7%) vs 36.9% (95% CI, 31.0%-43.0%), respectively. The median OS was 52.6 months (95% CI, 48.7-not evaluable [NE]) vs 42.7 months (95% CI, 35.4-NE), respectively.

Investigators are also examining the potential role of T-DXd alone and in combination with pertuzumab (Perjeta) in patients with previously untreated HER2-positive advanced/metastatic breast cancer in the phase 1/2 DESTINY-Breast07 study (NCT04538742). The primary end points of the trial are safety and tolerability; key secondary end points include investigator-assessed ORR and PFS.

Antibody-drug conjugates (ADCs) targeting HER2 are becoming standard-of-care across various cancers, including breast, gynecologic, gastrointestinal, lung, and genitourinary. The understanding of HER2's role in cancer biology is evolving, with HER2-directed ADCs showing efficacy in HER2-positive, -mutated, and -amplified diseases. Recent clinical trials have demonstrated significant efficacy of ADCs like T-DXd and T-DM1 in breast cancer, leading to FDA approvals. ADCs are also being explored in other cancers, such as gynecologic, gastrointestinal, and lung cancers, with promising results in HER2-expressing tumors.

A panel of experts take stock of the current standing of HER2-directed ADCs in solid tumors, including breast, gynecologic, GI, lung, and GU cancers. 

Vol. 25/No. 11 | Oncology Live®

ODAC Weighs In on the Future of Perioperative Trial Designs in Resectable NSCLC

PARP1-Selective Inhibitors Generate Excitement in Solid Tumors

Next Generation of CDK Inhibitors Are Breaking Ground in HER2– Breast Cancer

The Scientific Validity of Peer-Reviewed Publications: A Concerning Situation With Implications for Oncology

HER2-Directed ADCs Spread Like Wildfire Across the Spectrum of Solid Malignancies

AI Is Poised to Influence Several Areas of Cancer Care With Some Fine-Tuning

From Bench to Bedside: HIF-2α Inhibition in RCC