ASCO 2023: Solid Tumors

Trastuzumab Deruxtecan Brings Encouraging Responses in HER2-Expressing Cancers Across Multiple Tumor Types

Trastuzumab deruxtecan, already used in to treat patients with breast, gastric, and lung cancers whose tumors express HER2, could be used across a range of cancers, based on early data that was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

DESTINY-PanTumor02 (NCT04482309) highlights the versality of trastuzumab deruxtecan (Enhertu), and may be the most important study yet for the antibody drug conjugate (ADC). Early phase 2 findings show the drug’s potential to receive a tumor-agnostic indication—a first in this class—which could offer an option for patients with rarer cancers expressing HER2.¹ Often, patients in small cancer populations have unmet need, as their numbers are insufficient to make up a tumor-specific study.

Meric-Bernstam

“For these patients there are no approved or targeted treatments, and often the disease is refractory to standard-of-care therapies,” said lead study author Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

After a median of 9.7 months of follow-up, trastuzumab deruxtecan brought strong responses in endometrial, cervical, ovarian, and urothelial cancers, especially for patients with HER2+ tumors with immunohistochemistry (IHC) scores of 3+.

In DESTINY-PanTumor02, only pancreatic tumors with HER2+ expression had poor responses, and Meric-Bernstam said that cohort has been closed.

“These results advance our clinical understanding of HER2 expression, reaffirm HER2 as an actionable biomarker across a broad range of tumor types, and show that trastuzumab deruxtecan could potentially provide a new treatment option for patients with advanced disease across these tumors, especially in patients with HER2 IHC 3+ or 2+ expression,” she said.

Methods and results. At the time of data cutoff, 267 patients had been treated with 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks. Patients had a median of 2 prior lines of therapy; 75 were IHC 3+ and 125 were IHC 2+ by central testing.

The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included duration of response (DOR), disease control rate, progression-free and overall survival, and safety.  By tumor type, ORRs were as follows:

• Endometrial cancer: 57.5% overall; 84.6% for IHC 3+, 47.1% for IHC 2+
• Cervical cancer: 50% overall; 75% for IHC 3+, 40% for IHC 2+
• Ovarian cancer: 45% overall; 63.6% for IHC 3+, 36.8% for IHC 2+
• Urothelial cancer: 39% overall; 56.3% for IHC 3+, 35% for IHC 2+
• Biliary tract cancer: 22% overall; 56.3% for IHC 3+, 0% for IHC 2+
• Pancreatic cancer: 4% overall; 0% for IHC 3+, 5.3% for IHC 2+

The median duration of response (DOR) was 11.8 months Among patients with IHC 3+ expression, the ORR was 61.3% and median DOR was 22.1 months.

Adverse events (AEs) of grade 3 or higher were seen 58.4% of patients; 11.6% discontinued therapy because of AEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 18 patients (6.7%), with 1 death.

During the news briefing, ASCO commentator Bradley Alexander McGregor, MD, medical oncologist, Dana-Farber Cancer Institute, pointed to the potential for trastuzumab deruxtecan to address unmet need. “This is really, really compelling data,” he said. The ADC mechanism of delivering therapy “right to the source” yielded encouraging results aside from pancreatic cancer.

“So, while early, I think this is really exciting and represents a shift in how we think about cancer care,” he said.

Investigators said the study is ongoing and data on progression-free survival (PFS) and overall survival (OS) will be presented at a later date.

Is IHC the right test? Evidence-Based Oncology (EBO) asked Andrew Hertler, MD, who advises payers and major employers in his role as chief medical officer for New Century Health, for his observations on the DESTINY-PanTumor02 findings. EBO had discussed the DESTINY-Breast04 results involving trastuzumab deruxtecan with Hertler earlier this year² after that trial identified a new classification of HER2-low breast cancer when it was presented at ASCO 2022.³

“It is interesting that response rates were superior in patients with HER2 scores of 3+ by IHC over 2+ which seems somewhat discordant with the activity of [trastuzumab deruxtecan] in HER2-low breast cancer,” Hertler said in an email.

He also noted that, “The rate of drug-related treatment-emergent adverse events (TEAEs) was high (84.3%) with 38.6% of patients experiencing grade 3 or higher TEAEs.”

The data presented, Hertler observed, involved only response rate and DOR. “Given that response rate correlates with overall survival improvement less than 50% of the time, I anxiously await these results to determine ultimate patient benefit,” he said. If trastuzumab deruxtecan “shows clinically meaningful OS and PFS benefits, it could be practice changing and an improvement over available options for these patients.”

However, Hertler said: “We need to resolve whether IHC is the best test for a tumor-agnostic approach, given the fact that discordant results have been seen when the same specimen is tested in different laboratories. Would next-generation sequencing be a superior test?”

AstraZeneca and Daiichi Sankyo funded the study.

References
1. Meric-Bernstam F, Makker V, Oaknin A. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41(suppl 17):abstract LBA3000. doi:10.1200/JCO.2023.41.17_suppl.LBA3000
2. Caffrey M. New Century Health’s Andrew Hertler, MD, FACP: “you have to be careful when you look at total cost of care.” Am J Manag Care. 2023;29(spec 2):SP101.
3. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

Study: Half of Patients Whose Cancers Were Detected With CancerSEEK MCED Test Are Cancer Free 4 Years Later

Half of all patients whose cancer was discovered with the CancerSEEK multicancer early detection (MCED) blood test remained cancer free more than 4 years after treatment following their initial test, according to results of the DETECT-A study.¹ Results of the study were presented in an abstract and poster during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

The observational study of 26 participants, who were diagnosed with 9 cancer types, found the cancers were discovered earlier than would have been the case with standard of care (SOC). These results included cases involving 7 patients diagnosed with cancer types for which no SOC screening option exists.

Investigators found that CancerSEEK, coupled with diagnostic PET-CT, safely identified cancers including those not detected by SOC screening, most of which were localized or regional. Other research has validated the combined use of MCED and PET-CT in clinical care to determine which patients need surgery with intent to cure.²

DETECT-A was the first large prospective interventional clinical trial to evaluate an MCED blood test. DETECT-A enrolled approximately 10,000 women, ages 65 to 75 years, with high adherence to SOC screening to evaluate CancerSEEK, an early version MCED test. Investigators extracted information from electronic medical records through November 2022 on cancer diagnosis, treatment, treatment response, remission status, recurrence, secondary cancer diagnoses, and mortality, both from cancer and all causes. Data collection for living participants took place a median of 3.7 years following confirmed cancer diagnosis and a median of 4.3 years following the initial CancerSEEK screening.

Of the 26 diagnosed patients, 14 (53.8%) underwent surgery. Among these patients, 5 had only surgery and 9 were treated with both surgery and adjuvant and/or neoadjuvant chemotherapy, radiation, or hormone therapy. Twelve of 14 (85.7%) surgically treated participants were in remission as of November 2022, including 10 with localized or regional disease at diagnosis.

For the remaining 12 patients among the 26 whose cancer was initially detected by CancerSEEK, 11 received nonsurgical treatment. Follow-up treatment for 1 participant was unknown. One patient with a stage I diagnosis was in remission, 9 patients who were stage III or IV at diagnosis were deceased (75.0%), and 2 patients diagnosed at stage II and stage III (16.7%) were in surveillance or ongoing treatment.

Overall, 13 of 26 participants were in remission at the time of follow-up. Four of those participants had ovarian cancer, 4 had thyroid cancer, 2 had cancer of the uterus, 1 had breast cancer, 2 had colorectal cancer, and 3 had lung cancer. Seven of the 13 patients in remission (54%) had cancers without recommended SOC screening modalities.

Eleven of 17 (64.7%) participants with localized or regional disease (stage I, II, or III) were in remission. Two of 9 patients (22.2%) with stage IV disease at diagnosis were in remission.

“CancerSEEK detected cancers earlier in patients who, when treated subsequently with conventional methods, achieved long-term survival,” the investigators concluded.

Evaluation of False-Positive Results. A related study presented at ASCO of 98 DETECT-A participants who received a false-positive (FP) result from the CancerSEEK test found that 96 participants remained cancer free more than 4 years later.³ The investigators defined an FP as a positive CancerSEEK result with subsequent PET-CT and clinical evaluation, with no evidence of cancer within 1 year of the initial CancerSEEK test. Of the 98 participants with FPs, 63 had no follow-up procedure performed after imaging and 35 subjects had noninvasive or minimally invasive follow-up procedures performed.

“Patients with a negative PET-CT and initial clinical evaluation after a positive CancerSEEK test had low [1% per year] risk for cancer in the ensuing 4 years after the initial CancerSEEK test,” the investigators concluded. “If confirmed, this result should prove reassuring to clinicians and to patients who have no evidence of cancer on comprehensive imaging following a positive MCED test. Further, these results provide preliminary support for the recommendation that patients who participate in MCED testing and receive an FP result can safely return to routine care after comprehensive anatomic and functional imaging and clinical evaluation reveal no suspicion of cancer.”

Both studies were sponsored by Exact Sciences Corp.

References
1. Buchanan AH, Lennon AM, Rego SP, et al. Long-term clinical outcomes of cancers diagnosed following detection by a blood-based multi-cancer early detection (MCED) test. J Clin Oncol. 2023;41(suppl 16):3037. doi:10.1200/JCO.2023.41.16_suppl.3037
2. Lennon AM, Buchanan AH, Kinde I, et al. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science. 2020;369(6499):eabb9601. doi:10.1126/science.abb9601
3. Lennon AM, Buchanan AH, Rego SP, et al. Outcomes in participants with a false positive multi-cancer early detection (MCED) test: results from >4 years follow-up from DETECT-A, the first large, prospective, interventional MCED study. J Clin Oncol. 2023;41(suppl 16):3039. doi:10.1200/JCO.2023.41.16_suppl.3039

Adding Olaparib and Durvalumab Improved PFS in Patients Newly Diagnosed With Advanced Ovarian Cancer

Patients newly diagnosed with advanced ovarian cancer without BRCA mutations who received olaparib, a PARP inhibitor, and durvalumab, an immune checkpoint inhibitor, along with standard of care saw improved progression-free survival (PFS), according to results presented June 3 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

An interim analysis from the DUO-O study,¹ an international, randomized, phase 3 clinical trial (NCT03737643), shows that adding this novel combination improved outcomes compared with standard of care for these patients, who may show no sign of cancer until their disease has progressed.² Despite treatment advances over the past decade, most ovarian cancers are not caught until later stages, and the 5-year survival rate for ovarian cancer caught at stage III is 41%.³ Thus, in advanced ovarian cancer, preventing relapse is key.

The current standard of care for patients who are newly diagnosed with advanced cancer is chemotherapy and bevacizumab. Prior studies of patients newly diagnosed with ovarian cancer showed success using olaparib in those with BRCA mutations; a study published in the Annals of Oncology combined olaparib with bevacizumab in patients with homologous recombination deficiency (HRD)–positive tumors. HRD limits the ability to repair double-strand DNA breaks, making these tumors strong candidates for treatment with PARP inhibitors—which stop cancer cells with damaged DNA from repairing themselves and replicating.

Olaparib currently has several indications in ovarian cancer: for first-line maintenance in BRCA-mutated advanced ovarian cancer, for first-line maintenance in HRD-positive advanced ovarian cancer in combination with bevacizumab, and for maintenance in recurrent ovarian cancer. Olaparib, sold as Lynparza, and durvalumab, sold as Imfinzi, are both made by AstraZeneca.

Harter

In DUO-O, 1130 patients with stage III or IV high-grade epithelial tumors were randomized into 3 arms. All patients received standard of care, which was paclitaxel/carboplatin chemotherapy plus bevacizumab, followed by maintenance bevacizumab.

In the second and third arms, patients also received durvalumab, both upfront and in the maintenance phase. Patients in the third arm also received olaparib in the maintenance phase. Interim results show¹:

• Investigators found no significant difference in PFS between the control arm and the durvalumab arm (arms 1 and 2).
• PFS increased in patients in the durvalumab-plus-olaparib arm compared with the standard-of-care arm. Among this group, for HRD-positive patients, PFS was 37.3 months vs 23 months for those in the control arm.
• In the intent-to-treat (ITT) population, PFS was 24.2 months in the durvalumab-plus-olaparib arm vs 19.3 months for those in the control arm. ITT refers to following all patients in the arms they were assigned, regardless of the treatment they ultimately received; 90% of patients completed the trial.
• Among patients in the durvalumab-plus-olaparib arm, the risk of the disease progressing was 51% lower in patients with HRD-positive tumors, for an HR of 0.49 (95% CI, 0.34-0.69; P < .0001). That risk was 37% lower for the ITT patients, compared with the control arm, for an HR of 0.63 (95% CI, 0.52-0.76; P < .0001).
• The risk of disease progression was 32% lower in all subgroups, including both HRD-positive and HRD-negative patients, compared with the control arm (HR, 0.68, 95% CI,
  0.54-0.86).
• Serious adverse events were reported in 34% of the control arm, 43% in the durvalumab arm, and 39% in the durvalumab-plus-olaparib arm.

“While there has been significant progress for patients with advanced ovarian cancer, an unmet need still remains,” Philipp Harter, MD, PhD, director in the Department of Gynecology and Gynecologic Oncology at the Evangelische Kliniken Essen-Mitte hospital in Essen, Germany, said in a statement from ASCO.⁴ “Our trial results provide encouraging evidence that we can find new treatment approaches for patients with advanced disease.”

Investigators noted that additional findings, including overall survival, will be presented as the study progresses.

Data from ASCO’s Cancer.net show that in 2023, an estimated 19,170 people will be diagnosed with ovarian cancer in the United States, and there will be 13,270 deaths from this disease.⁵ Most new diagnoses will be epithelial ovarian cancer (90%), which begins in the fallopian tube. Cases of ovarian cancer fell each year by 1% to 2% from 1990 to the mid-2010s, and by close to 3% each year from 2015 to 2019, which ASCO attributes to higher use of oral contraceptives and the reduced use of hormone therapy for menopause in the 2000s. About half of those diagnosed with ovarian cancer are 63 years or older.

Commentator Merry Jennifer Markham, MD, of the University of Florida, emphasized the need for more treatment options given the lack of early detection methods for ovarian cancer. In a news briefing, she noted that women who do not have a BRCA mutation are sometimes “disappointed” because until now this has limited their choices of therapy.

“While more research is needed, this trial’s finding that a novel combination of therapies can prolong progression-free survival is indeed promising for patients with advanced ovarian cancer,” she said in the ASCO statement.⁴

References
1. Harter P, Trillsch F, Okamoto A, et al. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): results from the randomized, placebo (pbo)-controlled phase III DUO-O trial. J Clin Oncol. 2023;41(suppl 17):abstr LBA5506. doi:10.1200/JCO.2023.41.17_suppl.LBA5506
2. Markman M. Ovarian cancer diagnosis. City of Hope. Updated May 23, 2022. Accessed June 13, 2023. https://bit.ly/3NrcPSZ
Stages of ovarian cancer. Ovarian Cancer Research Alliance. Accessed June 13, 2023. https://ocrahope.org/get-the-facts/staging/
3. Addition of olaparib and durvalumab prolonged progression-free survival in patients with advanced ovarian cancer. News release. American Society of Clinical Oncology; June 3, 2023. Accessed June 3, 2023. https://bit.ly/3qALJ2F
4. Ovarian, fallopian tube, and peritoneal cancer. American Society of Clinical Oncology / Cancer.net. Accessed June 3, 2023. https://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer

NATALEE Trial: Ribociclib With Hormonal Therapy Cuts Recurrence Risk by 25% in Most Common Type of Breast Cancer

Adding the CDK4/6 inhibitor ribociclib (Kisqali, Novartis) to hormonal therapy made cancer 25% less likely to return for those patients with hormone receptor (HR)–positive, HER2-negative early-stage breast cancer (EBC), according to results presented on June 2, 2023, at the 2023 Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois.¹

Interim findings from the NATALEE trial (NCT03701334) could have widespread impact, as HR+/HER- breast cancer accounts for 70% of all new breast cancer cases, according to National Institutes of Health data.²

Slamon

NATALEE enrolled patients with stage II and stage III HR+/HER2– EBC, regardless of nodal involvement. The primary end point, invasive disease-free survival (iDFS), measures whether a patient’s cancer has returned.
“NATALEE is different from some other early breast cancer studies with CDK4/6 [inhibitors] in 3 important ways,” said lead investigator Dennis J. Slamon, MD, PhD, director of clinical/translational research, professor of medicine, and chief of the Division of Hematology/Oncology at UCLA’s Department of Medicine, during a press briefing held prior to ASCO.

He listed the ways the trial broke new ground:

• The trial included patients with earlier-stage disease, who Slamon said are “normally considered lower risk than the high-risk population.”
• In an effort to improve safety, the dose was reduced from the usual 600 mg to 400 mg based on findings from other trials involving patients with metastatic breast cancer that showed when doses were reduced due to tolerability, efficacy was not lost.
• The study treated patients for 3 years instead of 2 years.

The trial randomized 5101 premenopausal and postmenopausal women and men with breast cancer who were at risk of recurrence. Patients received either adjuvant ribociclib with hormonal therapy (2549 patients) or hormonal therapy alone (2552 patients). After a median follow-up of 34 months, 20.2% of those in the ribociclib group completed 3 years of treatment, and 56.8% completed 2 years.

The prespecified analysis evaluated data once there were 426 iDFS events. Data presented at ASCO showed 189 people in the ribociclib group (7.4% of patients) had a cancer recurrence, compared with 237 people in the group receiving hormonal therapy alone (9.2% of patients).Pairing ribociclib with hormonal therapy in this setting created significant improvement in survival.

Results showed:

• 3-year iDFS rates were 90.4% in the ribociclib group, compared with 87.1% in the hormonal therapy–alone group. Adding ribociclib reduced the risk for recurrence by 25%.
• The addition of ribociclib improved survival for a broad population of people with HR+/HER2– EBC.
• This therapeutic option would help patients whose cancer has not spread to the lymph nodes.
• Overall, 74.7% of participants were still being treated at the data cutoff, with 1984 patients treated with ribociclib and 1826 patients treated with hormonal therapy alone.

“Based on the number of patients who are challenged with this subtype of disease,” Slamon said, the findings “could result in a significant efficacy improvement.”

He noted that findings were consistent across subgroups, disease stage, menopausal status, and nodal status. “So that means even patients with node-negative disease—who are normally thought to be those with lower-risk disease—benefited as well,” he said.

Slamon noted that the reduced dose appeared to improve some safety signals in cardiotoxicity.

“While early, these results are very promising and suggest that there will be a role for adjuvant ribociclib for stage II and higher [HR-positive], HER2– negative breast cancer,” said commentator Rita Nanda, MD, an associate professor of medicine at the University of Chicago in Illinois.

The NATALEE study protocol calls for ongoing follow-up to evaluate long-term outcomes, including overall survival.

In January, an update to the National Comprehensive Cancer Network clinical guidelines for breast cancer recommended ribociclib as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of patients with HR+/HER2– metastatic breast cancer when combined with an aromatase inhibitor.³

In March, when Novartis officials announced top-line results for NATALEE, they said it represented the broadest patient population of any CDK4/6 inhibitor trial to date. Citing data published in the New England Journal of Medicine,⁴ the officials said 30% to 60% of the patient population represented in the NATALEE trial currently remains at risk of breast cancer recurrence with endocrine therapy only, and that EBC represents more than 90% of patients with breast cancer.

References
1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17). doi:10.1200/JCO.2023.41.17_suppl.LBA500
2. National Cancer Institute. Cancer stat facts: female breast cancer subtypes. Accessed June 12, 2023. https://bit.ly/45WFEOl
3. Novartis ribociclib (Kisqali) only category 1 preferred first-line treatment option in HR+/HER2- mBC combination with an AI in updated NCCN clinical practice guidelines in oncology (NCCN guidelines). News release. Novartis. March 28, 2023. Accessed June 12, 2023. https://bit.ly/3X0q3JE
4. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi:10.1056/NEJMoa1701830

SPOTLIGHT: Dennis Slamon, MD, PhD, on What Sets the NATALEE Trial Apart From Other Breast Cancer Studies

Dennis Slamon, MD, PhD, lead investigator on the NATALEE trial1 of ribociclib plus hormonal therapy in hormone receptor–positive, HER2-negative early-stage breast cancer (NCT03701334), discussed interim findings of the study’s broad population and potential payer reactions with Evidence-Based Oncology (EBO).

EBO: What elements make this trial different from other studies in early breast cancer?

Slamon: The biggest element that differentiates this trial from other trials is the inclusion of a broader population of these patients—in other words, patients with node-negative disease, patients with lower-stage disease. Some of the trials were really focused on high-risk patients. Are those the only patients who can benefit from the drug? Patients who have lower risk but are still at risk for having—30% will have a recurrence 2 or 3 decades out—can those patients be benefited? Well, the trial is including those patients in the study.

EBO: If this treatment approach is used in real-world settings, do you feel payers will see value in the improved safety profile vs the longer treatment duration?

Slamon: My sense is that it all depends on the data. If the data are strong enough and there is a survival advantage, I think payers would be hard pressed not to provide reimbursement for the drug. Clearly, drug pricing is important. And it should be rational in terms of what the drug costs are. But if it provides real value and really makes an impact both on quality of life and life itself, I think those drugs should be paid for. 

Reference
Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17):abstr LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500

Abemaciclib Plus ET Is Effective for Older Patients With HR+, HER2–, Early Breast Cancer, but Need for Dosing Management Seen

The benefit seen for patients with hormone receptor–positive, HER2-negative, high-risk, early breast cancer who receive adjuvant abemaciclib plus endocrine therapy holds up regardless of age, according to a new analysis from the monarchE trial (NCT03155997) presented during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Hamilton

However, Erika P. Hamilton, MD, director of the Breast and Gynecologic Cancer Research Program at Sarah Cannon Research Institute, Nashville, Tennessee, who reported the latest results at ASCO, noted that patterns of adverse events (AEs) and drug discontinuation show the need to try dose reductions before stopping therapy, especially among older patients.

Older patients typically went into cancer treatment with more comorbidities, were more likely to have a dose reduction, and were more likely to stop therapy, she said in an interview.

“Despite the fact that tolerability was pretty similar across the board, we did see more dose discontinuations and reductions in our older patients compared to younger patients,” Hamilton said. “So discontinuations were actually more than double—about 15% in patients that were less than 65 and about 38% in those patients that were greater than 65.”

Abemaciclib, sold as Verzenio, is the first of a class of targeted therapies called CDK4/6 inhibitors to show an adjuvant benefit for these patients in an analysis of monarchE presented at the 2022 San Antonio Breast Cancer Congress and published in The Lancet Oncology.² After a median follow-up of 42 months, a 34% reduction in the risk of developing an invasive disease-free survival (iDFS) event was seen with adjuvant abemaciclib plus endocrine therapy (ET) vs ET alone (HR, 0.664; 95% CI, 0.578-0.762; nominal P < .0001). Four-year iDFS rates were 85.8% vs 79.4%, with and without abemaciclib, respectively.²

At ASCO, Hamilton reported that the 4-year iDFS rate for patients 65 years or older in the abemaciclib group (n = 437) was 82.0% vs 76.8% for patients who received endocrine therapy alone (n = 413). For the older patients, the absolute magnitude of benefit was 5.2% (HR, 0.767; 95% CI, 0.556-1.059). For patients who were younger than 65 years, the 4-year iDFS rates were 86.5% with abemaciclib and ET (n = 2371) vs 79.8% with ET alone (n = 2416) for an absolute magnitude of benefit of 6.7% (HR, 0.646; 95% CI, 0.554-0.753).¹

“For our patients that were 65 years of age or greater, consistent results were observed in cohort 1,” Hamilton said. “For patients with hormone receptor–positive, HER2-negative, high-risk, early breast cancer, adjuvant abemaciclib plus ET showed consistent treatment benefit across age subgroups with clinically meaningful absolute risk reduction in both iDFS as well as DRFS rates observed in both younger and older patients.”

Results for distant relapse-free survival (DRFS) showed an absolute magnitude of benefit of 6.2% among the younger patient population and 4.6% benefit was observed in the older population.¹ The 4-year DRFS rates for younger patients was 88.8% among those taking abemaciclib plus ET vs 82.6% for ET alone (HR, 0.647; 95% CI, 0.548-0.764). In older patients the 4-year DRFS rate was 86.1% with the addition of abemaciclib to ET vs 81.5% with ET alone (HR, 0.748; 95% CI, 0.520-1.077).¹

In the phase 3 monarchE trial, patients were randomly assigned to receive 150 mg of adjuvant abemaciclib twice daily for 2 years in addition to standard-of-care ET or ET alone. “The objective of this analysis of monarchE was to explore the efficacy and safety of adjuvant abemaciclib and the subgroup of older patients [who] were enrolled,” Hamilton said. “All patients went on to receive 3 to 8 years of standard single-agent ET per patient and physician decision. All patients are off abemaciclib with a median follow-up of 42 months. Efficacy, safety, and patient-reported outcome analyses were conducted in 2 age groups: those patients who were [younger] than 65 years and those that were 65 years or greater. Patients who were [older] than 75 years made up only 3% of the study population, which really precluded a detailed outcome analysis in this subgroup.”

The baseline characteristics for the intention-to-treat population were well balanced with a median age of 51 years (range, 44-60).² Baseline factors included pathologic tumor size, number of positive lymph nodes, histopathological grade, prior neoadjuvant chemotherapy, and ECOG performance status.

More Comorbidities Among Older Patients. Most younger patients had a tumor size of 20 mm to less than 50 mm (48%), at least 4 positive lymph nodes (59%), and G2 disease (49%), had received neoadjuvant chemotherapy (97%), and had an ECOG performance status of 0 (86%).

Older patients mostly had tumor size of 20 mm to less than 50 mm (57%),⁴ or more positive lymph nodes (64%), and G2 disease (52%). Hamilton highlighted the fact that fewer older patients had neoadjuvant chemotherapy (82%) and ECOG performance status of 0 (77%), which was expected.

“Similarly, in terms of patients who had 4 or more baseline preexisting comorbidities, only 33% of our younger patients experienced this [compared with] more than half at 51% of our older patients,” Hamilton said. Further, among treated patients, 95% of older patients (n = 840) received aromatase therapy as their initial endocrine therapy compared with 64% of younger patients, more of whom received tamoxifen.¹

Adverse event (AE) rates were similar between age groups, Hamilton noted. “In terms of neutropenia, ALT increase, venous thromboembolism [VTE], or ILD [interstitial lung disease] there were not even numerical increases for older patients compared with younger patients,” she said.

Clinically relevant AEs for the overall population (n = 2791), younger patients (n = 2361), and older patients (n = 430), were reported as follows:
grade 1 diarrhea (45% vs 46% vs 37%), grade 2 diarrhea (31% vs 31% vs 30%), and grade 3 diarrhea (8% vs 7% vs 12%); grade 1 fatigue (23% vs 23% vs 21%), grade 2 fatigue (15% vs 14% vs 20%), and grade 3 fatigue (3% vs 2% vs 6%); grade 1/2 neutropenia (26% vs 27% vs 22%), grade 3 or higher neutropenia (20% vs 20% vs 19%); grade 1/2 ALT increase (10% vs 10% vs 7%), grade 3 or higher ALT increase (3% vs 3% vs 3%); and any-grade VTE (3% vs 2% vs 3%), grade 3 or higher VTE (1% vs 1% vs 1%), any-grade ILD (3% vs 3% vs 3%), and grade 3 or higher ILD (all less than 1%).¹

“In terms of diarrhea, any-grade diarrhea was actually 5% less common in older patients than younger patients,” Hamilton said. “However, grade 3 or higher severe diarrhea was 5% more frequent…. Despite this, dose adjustments were more common in older patients with 42% of the younger patients [having] dose reductions, whereas 55% of the patients 65 years of age or older did.” She added that discontinuations were more than double in older patients at 38% compared with 15% for younger patients. “Over half of patients who discontinued on study did so without attempting a dose reduction, and this was across both age groups.”

Patients who were treated with abemaciclib who required a dose reduction were placed into 3 equal-sized subgroups according to dose intensity (0%-66% [n = 926]; 66%-93% [n = 928]; and ≥ 93% [n = 927]). The 4-year iDFS rates were similar across the groups at 87.1%, 86.4%, and 83.7%, respectively.¹

“Based on this, I would suggest that in order to maintain treatment compliance—particularly seeing that over half of the patients who discontinued abemaciclib did so without utilizing a dose reduction—that older patients should be counseled about symptom management and monitored closely for AEs that should prompt a dose modification,” Hamilton said.

She noted that quality of life was preserved in both age groups during the 2-year treatment period.

“These data support the use of adjuvant abemaciclib across age groups and can be used to counsel patients about expectations of treatment experience, and also the safety and utilizing of dose reductions if needed,” she concluded.

Eli Lilly and Co is the sponsor of monarchE.

A version of this article first appeared in OncLive®.

References
1. Hamilton EP, Kim JH, Eigeliene N, et al. Efficacy and safety results by age in monarchE: adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2, node-positive, high-risk early breast cancer (EBC). J Clin Oncol. 2023;41(suppl 16):501. doi:10.1200/JCO.2023.41.16_suppl.501
2. Johnston SRD, Toi M, O’Shaughnessy J, et al; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. doi:10.1016/S1470-2045(22)00694-5

SPOTLIGHT: Debra Patt, MD, PhD, MBA, Discusses ASCO Data on CDK4/6 Inhibitors

Medical oncologist and breast cancer specialist Debra Patt, MD, PhD, MBA, is executive vice president of Texas Oncology and a clinical professor at the Dell

Patt

Medical School at The University of Texas at Austin. Evidence-Based Oncology (EBO) asked Patt to discuss recent results involving CDK4/6 inhibitors and data from the phase 3 NATALEE trial¹ (NCT03701334) for ribociclib (Kisqali). Other results discussed included additional data from the monarchE trial² (NCT03155997) for abemaciclib (Verzenio). The data were presented at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting.

EBO: Results were presented at ASCO involving CDK4/6 inhibitors. Did they offer additional insights on when to use the different therapies?

Patt: Yes, actually. Prior to the ASCO meeting, only abemaciclib had been demonstrated to be effective in the in the adjuvant setting.³ [These are] patients with high-risk ER+/HER2– breast cancers with either 4 or more nodes positive or 1 to 3 nodes positive that are either [larger than] than 5 cm or grade 3. [With] these high-risk features, they would benefit from 2 years of adjuvant abemaciclib in addition to endocrine blockade, and that would reduce their risk of recurrence substantially. What we learned from the ASCO meeting that is new is from the NATALEE trial. The trial looked at ribociclib, given 3 weeks on and 1 week off at a lower dose, actually 400 mg [instead of 600 mg] for 3 years in the adjuvant setting. And what we saw is that it also [led to] statistically significant improvement of progression-free survival.¹ I would say that it’s a relative risk reduction of [approximately] 25% in comparison with what it otherwise would be with endocrine therapy alone. And there was a trend—but early and not yet statistically significant—toward the survival advantage. So, all that being said, it’s not FDA approved yet. We’ll continue to watch for approval, but it does look like there’s clear evidence for efficacy of adjuvant ribociclib in this space. It gives us another tool in our toolbox. 

References
1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase 3 NATALEE trial. J Clin Oncol. 2023;41(suppl 17):LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500
2. Hamilton EP, Kim JH, Eigeliene N, et al. Efficacy and safety results by age in monarchE: adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC). J Clin Oncol. 2023;41(suppl 16):501. doi:10.1200/JCO.2023.41.16_suppl.501
3. Johnston SRD, Harbeck N, Hegg R, et al for the monarchE Committee Members and Investigators. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. doi: 10.1200/JCO.20.02514.

Osimertinib Shows Significant OS Benefit in Patients With Resected EGFRm NSCLC

Adjuvant osimertinib (Tagrisso) with or without chemotherapy substantially improved overall survival (OS) vs placebo among patients with resected EGFR-mutated (EGFRm) non–small cell lung cancer (NSCLC), according to final data presented during the June 4 plenary session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.¹ Results from the OS analysis of the phase 3 ADAURA trial (NCT02511106) showed an estimated 88% of patients treated with osimertinib were alive at 5 years compared with 78% on placebo, AstraZeneca officials noted in a statement.²
Osimertinib demonstrated improved disease-free survival (DFS)—the main study end point—in the primary analysis of ADAURA, which was featured in

Herbst

the plenary session at the 2020 ASCO Annual Meeting in Chicago.³ In addition to OS improvement, the updated data show sustained DFS and central nervous system DFS at 2 additional years of follow-up.

The third-generation EGFR tyrosine kinase inhibitor was the first targeted agent to be FDA approved for adjuvant management of resected EGFRm NSCLC in 2020.4 But the lack of OS data at the time was a sticking point for some, lead study author Roy S. Herbst, MD, PhD, explained during a press briefing ahead of the 2023 plenary session. Herbst is deputy director of Yale Cancer Center and assistant dean for translational research at Yale School of Medicine, both in New Haven, Connecticut.

“Despite the fact that we had these [DFS] data and this drug is approved in the [United States] and many countries, overall survival is considered the gold standard for treatment efficacy, and everyone was keenly awaiting these data,” Herbst said. “There are some places that have not approved it yet. There are some physicians, many surgeons—even some of my surgeon colleagues at Yale—[who] do not recommend this because they’re waiting to see, does this improve survival?”

Osimertinib demonstrated unprecedented and statistically significant OS with or without chemotherapy in the updated analysis, and the findings were consistent across patient subgroups. A tolerable safety profile in line with previous reports was also seen over the course of the extended follow-up. These findings are poised to broaden access to osimertinib in this patient population.

“With the unequivocal, highly clinically significant improvement in overall survival at 5 years with 3 years of osimertinib across stage I, II, and IIIA, we’ve now firmly put to rest the question about whether we should be using our most effective treatment in these [patients] based upon biomarkers,” said ASCO expert Nathan Pennell, MD, PhD, FASCO, associate professor and director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute. “And we should firmly close the door on one-size-fits-all treatment for [patients] with non–small cell lung cancer.”

In the ADAURA trial, a total of 682 patients with stage IB to IIIA EGFRm NSCLC were randomly assigned to receive either osimertinib (n = 339) or placebo (n = 343) once daily until disease recurrence, treatment completion at 3 years, or treatment discontinuation due to meeting discontinuation criteria. In the overall population, the HR for OS was 0.49 (95% CI, 0.34-0.70; P < .0001; 124/682 events, 18% maturity), a finding mirrored in patients with stage II to IIIA disease (HR, 0.49; 95% CI, 0.33-0.73; P = .0004; 100/470 events, 21% maturity).

In the overall population, the 5-year OS rates in the osimertinib and placebo cohorts were 88% and 78%, respectively. Median follow-up for OS was 60.⁴ months in the osimertinib cohort and 59.4 months in the placebo cohort. In patients with stage II to IIIA disease, the 5-year OS rate was 85% in the osimertinib cohort compared with 73% in the placebo cohort at median follow-ups of 59.9 months and 56.2 months, respectively. “It’s the first global phase 3 study [with findings] to demonstrate statistically significant and clinically meaningful DFS and OS benefit with targeted therapy in this patient population, reinforcing osimertinib as the standard of care in this group,” Herbst said.

Approximately 12% to 25% of lung cancers in the United States and 30% to 40% of lung cancers in Asia have EGFR mutations, but patients who could benefit from targeted therapies, including osimertinib, must first be identified, Herbst said. Therefore, spreading awareness of the importance of genomic testing for targetable mutations and minimizing socioeconomic barriers to testing is crucial.

“One of the things we’re hoping will come out from these data is that we have new therapies we can offer to patients. If we screen, if we find these mutations, we can make a difference—but only if we find those patients,” Herbst said.

References
1. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 17):LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3
2. Tagrisso achieved unprecedented survival in early-stage EGFR-mutated lung cancer, with 88% of patients alive at five years in ADAURA phase III trial. AstraZeneca. June 4, 2023. Accessed June 14, 2023. https://bit.ly/3CrlwGr
3. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5
4. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed June 14, 2023. https://bit.ly/3X4N1PQ

Searching for New Solutions in Treating EGFR-Mutant NSCLC

Worldwide, about 2.2 million people receive a diagnosis of lung cancer each year; between 80% and 85% of these cases are non–small cell cancer (NSCLC).¹ About 33% of those who receive a diagnosis of NSCLC have EGFR mutations, although these are not evenly distributed—those with EGFR-mutant NSCLC are more likely to be Asian, female, and nonsmokers^.2

As the number of lung cancer cases drops overall because of declining smoking rates, the need for treatments for those with EGFR-mutant driven lung cancer rises in importance. This was reflected by 3 abstracts on potential new regimens featured in an oral abstract session on metastatic lung cancer during the final day of the 2023 American Society of Clinical Oncology Annual Meeting.

For reasons not entirely clear, treatment of patients with EGFR-mutated NSCLC with immune checkpoint inhibitors (ICIs) presents certain challenges;³ following development of tyrosine kinase inhibitor (TKI) resistance, treatment with single-agent immunotherapy is not very effective, according to a July 2022 review article in Frontiers in Immunology.⁴ However, the authors wrote, “compared with monotherapy, ICIs combined with chemotherapy can improve efficacy.”

Thus, strategies presented at the ASCO session included both pairing ICIs with additional agents or developing new therapies, including those designed to cross the blood-brain barrier to deal with one of the more challenging effects of lung cancer: brain metastases.

Reiss

ASCO commentator Jonathan W. Riess, MD, medical director of thoracic oncology, University of California, Davis, Comprehensive Cancer Center, saw promise in sunvozertinib, a therapy to treat NSCLC with EGFR exon 20 insertion. But when it came to another therapy, zorifertinib, he did not recommend moving away from osimertinib as first-line therapy for EGFR-mutated lung cancer.

Riess said the issue of sequencing therapies will also offer challenges for clinicians moving forward.

Pembrolizumab with pemetrexed + platinum chemotherapy. James Yang, MD, PhD, professor and director, Graduate Institute of Oncology, National Taiwan University Cancer Center, presented late-breaking results from KEYNOTE-789 (NCT03515837), a randomized, phase 3 study of pemetrexed plus platinum chemotherapy with or without pembrolizumab (Keytruda) in patients with TKI-resistant EGFR-mutated metastatic NSCLC.⁵
EGFR-TKI therapies are standard for patients with previously untreated NSCLC with sensitizing EGFR mutations, Yang said. “However, most patients will develop resistance, and at the time of resistance the standard of care is still a combination chemotherapy.”

Although studies in metastatic NSCLC showed overall survival (OS) benefit by combining ICIs with combination therapy, Yang noted “all or most of these studies did not include patients with EGFR mutations,” because in prior studies, use of ICIs in this group was shown to be inferior. However, a prior study showed a signal for a small group of EGFR-mutated patients with PD-L1 expression who received pembrolizumab vs docetaxel.⁶

“In order to answer this question, it is important to perform this study to figure out the role of immune checkpoint inhibitors adding to chemotherapy for salvage after EGFR-TKI failure,” Yang said.

Investigators enrolled adults with confirmed stage IV nonsquamous NSCLC, ECOG performance status of 0 or 1, documented EGFR mutation, and progression after EGFR-TKI therapy. Patients were randomly assigned to 35 cycles of pembrolizumab (245 patients) or placebo (247 patients), plus 4 cycles of pemetrexed and carboplatin or cisplatin followed by maintenance pemetrexed. Patients were also stratified by PD-L1 tumor proportion score (TPS), prior osimertinib, and whether or not they were from East Asia.

Progression-free survival (PFS) was assessed at a second interim analysis, and other end points, including overall survival (OS) and safety, were assessed at the final data cutoff in January 2023. Results for median PFS favored pembrolizumab, 5.6 months vs 5.5 months (HR 0.80; 95% CI, 0.65-0.97; P = .0122) but did not reach statistical significance. Results for OS also favored pembrolizumab, 15.9 months vs 14.7 months, but did not reach clinical significance (HR 0.84; 95% CI, 0.69-1.02; P = .0362). OS rates at 12 months were 61.6% vs 59.4% and at 24 months were 30.6% vs 26.4%, favoring pembrolizumab. Results for OS were improved for patients in the pembrolizumab group among those with PD-L1 TPS greater than or equal to 1% vs those with PD-L1 TPS less than 1% (+4.5 months vs +1.0 month). Grade 3 or higher treatment-related adverse events (AEs) were higher in the pembrolizumab arm.

“Results were consistent with prior findings that TKI-resistant, EGFR-mutant metastatic non–small cell lung cancer derived less benefit from anti–PD-1 or PD-L1 treatment in EGFR wild-type patients, yet there [was] a biomarker that was identified, which is PD-L1 status more than 1%, which deserves further investigation in the future,” Yang said.

Results for Zorifertinib. Yi-Long Wu, MD, professor at Guangdong Lung Cancer Institute, presented results from EVEREST (NCT03653546), the randomized phase 3 study of first-line zorifertinib, a next-generation EGFR-TKI inhibitor, vs first-generation gefitinib or erlotinib in EGFR-mutant NSCLC with central nervous system (CNS) metastasis.⁷

Zorifertinib is being developed by Alpha Biopharma, which paid for the study.

“As you know, more than 50% of patients with non–small cell lung cancer and the EGFR-mutant patients develop brain metastases during their lifetime,” Wu said, noting these patients have a very poor prognosis. Thus, developing therapies that can demonstrate intercranial antitumor activity represents a critical need.

“Approved EGFR-TKIs show variable penetration across the brain barrier, with the ratio of the [cerebrospinal fluid] concentration to free plasma concentration ranging from 0.066 to 0.21,” he said.

Zorifertinib has shown promise in having higher blood-brain barrier penetration in phase 1 and phase 2 trials, and Wu presented the first phase 3 results, comparing the efficacy and safety of first-line zorifertinib with that of earlier-generation TKIs in patients with advanced EGFR-mutated lung cancer and confirmed CNS metastasis. Patients in EVEREST had no prior system or radiotherapy and more than 1 brain lesion. They were randomized to zorifertinib, 200 mg given twice a day, vs gefitinib or erlotinib given once a day.

The trial randomly assigned 439 patients at 58 sites in China, Taiwan, South Korea, and Singapore; 220 received zorifertinib and 215 received a first-generation TKI.

The primary end point was PFS, which was assessed by blinded independent central review (BICR) per RECIST 1.1 criteria. After median follow-up of 20.4 months, a 28% improvement in PFS, which study authors called “significantly superior,” was seen in the zorifertinib group. Those taking the study drug had a PFS of 9.6 months compared with 6.9 months in the control group (HR 0.719; 95% CI, 0.580-0.893; P = .0024).

The objective response rate (ORR) was 68.6% for zorifertinib vs 58.4% for the control group (P = .027), “with a trend toward longer median duration of response favoring zorifertinib (8.2 months vs 6.8 months; P = .0997). OS data are not mature. Any grade treatment-related adverse events (TRAEs) were similar between the 2 groups (97.7% vs 94.0%). Grade 3 or higher TRAEs occurred in 65.9% of the zorifertinib group vs 18.3% of the control group; common events were skin and subcutaneous tissue events, gastrointestinal events, and abnormal liver function. No new safety signals arose. Wu said this was consistent with second-
generation EGFR-TKIs.

“In conclusion, EVEREST is the first randomized, controlled, open-label, multiple national study designed specifically to address the unmet medical need for the patient with the EGFR-mutant non–small cell lung cancer and brain metastasis,” he said.

Sunvozertinib in NSCLC With EGFR Exon 20 Insertions. Mengzhao Wang, MD, of Peking University Medical College and the Chinese Academy of Medical Science, presented the first pivotal study results in WU-KONG6 (NCT05712902), which is evaluating sunvozertinib for this subset of patients.⁸

“EGFR exon 20 insertion occurs in about 2% of [cases in] non–small cell lung cancer,” Wang said. “Sunvozertinib is a rationally designed, oral, potent EGFR inhibitor targeting EGFR exon 20 insertion as well as other EGFR mutations.”

The therapy, being developed by Dizal, has received Breakthrough Therapy designations in both the United States and China, leading to 2 single-arm pivotal studies—WU-KONG6 in China and a multinational study, WU-KONG1 (NCT0397402) in the rest of Asia, Europe, the United States, Australia, and other countries. A randomized phase 3 study is ongoing as well.

Patients in WU-KONG6 received a 300-mg dose per day, with the tumor assessed every 6 weeks. Primary end point was response rate as assessed by BICR; secondary end points are duration of response, PFS, OS, and safety. A total of 104 with exon 20 insertions were enrolled; however, 7 patients did not have the mutation confirmed in a central lab, so only 97 were included in the efficacy analysis. Wang noted that 32% had baseline brain metastasis, and the median number of prior therapies was 2; all had failed 2 platinum-based chemotherapy regimens.

What’s next? Riess discussed each trial, noting that a meta-analysis found that “efficacy of single-agent, PD-1, PD-L1, immune checkpoint blockade in EGFR-mutant lung cancer is suboptimal.”⁹

The review found that “for EGFR wild-type, there was an impressive survival benefit, but for EGFR-mutant lung cancer, it fared no better than docetaxel.”
These tumors, Riess said, were characterized by a suppressed immune microenvironment, low PD-L1 expression, low tumor mutational burden, low tumor-infiltrating lymphocytes, and low T-cell clonality. So for these reasons, among others, patients were excluded from the pivotal first-line studies, including KEYNOTE 189,10 that showed a substantial and significant PFS and OS benefit, adding pembrolizumab to platinum pemetrexed chemotherapy,” he said.

KEYNOTE 789 attempts to fill some knowledge gaps, but Riess said the minor improvement seen by adding pembrolizumab to the combination stands in contrast to the “wide gap” in the curves in KEYNOTE 189.5,¹⁰
He went through a roster of studies that showed adding immunotherapy for EGFR-mutant lung cancer has resulted in either a negative outcome or a benefit so marginal that “the juice is not worth the squeeze.”

But there are other studies to watch, he said, notably those that add antiangiogenesis agents. And the search for better biomarkers should continue. “We saw in KEYNOTE 789, stratified by PD-L1 status, for overall survival, the PD-L1–positive patients seemed to do a bit better.”

“There are other strategies in terms of combining with chemotherapy in addition to immunotherapy,” Riess said, taking note of the recent announcement that FLAURA2 study, which compares first-line osimertinib to osimertinib-platinum-pemetrexed, had met its primary end point.¹¹

“We really need to study exceptional responders and study why patients with EGFR-mutant lung cancers are IO [immuno-oncology] refractory, because that represents a lot of patients we could impact with IO treatments.”

On zorifertinib, Riess observed that while the study results were significant, the control arm was a first-generation TKI. Today, standard of care is osimertinib, which has demonstrated a PFS and OS benefit vs first-generation TKIs in the FLAURA trial, with a median PFS Of 15.2 months.^12,13 “Of course, there are cross-trial comparisons but zorifertinib was 9.6 months,” he said.

Noting that osimertinib may not be available everywhere, Riess said, “in terms of our next-generation TKIs, we need to globalize the best therapies worldwide.”

References
1. What is lung cancer? American Cancer Society. Revised January 12, 2023. Accessed June 25, 2023. https://bit.ly/44cTOK9
2. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. doi:10.18632/oncotarget.12587
3. To KKW, Fong W, Cho WCS. Immunotherapy in treating EGFR-mutant lung cancer: current challenges and new strategies. Front Oncol. 2021;11:635007. doi:10.3389/fonc.2021.635007
4. Shi C, Wang Y, Xue J, Zhou X. Immunotherapy for EGFR-mutant advanced non-small cell lung cancer: current status, possible mechanisms and application prospects. Front Immunol. 2022;13:940288. doi:10.3389/fimmu.2022.940288
5. Yang JCH, Lee DH, Lee JS, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study. J Clin Oncol. 2023;41(suppl 17):abstr LBA9000. doi:10.1200/JCO.2023.41.17_suppl.LBA9000
6. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. doi:10.1016/S0140-6736(15)01281-7
7. Yi-Long Wu, Qing Zhou, Jie Wang, et al. Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. J Clin Oncol. 2023;41(suppl 16):abstr 9001. doi:10.1200/JCO.2023.41.16_suppl.9001
8. Wang M, Fan Y, Sun M, et al. Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: the first pivotal study results. J Clin Oncol. 2023;41(suppl 16):abstr 9002. doi:10.1200/JCO.2023.41.16_suppl.9002
9. Dong ZY, Zhang JT, Liu SY, et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. Oncoimmunology. 2017;6(11):e1356145. doi:10.1080/2162402X.2017.1356145
10. Rodriguez-Abreu D, Powell SF, Hochmair MJ, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021;32(7):881-895. doi:10.1016/j.annonc.2021.04.008
11. Tagrisso plus chemotherapy demonstrated strong improvement in progression-free survival for patients with EGFR-mutated advanced lung cancer in FLAURA2 Phase III trial. News release. AstraZeneca. May 17, 2023. Accessed June 25, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemo-improved-pfs-in-lung-cancer.html
12. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
13. Ramalingam SS. Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662

Study Results Find PSMA-PET May Hold Prognostic Utility in Prostate Cancer

In results from a study of patients with high-risk, nonmetastatic castration-resistant prostate cancer (nmCRPC) defined by conventional imaging methods, polymetastatic disease with 5 or more nodes based on prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) and initial pathological lymph node involvement (pN1) status were associated with significantly shorter overall survival (OS).1 The findings were presented at the 2023 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, and published in the Journal of Clinical Oncology.
In previous research, PSMA-PET identified distant metastases in more than half of patients with disease considered nmCRPC by conventional imaging, with 39% of patients showing distant nodes, 24% showing bone metastases, and 6% showing visceral organ metastases.2 But the prognostic value of PSMA-PET–based disease extent and whether it affects outcomes is not characterized, according to the authors of the current study.
The new analysis assessed the utility of PSMA-PET–based disease extent for OS and new metastases-free survival (nMFS) in patients with nmCRPC defined by traditional imaging. A total of 200 patients with nmCRPC as determined by conventional imaging and prostate-specific antigen doubling time of 10 months or fewer and/or International Society of Urologic Pathologists grade group 4 or higher underwent PSMA-PET at 6 centers. Follow-up time ranged from 4 to 9 years, and patient data were analyzed retrospectively.
The median OS among all patients was 74 months, and polymetastatic disease with 5 or more lesions as determined by PSMA-PET was associated with shorter OS. Polymetastatic disease was also associated with shorter PSMA-PET nMFS. Metastatic disease by PSMA-PET with any lesions and whole-body PSMA tumor volume were not prognostic for OS, however. Initial pN1 status also showed an association with shorter OS but not with PSMA-PET nMFS.
After PSMA-PET, disease was managed mostly with local or targeted therapy among patients who did not have locoregional or other visible disease. Patients with nodal or bone metastases were most often treated with androgen receptor–signaling inhibition therapy.
Overall, the researchers concluded that 5 or more metastases as determined by PSMA-PET and initial pN1 status were significantly associated with OS, potentially providing a novel additional risk stratification measure in patients with nmCRPC who show no distant metastases in conventional imaging. “Based on these findings, disease extent on PSMA-PET [scans] could represent a novel tool to risk-stratify patients who have nmCRPC defined by conventional imaging,” lead study author Boris A. Hadaschik, MD, director and chair, Department of Urology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany, said. “PSMA-PET–based disease extent and PSMA avidity may contribute to risk-adapted treatment after further validation of results.”

References
1. Hadaschik BA, Eiber M, Weber M, et al. Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): an international multicenter retrospective study. J Clin Oncol. 2023;41(suppl 16):5010. doi:10.1200/JCO.2023.41.16_suppl.5010
2. Fendler WP, Weber M, Iravani A, et al. Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25(24):7448-7454. doi:10.1158/1078-0432.CCR-19-1050

FDA Sets Priority Review for Fruquintinib as ASCO Data Confirm Safety Results

The days ahead of the 2023 American Society of Clinical Oncology Annual Meeting brought good news for patients with metastatic colorectal cancer (mCRC), as Takeda and Hutchmed announced that FDA had granted priority review for their application for fruquintinib, the oral therapy already in use in China.¹

Fruquintinib, a highly selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) -1, -2, and -3, works by blocking growth of blood vessels that feed tumor growth; its unique mechanism of action targets multiple receptors and thus could improve survival in patients regardless of biomarker status.

Awny Farajallah, MD, head of global medical affairs, oncology, for Takeda, said approval of fruquintinib beyond China would fill a void in patient care.
“We really do not have good solutions for CRC. Specifically for metastatic patients who continue to relapse from the disease, there is definitely an unmet need,” Farajallah said in an interview with Evidence-Based Oncology, noting that 70% of these patients do not have a mutation that can be treated with a targeted therapy.

Fruquintinib, he said, offers a combination of efficacy, safety, and targeting features that could help rising numbers of younger patients who will need treatments in mCRC. “We want to bring this to patients,” Farajallah said.
Besides being an oral drug, fruquintinib is designed to aid patients’ ability to stay on therapy by improving kinase selectivity, which limits off-target toxicities and increases tolerability. Fruquintinib was generally well tolerated during clinical trials, and results presented during ASCO included phase IV data from China that showed the safety profile among 3000 real-world patients was consistent with clinical trial results.²

Those trials were FRESCO (NCT02314819), conducted in China,³ and FRESCO-2 (NCT04322539), which involved 691 patients in the United States, Europe, Japan, and Australia, and investigated the use of fruquintinib plus basic supportive care (BSC) vs placebo plus BSC in patients with previously treated mCRC. Results for FRESCO-2, presented in September 2022 at the European Society of Medical Oncology (ESMO) Congress and published June 15, 2023, in The Lancet, showed a 34% improvement in overall survival (OS) among the patients taking fruquintinib (HR, 0.66; 95% CI, 0.55-0.80, P <. 0001).⁴

In FRESCO-2, patients treated with fruquintinib achieved a median OS of 7.4 months vs 4.8 months with placebo; also, those treated with fruquintinib achieved a median progression-free survival of 3.7 months vs 1.8 months with placebo. The share of patients with adverse events of grade 3 or higher was 62.7% for the fruquintinib group vs 50.4% for the placebo group.

Cathy Eng, MD, who is the David H. Johnson Chair in Surgical and Medical Oncology and professor of Medicine at Vanderbilt University Medical Center and senior author of FRESCO-2, released a statement to coincide with publication of results in The Lancet.

“The majority of stage IV patients will have surgically unresectable disease. Hence, we must continue to pursue new treatment options to extend the overall survival of our patients with quality of life,” she said. “These findings from international FRESCO-2 validated the findings of the phase III FRESCO trial which was conducted only in China. Here we have a promising agent with overwhelming single agent activity.

“I look forward to the FDA approval as well as approvals from the European Medicines Agency and the Pharmaceuticals and Medical Devices Agency in Japan, so we can offer fruquintinib to all metastatic colorectal cancer patients.”⁵

Following the presentation at ESMO, Takeda and Hutchmed announced the partnership in January 2023 to develop and market fruquintinib outside China.⁶ Thus, ASCO offered Takeda officials the opportunity to discuss both updated data and recent FDA activity, including a target action date of November 30, 2023, under the Prescription Drug User Fee Act.¹ (On June 15, 2023, the European Medicines Agency also accepted the application for fruquintinib.⁷)

In the interview, Farajallah said there is an increased need for treatments such as fruquintinib, which can treat a broad spectrum of patients with mCRC. More patients are receiving diagnoses of the disease in their 40s, he said, as seen by the current US Preventive Services Task Force guidelines to screen for colon cancer starting at aged 45 years.^8,9

“So that tells you that we’re going to have more patients being diagnosed early, and unfortunately, more patients are going to progress and will require several lines of therapy,” he said.

Data on FRESCO-2 presented in 2022 at ESMO “caught our attention,” Farajallah said, “that this is a medicine that is effective not just in in the fact that it actually prolongs survival,” but also in the tolerability profile and the fact that it targets VEGF-1, -2, and -3.

“It’s very specifically targeting those mechanisms,” he said. “We think it lends itself to have better affordability. And we see that in the clinical trials as well.”

The next step, Farajallah said, is identifying how fruquintinib can work in other cancers; indeed, an abstract presented at ASCO presented phase 2 data from a small trial (NCT04156958) in which fruquintinib showed promise as a second-line or later treatment in biliary tract cancer.¹⁰

Other abstracts presented at ASCO included real-world data on the use fruquintinib with and without PD-1 inhibitors,¹¹ and a subgroup analysis of FRESCO-2 based on prior lines of therapy.¹²

Farajallah

“I’m really eager to bring this medicine to patients,” Farajallah said. “Given the median overall survival that we’re seeing, this is what really makes an impact for patients…. When I took care of patients, even 2 and a half months of survival for them was very meaningful. At a personal level, this is what gets you to see your son or your daughter graduate, if you’re waiting for that, so it’s very meaningful for patients.”

References
1. Takeda and Hutchmed announce New Drug Application (NDA) for fruquintinib for treatment of previously treated metastatic colorectal cancer granted priority review. News release. Takeda Pharmaceuticals. May 25, 2023. June 20, 2023. https://bit.ly/3CIfcug
2. Li J, Wang ZQ, Zhong H, et al. A phase IV study to evaluate the safety of fruquintinib in Chinese real-world clinical practice. J Clin Oncol. 2023;41(suppl 16);abstract e15568. doi:10.1200/JCO.2023.41.16_suppl.e15568
3. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855
4. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;S0140-6736(23)00772-9. doi:10.1016/S0140-6736(23)00772-9
5. Wilemon T. New treatment option for metastatic colorectal cancer prolongs survival. Vanderbilt University Medical Center. June 15, 2023. Accessed June 20, 2023. https://news.vumc.org/2023/06/15/new-treatment-option-for-metastatic-colorectal-cancer-prolongs-survival/
6. Hutchmed announces license to Takeda to develop and commercialize fruquintinib outside China. News release. Hutchmed. January 23, 2023. Accessed June 20, 2023. https://www.hutch-med.com/fruquintinib-outside-china-partnership-with-takeda
7. Takeda and Hutchmed announce marketing authorization application of fruquintinib. News release. Takeda Pharmaceuticals. June 15, 2023. Accessed June 20, 2023. https://bit.ly/3XwJxG9
8. Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233-254. doi:10.3322/caac.21772
Klimkiewicz P. USPSTF colorectal cancer screening update 2021: a review of evidence. Nurse Pract. 2022;47(12):37-42. doi:10.1097/01.NPR.0000884892.06046.34
Zhang P, Yang Y, Gou H, Li Q. Phase II study of fruquintinib as second or further-line therapy for patients with advanced biliary tract cancer. J Clin Oncol. 2023;41(suppl 16); abstract e16161. doi:10.1200/JCO.2023.41.16_suppl.e16161
He L, Cheng X, Tu S. Fruquintinib versus fruquintinib combined with PD-1 inhibitors for metastatic colorectal cancer: real-world data. J Clin Oncol. 2023;41(suppl 16);abstract e15592. doi:10.1200/JCO.2023.41.16_suppl.e15592
Dasari A, Lonardi S, Garcia-Carbonero R, et al. Subgroup analyses of safety and efficacy by number and types of prior lines of treatment in FRESCO-2, a global phase III study of fruquintinib in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2023;41(suppl 16);abstract 3604. doi:10.1200/JCO.2023.41.16_suppl.3604