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An economic analysis showed that neither polatuzumab vedotin-piiq (Polivy) added to standard of care (SOC) chemotherapy nor CD19-directed chimeric antigen receptor (CAR) T-cell therapy is likely to be the most cost-effective for patients with diffuse large B-cell lymphoma (DLBCL). The findings published in the 

 showed that polatuzumab vedotin with rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) vs SOC and second-line CAR T-cell therapy vs SOC were not cost-effective options for patients in the United States or Canada, despite both therapies demonstrating improvements in progression-free survival (PFS).

In 10,000 simulations, each strategy was found to be incrementally more effective than its respective SOC, but also more costly. Adding pola-R-CHP to SOC incurred an incremental cost-effectiveness ratio (ICER) of $546,956 (range, $338,797$1,199,923) US$/quality-of-life adjusted years (QALY) and $245,381 (range, $151,671-$573,250) CAD$/QALY.

The addition of second-line CAR T-cell therapy to SOC led to an ICER of $309,813 (range, $190,197-$694,200) USD$/QALY and $303,163 (range, $221,300-$1,063,864) CAD$/QALY. Lastly, adding both pola-R-CHP and second-line CAR T-cell therapies to the SOC yielded an ICER of $488,284 (range, $326,765-$840,157) US$/QALY and $267,050 (range, $182,832-$520,922) CAD$/QALY.

“Although there is great excitement regarding the important PFS improvements in the frontline and second-line treatments of [patients with] DLBCL reported by the POLARIX (NCT03274492), ZUMA-7 (NCT03391466), and TRANSFORM (NCT03575351) trials,

 this must be tempered with a realistic consideration of the costs of these therapies and their implementation,” Abi Vijenthira, MD, SM, a hematologist in the Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre in Toronto, Canada, and coinvestigators wrote in the study. “On the basis of the current prices of these therapies, we found that alone or together, they were unlikely to be cost-effective from both a US and a Canadian payer perspective.”

R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] has been the SOC for DLBCL for nearly 2 decades, and autologous stem cell transplant (ASCT) has been an SOC for relapsed disease for even longer. Recently, data from the POLARIX trial showed that pola-R-CHP yielded a superior PFS benefit to R-CHOP, although a 2-year analysis did not show a survival benefit.

 Of note, polatuzumab vedotin is expensive. In the United States it is listed at $15,600 per 140-mg vial. This means a 6-cycle treatment for a 70-kg patient, which was the model used for the analysis, would cost $93,600.

Other recent developments in the DLBCL space include results of the recently published ZUMA-7 trial and the TRANSFORM studies,

 which compared axicabtagene ciloleucel (Yescarta) and lisocabtagene maraleucel (Breyanzi) to salvage chemotherapy with or without ASCT for patients with primary refractory or early relapse of DLBCL within 12 months of frontline therapy. Both trials showcased significant PFS benefits for these patients. However, follow-up remains short and long-term survival is still largely undocumented. As with polatuzumab vedotin, CAR T-cell therapy comes with a significant cost, ranging from $399,000-$410,300 US$, not including additional inpatient supportive care costs.

The FDA approved these 2 CAR T-cell agents on April 1, 2022, and June 24, 2022, respectively; neither has been approved yet in Canada.

Investigators constructed a Markov model to compare 4 strategies for patients with newly diagnosed intermediate- to high-risk DLBCL. The first strategy consisted of pola-R-CHP plus second-line CAR T-cell therapy for early relapse (< 12 months); the second was pola-R-CHP plus second-line salvage therapy with or without ASCT; the third was R-CHOP plus second-line CAR T-cell therapy for early relapse; and the last strategy was SOC, which consisted of R-CHOP plus second-line salvage therapy with or without ASCT.

Trial data were used to estimate transition probabilities. Investigators then calculated lifetime costs, QALYs, and ICERs from an American and Canadian payer perspective. Willingness-to-pay (WTP) thresholds were designed for both populations. The WTP thresholds were $150,000 US$/QALY and $150,000 CAD$/QALY.

 In the 10,000 simulations using the American WTP of $150,000 US$/QALY, strategy 3 was the most cost-effective in 0.1% of iterations and strategy 4 was the most cost-effective in 99.9% of iterations.

Investigators then conducted a 1-way sensitivity analysis comparing the f irst 3 strategies against the SOC. Using the range of HR reported for polaR-CHP compared with R-CHOP in POLARIX (0.56-0.95), the therapy did not represent a cost-effective strategy even for American patients when maximizing for efficacy at a 4.4% improvement. The 5-year OS improvement would need to be 7.4% for this treatment to be cost-effective.

Of note, from a Canadian perspective, this strategy became cost-effective if the HR was less than 0.59, translating to a 5-year OS improvement of at least 4.1% with OS rates of 78.5% vs 74.4% for the therapies, respectively. 

For the CAR T-cell therapies, varying the HR across the ranges reported in the ZUMA-7 trial (0.37-0.65) did not cross the WTP for either country. This meant that even if the 5-year OS improvement for second-line CAR T-cell therapy was maximized to 7.3% for a 5-year OS rate of 47.3% vs 40.0%, second-line CAR T-cell therapy would not be cost-effective over SOC in either the US or Canada. The 5-year OS improvement over SOC would need to be 9.5% or 11.3% from a US or Canadian payer perspective, respectively.

Study authors acknowledged that the model had limitations. For instance, long-term follow-up was not available for all inputs in the model, meaning that assumptions regarding risk of relapse and probability of cure in the frontline and relapse settings had to be made. In addition, the efficacy of second-line CAR T-cell therapy has not been studied in patients exposed to polatuzumab vedotin in the front line, and so the efficacy in this setting had to be estimated. Further, CAR T-cell therapy tends to incur additional costs with inpatient supportive care, and insurance coverage is variable, making its cost difficult to estimate.

The study authors noted that despite the short follow-up data, pola-R-CHP and second-line CAR T-cell therapies may hold the potential to alter the treatment landscape for patients with newly diagnosed or relapsed/refractory DLBCL. However, at a unique time where positive frontline and second-line trials have been reported in quick succession, funding decisions for 1 therapy may affect the cost-effectiveness implications of the other.

“Although many drug approvals are based on PFS and overall response rate, rather than OS, health care systems must balance costs with uncertain incremental benefit,” study authors concluded.

 “Expert analysis from policymakers is required to determine the appropriateness of funding these therapies.”

Articles

An economic analysis showed that neither polatuzumab vedotin-piiq added to standard of care chemotherapy nor CD19-directed chimeric antigen receptor T-cell therapy is likely to be the most cost-effective for patients with diffuse large B-cell lymphoma. 

Frontline Pola-R-CHP, CAR T-Cell Second-line Therapies Are Not Cost-effective in DLBCL 

More than 20,000 adults in the United States are diagnosed with esophageal cancer every year.

 Although the incidence, location, and histology of esophageal cancer vary globally, patients in the Western World typically develop esophageal cancer in the distal esophagus or at the gastroesophageal junction (

 The most common disease type is esophageal adenocarcinoma (EAC), which may point to obesity as a factor.

Rising obesity rates across the United States have led to increasing reflux disease, Barrett esophagus, and esophageal adenocarcinoma.

 Overall survival for esophageal cancer remains poor, especially for metastatic disease with a median survival of slightly over 1 year from the time of diagnosis.

 Metastatic EAC is typically managed with chemotherapy and immunotherapy, but many patients eventually develop resistance to these therapies, leading to poor outcomes.

Exploring and targeting the underlying mechanisms of therapeutic resistance are critical for improving the outlook for esophageal cancer. Therefore, it is of utmost importance to identify new treatment options or repurpose commonly used drugs in novel combinations to improve outcomes in this difficult-to-treat patient population.

Targeting the Role of Stress in Therapeutic Resistance

Study results have recently discovered that adrenergic stress hormones produced during the fight-or-flight response are key players in psychological stress, such as anxiety or depression, which are significantly increased following a cancer diagnosis. Our team at Roswell Park Comprehensive Cancer Center in Buffalo, New York, led by Elizabeth Repasky, PhD, discovered that stress can reduce the efficacy of chemotherapy and the immune system’s power to control tumor growth.

 Interestingly, our work has also revealed a solution to this problem.

Propranolol, a type of beta-blocker, is commonly prescribed for heart problems such as hypertension or arrhythmia and management of anxiety and migraines. Propranolol blocks the β-adrenergic receptors by which stress hormones act on both tumors and immune cells. Using propranolol in mice enhances long-term immune control of tumor growth by reducing the accumulation of myeloid-derived suppressor cells.

 Moreover, the resistance to cytotoxic chemotherapy caused by stress can be reversed by using propranolol.

 The same phenomenon might be possible in humans.

A team of researchers at Roswell Park Comprehensive Cancer Center, led by Anurag Singh, MD, showed that patients undergoing chemoradiation for esophageal cancer who took β-blockers for high blood pressure did better than those patients not taking β-blockers.

 Our previous clinical trial in advanced melanoma patients, led by Shipra Gandhi, MD, showed that combining immunotherapy (pembrolizumab [Keytruda]) with propranolol produces an unprecedented response rate, one not seen historically with immunotherapy alone without significantly increased adverse effects (AEs).

 Therefore, we hypothesize that adding propranolol to standard chemotherapy and immunotherapy for esophageal cancer will significantly improve outcomes and not cause additional AEs.

Based on these premises, our team at Roswell Park is conducting a multicenter, nonrandomized, single-arm, phase 2 clinical trial (NCT05651594). Patients with advanced or metastatic EAC will be treated with a combination of standard chemotherapy-immunotherapy and propranolol (

We aim to enroll a total of 40 patients over 2 years, with at least 20 patients enrolled at our site. The study’s primary end point is the overall response rate (ORR) as determined by RECIST 1.1 criteria. Secondary end points include safety (toxicities and AEs) assessed as per Common Terminology Criteria for Adverse Events Version 5.0, progression-free survival, overall survival, and ORR as determined by immune-based RECIST criteria. The correlative studies will analyze blood- and tissue-based biomarkers, including immune markers. Perceived stress and the chronotropic effect of exercise will be correlated with clinical outcomes to determine the efficacy of the study treatment combination.

Survival with standard chemotherapy- immunotherapy for esophageal cancer remains very poor. Propranolol is affordable and very well tolerated. If the study results are favorable, propranolol could be quickly and widely implemented in clinical practice.

Sarbajit Mukherjee, MD, MS, is an assistant professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

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Propranolol in combination with pembrolizumab and standard chemotherapy for the treatment of unresectable locally advanced or metastatic esophageal or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov. Updated December 19, 2022. Accessed January 3, 2022. https://clinicaltrials.gov/ct2/show/NCT05651594

Although the incidence, location, and histology of esophageal cancer vary globally, patients in the Western World typically develop esophageal cancer in the distal esophagus or at the gastroesophageal junction. 

Investigators Seek Simpler Solution to Treatment Resistance in Esophageal Cancer

The prevalance of HER2 overexpression in metastatic colorectal cancer (CRC) is only approximately 3% to 5%. However, investigators have concluded that it presents an actionable target, and therapeutic advances with the biomarker have risen its prominence in the tumor type. Treatment strategies for this population began by mimicking successes seen in breast and gastric cancers, but investigators discovered that single-agent approaches were not as effective as in other tumor types.

“CRC is becoming an area of significant development in the 

 space,” Tanios S. Bekaii-Saab, MD, said in an 

 postconference perspectives program. “

 is a receptor part of the HER family that essentially has 

, and has been known to be a driver for many cancers from breast to colon to gastric, including biliary and gastroesophageal junction, [as well as] others. The story of HER2 targeting started primarily in breast, where, in addition to chemotherapy, single-agent trastuzumab [Herceptin] has moved the needle significantly for patients who overexpress HER2. From there, we saw that gastric cancer was primed for that [targeting, as well].”

Bekaii-Saab, who is leader of the Gastrointestinal Cancer Program, medical director of the Cancer Clinical Research Office, vice chair and section chief for medical oncology in the Department of Internal Medicine at Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, noted that early data from combining single-agent trastuzumab with irinotecan suggested that there is an interesting response,

 although it did not appear to elicit the same responses observed in breast and gastric cancers. “The question became: What is the difference?

“[Early] work suggested that in colon cancer you needed dual inhibition to be able to have the maximum [effect on] CRC,” Bekaii-Saab said. The HERACLES trial (NCT03225937) conduced in Italy demonstrated that dual blockade with lapatinib (Tykerb) and trastuzumab was effective for eliciting an objective response rate (ORR) of 31% among 30 treated patients with RAS wild-type disease.

 “One of the limiting factors with lapatinib was that although it is a HER2 inhibitor, it did not have a high enough potency and it did have some HER1 inhibition. Toxicity levels were [also] a little higher.”

Following these data, Bekaii-Saab noted that other trials added to the proof of the principal that trastuzumab in combination with other inhibitors, such as pertuzumab (Perjeta) in the MyPathway study,

 showed similar outcomes in terms of response rate. “Overall, the key aspect of all of this is the patients had to have 

 wild-type tumors to have the benefit of the dual inhibition,” he said. “An agent that was initially being looked at in breast cancer, the tyrosine kinase inhibitor tucatinib [Tukysa], which targets HER2, and is highly selective, and had minimal inhibition of EGFR, [made for] highly desirable properties in the sense that it is cleaner and more potent.”

To evaluate the potential role of tucatinib, the phase 2 MOUNTAINEER trial (NCT03043313) was initiated. At the 2022 European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer, data showed that tucatinib plus trastuzumab improved radiographic response rates in patients with metastatic HER2-positive CRC. At a median follow-up of 20.7 months, the confirmed ORR among 86 patients who received the combination was 38.1% (95% CI, 27.7%-49.3%) as assessed by blinded independent central review (BICR), with a median duration of response of 12.4 months (95% CI, 8.5-20.5). Further, the median progression-free survival (PFS) was 8.2 months (95% CI, 4.2-10.3) and the median overall survival was 24.1 months (95% CI, 20.3-36.7).

In terms of safety, commonly reported grade 1/2 treatment-emergent adverse effects (TEAEs) among patients who received tucatinib and trastuzumab were diarrhea (60.5%), fatigue (41.9%), nausea (34.9%), and infusion-related reaction (20.9%). Grade 3 or higher TEAEs included diarrhea (3.5%) and fatigue (2.3%). In terms of overall AEs observed in the study, hypertension was the most common grade 3 or higher AE (7.0%).

This analysis included patients who were initially enrolled in the single-arm study of the combination and those enrolled to the expansion cohort for the combination. “MOUNTAINEER was an open-label, global, phase 2 study [that] enrolled patients with 

 wild-type metastatic CRC that had progressed on prior [fluoropyrimidines], oxaliplatin, irinotecan, and anti-VEGF [monoclonal] antibodies,” John H. Strickler, MD, associate professor of medicine and a medical oncologist at the Duke University School of Medicine in Durham, North Carolina, said in an interview with 

. “All patients enrolled had HER2-positive disease by local testing, and that could have been immunohistochemistry, [fluorescence in situ hybridization], or next-generation sequencing. These patients were initially enrolled into cohort A, which was a pilot cohort of tucatinib and trastuzumab. Based on very favorable results from that initial experience, the study was expanded. There was a randomization when the study was expanded to cohort B, which was the tucatinib/trastuzumab combination, or cohort C, which was tucatinib [alone].”

At the ESMO Congress 2022 additional data from MOUNTAINEER were presented for patients who were enrolled to an additional arm of tucatinib monotherapy and who subsequently crossed over to the combination.

 Among the 30 patients treated with tucatinib, ORR by 12 weeks was 3.3% (95% CI, 0.1%-17.2%) and disease control rate (DCR) was 80.0%. Twenty-eight patients crossed over to the combination regimen and the confirmed ORR was 17.9% (95% CI, 6.1%36.9%), with a DCR of 82.1%. Among patients who crossed over, 5 (17.9%) had a partial response, 18 (64.3%) had stable disease, and 5 (17.9%) had progressive disease.

In cohort C, 93.3% of patients experienced any-grade AEs, including 26.7% with grade 3 or higher events. Three patients reported serious AEs. The most common AEs with tucatinib included diarrhea (33.3%), abdominal pain (20.0%), and fatigue (20.0%), all of which were grade 1 or 2. The most common grade 3 or higher AEs were increased aspartate/alanine aminotransferase (AST/ALT; 6.7% each).

Among patients who crossed over to the combination regimen, 82.1% of patients reported any-grade AEs, with 21.4% experiencing grade 3 or higher events. Two patients had serious AEs. The most common AE was diarrhea (35.7%), of which all events were grade 1 or 2. Also in this group, the most common grade 3 or higher AEs included ALT/AST increase (7.1% and 10.7%, respectively). Two patients in the crossover group discontinued treatment because of AEs.

“We did see [more favorable] responses after combining tucatinib with trastuzumab,” Strickler said. “For patients experiencing [AEs] and toxicity [from] chemotherapy, this is a welcome relief. Most [AEs] are manageable, and it’s fairly rare for [AEs] to lead to tucatinib discontinuation or dose reduction. [Tucatinib plus trastuzumab] represents not [only] an active regimen, but [also] a regimen that provides many patients [with] a high quality of life.”

In September 2022, the supplemental new drug application for the treatment regimen was granted priority review, with a decision date of January 19, 2023.

“Our initial goal with MOUNTAINEER was to make tucatinib and trastuzumab an option for patients with HER2-positive metastatic CRC,” Strickler said. “[One] exciting component of [our analysis] is that we [observed] much higher response rates than expected [beyond the firstline] setting. [These] response rates [were also observed] in a tolerability profile that’s very favorable. [Accordingly, we hope] this will become a standard-of-care [SOC] option in the future for these patients.”

The next step for the combination is the ongoing, randomized, global, phase 3 MOUNTAINEER-03 trial (NCT05253651). This trial is designed to evaluate the efficacy of the combination regimen plus modified leucovorin calcium, fluorouracil, and oxaliplatin, (mFOLFOX6) compared with SOC, first-line therapy for metastatic HER2-positive CRC.

SOC options for patients with HER2-positive therapy in the MOUNTAINEER-03 study include mFOLFOX6 alone, mFOLFOX6 with bevacizumab (Avastin), or mFOLFOX6 with cetuximab (Erbitux).

 Investigators will randomly assign patients with histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum that is metastatic and/or unresectable to either the SOC arm or the investigative arm (

HER2-positive disease will be determined via tissue-based assay performed at a central laboratory, and patients must have 

 wild-type disease as determined by local or central testing. An ECOG performances status of 0 or 1 is also required. Patients with central nervous system requirements and those with no evidence of brain metastases or brain metastases that are asymptomatic are permitted.

The primary end point is PFS per RECIST 1.1 criteria by BICR, with secondary outcome measures of overall survival, ORR, PFS by investigator assessment, duration of response, time to second disease progression, and toxicity. The safety analysis will include incidence of dose alterations and changes in patient-reported outcomes.

 is an actionable target,” Strickler said. “[It] is a biomarker that we can use to select patients away from certain therapies that will be less active, [such as] antiEGFR therapies, but it’s also a biomarker we can use to select for therapies that will be more active [in some] patients….These anti-HER2 regimens [often] offer patients strong clinical benefit and high response rates. In some cases, [they even offer] long duration of response and a very favorable tolerability profile.”

MOUNTAINEER-03 is actively enrolling patients.

Ahcene Djaballah S, Daniel F, Milani A, Ricagno G, Lonardi S. HER2 in colorectal cancer: the long and winding road from negative predictive factor to positive actionable target. 

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Meric-Bernstam F, Hainsworth J, Bose R, et al. MyPathway HER2 basket study: pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors. 

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Seagen announces results from pivotal MOUNTAINEER trial demonstrating clinically meaningful antitumor activity of TUKYSA (tucatinib) in combination with trastuzumab in previously treated HER2-positive metastatic colorectal cancer. News release. Seagen Inc. July 2, 2022. Accessed January 5, 2023. https://bwnews.pr/3yC4xQH

Strickler JH, Cercek A, Siena S, et al. Additional analyses of MOUNTAINEER: a phase II study of tucatinib and trastuzumab for HER2-positive mCRC. 

. 2022;33(suppl 7):S1394. doi:10.1016/j.annonc.2022.08.023

Seagen announces TUKYSA (tucatinib) in combination with trastuzumab granted priority review by FDA for previously treated HER2-positive metastatic colorectal cancer. News release. Seagen Inc. September 19, 2022. Accessed January 5, 2023. https://bit. ly/3DyydRB

A study of tucatinib with trastuzumab and mFOLFOX6 versus standard of care treatment in first-line HER2+ metastatic colorectal cancer (MOUNTAINEER-03). Clinicaltrials.gov. Updated January 6, 2022. Accessed January 8, 2023. https://clinicaltrials.gov/ct2/ show/NCT05253651

The MOUNTAINEER-03 trial is designed to evaluate the efficacy of tucatinib and trastuzumab plus modified leucovorin calcium, fluorouracil, and oxaliplatin, compared with standard-of-care, first-line therapy for metastatic HER2-positive colorectal cancer.

MOUNTAINEER-03 Propels Progress in Metastatic HER2+ CRC

When a physician-scientist is closely identified with a particular landmark clinical trial, one might expect that study to top a personal list of meaningful accomplishments. For Kevin Kalinsky, MD, MS, director of breast medical oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia, who is best known for his work on the RxPONDER trial (NCT01272037), it serves as one of a few accomplishments for which he is grateful that have impacted clinical care. The study findings showed that postmenopausal women with low-risk hormone receptor–positive, node-positive, HER2-negative breast cancer who received endocrine therapy do not benefit from adjuvant chemotherapy.

Kalinsky also singles out his contributions to the development of sacituzumab govitecan-hziy (Trodelvy), a Trop-2–directed antibody-drug conjugate, calling that work “probably the most meaningful experience I’ve had as a clinical trialist and investigator.” He participated in the early-stage and pivotal trials that led to the agent's initial approval in patients with metastatic triple-negative breast cancer, including the phase 3 ASCENT trial (NCT02574455).

“What made it so meaningful was seeing in real time that patients who had not had much benefit from other treatments were getting real benefit from this drug that was reasonably well tolerated,” Kalinsky said.

In ASCENT, patients with relapsed or refractory metastatic triple-negative breast cancer were randomly assigned to receive either sacituzumab govitecan or physician’s choice of single-agent chemotherapy (eribulin [Halaven], vinorelbine, capecitabine, or gemcitabine). The median progression-free survival (PFS), the trial’s primary end point, was 5.6 months (95% CI, 4.3-6.3) with sacituzumab govitecan vs 1.7 months (95% CI, 1.5-2.6) in the chemotherapy group (HR, 0.41; 95% CI, 0.32-0.52; 

Kalinsky’s response does not surprise Komal Jhaveri, MD, FACP, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “He absolutely is best known for RxPONDER, which changed our treatment paradigm for postmenopausal women with 1 to 3 positive nodes with an Oncotype DX score of less than 26,” she said. “But his scientific vigor to bring new treatments to patients and improve outcomes is matched by his passion and drive to deliver optimal care to all patients.”

That passion started early. “What drew many of us into oncology was seeing a loved one cope with cancer when we were young,” Kalinsky said, explaining that his grandfather died from small cell lung cancer when Kalinsky was 6 years old. “One aspect that made a huge impression on me was watching him seek the expertise of a specialist and the importance of that information to guide expectations and treatment options.”

Jane L. Meisel, MD, an associate professor at Winship Cancer Institute, sees that influence on Kalinsky to this day. “He’s been able to take some of the biggest questions that patients ask, turn them into research questions, and get them answered on a much larger level,” she said. “His work has both changed practice and the way we’re able to speak to patients with confidence on these issues.”

Kalinsky brings that dual focus on clinical care and scientific discovery to all his roles at Winship, where he serves as the Louisa and Rand Glenn Family Chair in Breast Cancer Research and director of the Glenn Family Breast Center. As a dedicated trialist, he has worked on increasing patient participation in phase 1 clinical studies. Kalinsky has served as coinvestigator, coprincipal, or primary investigator on research grants worth approximately $2.7 million in federal funding and $1.6 million in private foundation funding.

He also has mentored numerous junior faculty, fellows, and residents. His teaching roles include serving on the steering committee of the 

) is hosting the 4-day event (March 2-5, 2023) as an in-person live conference in Miami Beach, Florida.

 to discuss trends in breast cancer therapeutics and reflect on progress made, RxPONDER seemed like a good place to start. He and his coauthors conceived the trial to try to definitively answer the question of whether the 21-gene Oncotype DX recurrence score (RS) could predict which patients with hormone receptor–positive, HER2-negative breast cancer would benefit from postoperative chemotherapy.

“One of the greatest unmet needs has been to determine who needs chemotherapy and who doesn’t, and we wanted to have patients be able to opt out of treatments that they don’t need,” he said.

RxPONDER grew out of an earlier trial, SWOG-8814 (NCT00929591), which had suggested that the RS could be used to predict which patients with node-positive breast cancer would benefit from having chemotherapy added to their endocrine therapy.

 This trial, which Kalinsky describes as “pivotal,” found that women with an RS of less than 18 saw no benefit from the addition of chemotherapy, whereas those with an RS of at least 31 lived longer if they had chemotherapy.

“What SWOG-8814 demonstrated was that there was a potential role for the RS to determine risk,” he said.

To meet the objective of determining the effect of chemotherapy on invasive disease–free survival (IDFS) and whether the RS influenced that effect, RxPONDER recruited 5083 women (33.2% premenopausal and 66.8% postmenopausal), of which 5018 participated in the trial. Participants with hormone receptor–positive, HER2-negative breast cancer; 1 to 3 positive axillary lymph nodes; and an RS of 25 or less were randomly assigned to endocrine therapy only or to chemotherapy followed by endocrine therapy.

In postmenopausal patients, the 5-year IDFS rates were 91.9% with endocrine therapy alone vs 91.3% with chemoendocrine therapy, a difference that was not statistically significant (HR, 1.02; 95% CI, 0.82-1.26; 

 = .89). In premenopausal patients, the 5-year IDFS rates were 89.0% for women who received endocrine therapy alone vs 93.9% for those on combined chemotherapy and endocrine therapy (HR, 0.60; 95% CI, 0.43-0.83; 

“This is a meaningful outcome for our patients,” Kalinsky said. “We’re now able to save thousands of patients the unnecessary toxicities and adverse effects and costs—both financial and quality of life—associated with chemotherapy.”

Most recently, Kalinsky’s coauthor, Yara Abdou, MD, an assistant professor at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, presented data from a new analysis of RxPONDER at the 2022 San Antonio Breast Cancer Symposium in December. Abdou was Kalinsky's mentee in the American Society of Clinical Oncology's virtual mentoring program.

The findings showed that non-Hispanic Black patients with hormone receptor–positive, HER2-negative breast cancer were more likely to have worse outcomes than non-Hispanic White, Asian, and Hispanic patients (

). The poorer outcomes were observed even with similar RS, Abdou noted.

In a multivariable analysis that accounted for RS, treatment arm, menopausal status, age, and grade, non-Hispanic Black patients had a 37% higher risk of invasive cancer than non-Hispanic White patients. Further data showed that non-Hispanic Black patients had a distant relapse–free survival rate of 90.1% vs 94.7% for non-Hispanic White patients (HR, 1.39; 95% CI, 1.01-1.91; 

Among RxPONDER’s 4048 evaluable patients, non-Hispanic White patients were the largest group at 70%. The remainder of patients were non-Hispanic Black (6.1%), Hispanic (15.1%), Asian (8.0%), or Native American or Pacific Islanders (0.8%). Recurrence scores were similar across all patient and racial subgroups, but non-Hispanic Black patients were more likely to present with high-grade tumors (18%) vs non-Hispanic White patients (10%).

Abdou’s presentation garnered conversation behind the scenes in San Antonio—and not just because of the findings she shared. “A lot of the younger oncologists were commenting on how Kevin could have chosen to take the podium himself, but he made an explicit effort to mentor and guide a much younger female researcher to both lead that aspect of the trials analysis and then also present the data,” Meisel noted. “He’s so respectful and works hard to lift junior people up, which not every leader does.”

Although RxPONDER clarified clinical decision-making for postmenopausal patients, questions remain regarding premenopausal patients. Younger patients appear to benefit most from chemotherapy, but no one yet knows why that is. A new study, not yet open for accrual, aims to answer this question, Kalinsky said, explaining that ovarian function suppression might hold the key.

NRG Oncology is planning a phase 3 randomized trial, OFSET Chemo (NRGBR009). NRG-BR009 will add ovarian suppression to the familiar equation of endocrine therapy (aromatase inhibitor or tamoxifen) with or without accompanying chemotherapy in the adjuvant setting. The study will seek to recruit nearly 4000 premenopausal patients with hormone receptor–positive, HER2negative breast cancer with pN0 disease with an RS of 16 to 20 plus high clinical risk or an RS of 21 to 25 or with pN1 disease with an RS of 0 to 25. Patients will be stratified by age (> 40 or ≤ 40 years), nodal status (pN0 vs pN1), and RS (0-15 vs 16-25).

“One of the limitations of all the genomic assay studies, including RxPONDER, is that less than 20% of patients underwent ovarian function suppression,” Kalinsky said. “Not all patients can tolerate it so it will be important to look at, in a genomically defined population, what the rate of adherence and tolerability is from ovarian function suppression.”

TAILORx (NCT00310180) is another landmark trial that has helped clarify which patients with breast cancer can safely forgo chemotherapy.

 Among 9719 evaluable patients with hormone receptor–positive, HER2-negative, node-negative breast cancer, 6711 (69%) had a midrange RS of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The primary outcome of this noninferiority trial was IDFS.

IDFS was very similar in both groups. Five years after treatment, the rate of IDFS among patients with an RS of 11 to 25 was 92.8% in the endocrine-only group and 93.1% for those who also had chemotherapy (HR, 1.08, 95% CI, 0.941.24; 

 = .26). At 9 years, the IDFS rate in this RS cohort was 83.3% for those who had endocrine therapy alone and 84.3% for those who had both therapies. None of these differences were considered statistically significant.

Thus, TAILORx was the first trial to prospectively establish that approximately 70% of women with hormone receptor–positive, HER2-negative, lymph node–negative breast cancer can safely skip chemotherapy. The finding applies to women who are older than 50 years at diagnosis with an RS of 11 to 25, any age with an RS of 0 to 10, or 50 years or younger with an RS of 11 to 15.

At the 2022 San Antonio Breast Cancer Symposium, Joseph A. Sparano, MD, deputy director of the Tisch Cancer Institute at Mount Sinai Health System in New York, New York, and TAILORx lead author, presented an additional 3.5 years of recurrence and survival outcomes, for a total median follow-up of 11.0 years.

 Importantly, the main study findings remain unchanged: RS continues to be a reliable guide for patients with hormone receptor–positive, HER2-negative disease, Sparano said.

Women with an RS of 0 to 25 who had received endocrine therapy alone had very low recurrence rates, at approximately 1% per year during the 12-year event period. However, more late recurrences occurred beyond 5 years than in the first 5 years. Distant recurrence rates remained low, and overall survival rates remained high for women with a score of 0 to 25 when treated with endocrine therapy alone. However, the rates of distant recurrence and IDFS diverged, suggesting the emergence of second primary cancers.

Finally, distant recurrence rates remained higher for those with a score above 26 despite adding chemotherapy to endocrine therapy.

The TAILORx updated recurrence data reinforce to Kalinsky the need to be able to prospectively identify patients who are likely to relapse. “One of the most commonly asked questions in clinic is, ‘How do I know this worked? And is there a blood test to tell us whether the cancer might come back?’ ” he said. “The tumor markers we have now are not terribly reliable, but we do have exciting new assays. So the technology is changing rapidly, and we need to figure out how to best use the blood tests.”

According to Kalinsky, exploring circulating markers, such as the use of circulating tumor DNA, may eventually help determine who may be at risk for late recurrence. “What’s going to have the greatest utility?” he mused. “Will it be these bespoke markers for minimal residual disease, meaning that you need the tumor tissue and then you look for specific alterations in the blood based upon what you see in the tissue, or can it be tissue agnostic?”

An RxPONDER substudy that might help answer this and other questions is ongoing. “If patients had not yet had a recurrence and were within 8 years from their randomization, we are collecting blood markers like circulating tumor cells or circulating tumor DNA just to see if we can f ind indicators for late recurrence,” Kalinsky said.

Unraveling the prognostication vs prediction issue is also a major unmet need in breast cancer overall, Kalinsky said. “One thing that’s still unclear is whether the blood-based biomarkers are purely prognostic, meaning simply that those patients who have presence of circulating cells are more likely to do worse. That’s what we’ve seen so far,” he said. “But can biomarkers be predictive? Maybe once we identify them, we could then change therapies to one of the new hormonal therapies, like an oral selective estrogen receptor downregulator, and change the biology of that cancer. That remains an interest as well, but we’re not there yet.”

In addition to his interest in new strategies for early breast cancer, Kalinsky is exploring various aspects of metastatic disease. He was the principal investigator on the phase 2 MAINTAIN trial (NCT02632045), which evaluated subsequent therapy for patients with hormone receptor–positive, HER2-negative metastatic breast cancer with disease progression following treatment with endocrine therapy plus a CDK4/6 inhibitor.

Patients were randomly assigned to receive ribociclib (Kisqali), a CDK4/6 inhibitor, plus a different endocrine therapy or placebo plus a different endocrine therapy. Participants who previously received an aromatase inhibitor as endocrine therapy received fulvestrant (Faslodex) whereas those who had prior fulvestrant were treated with exemestane. Most participants had previously taken a different CDK4/6 inhibitor— palbociclib (Ibrance).

MAINTAIN investigators randomly assigned 119 patients to either treatment arm, with median PFS as the primary end point. After a median follow-up of 18.2 months, patients in the ribociclib arm (n = 60) had a median PFS of 5.29 months (95% CI, 3.02-8.12), compared with 2.76 months (95% CI, 2.66-3.25) in the placebo arm, a finding that favored the ribociclib regimen (HR, 0.57; 95% CI, 0.39-0.95; 

 = .006). At 6 months, the PFS rates were 41.2% and 23.9%, respectively, and at 12 months, they were 24.6% and 7.4%, respectively.

“CDK4/6 inhibitors have been such a game changer for our patients, so is there a role for just switching the endocrine therapy and continuing the CDK4/6 inhibitor when progression occurs?” Kalinsky asked. “MAINTAIN was the first randomized study to suggest that there was a benefit to doing ribociclib at the time of CDK4/6 inhibitor progression.”

Kalinsky serves as the study principal investigator for postMONARCH (NCT05169567), an ongoing phase 3 trial looking at fulvestrant with or without abemaciclib (Verzenio), a CDK4/6 inhibitor, in a post-CDK4/6 inhibitor population.

Meisel pointed out that many oncologists had been using such strategies even before the MAINTAIN findings were reported at the 2022 American Society of Clinical Oncology Annual Meeting in June. “But Kevin was the first to ask that question in a research setting and then showed a statistically significant benefit to adding ribociclib,” she said. “But every good trial, especially in the metastatic space, answers some questions and then raises others.”

In the case of MAINTAIN, Meisel noted that most study patients had received adjuvant palbociclib in the first line and that all had switched to ribociclib on the study. “So, was it switching to a CDK4/6 inhibitor that mattered, or do you have to switch to that specific CDK4/6 inhibitor?” she said. “Does it matter which CDK4/6 inhibitor you use?”

Although MAINTAIN was a positive trial, it’s also sobering that the results weren’t extremely meaningful clinically, Meisel noted. “The benefit was only a few months," she said, adding that "Kevin is the first to say there’s more work to do.”

Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. 

. 2021;385(25):2336-2347. doi:10.1056/NEJMoa2108873

Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. 

. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Updated April 8, 2021. Accessed December 10, 2022. 

Albain KS, Barlow WE, Shak S, et al; Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. 

. 2010;11(1):55-65. doi:10.1016/S1470-2045(09)70314-6

Abdou Y, Barlow WE, Gralow JR, et al. Race and clinical outcomes in the RxPONDER trial (SWOG S1007): a clinical trial Rx for positive node, endocrine responsive breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Accessed December 19, 2022. 

Mamounas T. Report from the Breast Cancer Working Group Meeting. Presented at: NRG Oncology Summer Meeting; July 21-23, 2022; Chicago, IL. Accessed December 19, 2022. https://bit.ly/3WA3NVg

Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. 

. 2018;379(2):111-121. doi:10.1056/NEJMoa1804710

TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy. News release. National Cancer Institute. June 3, 2018. Accessed December 20, 2022. 

Sparano JA, Gray RJ, Makower DF, et al; on behalf of the TAILORx Investigators. GS1-05 Trial Assigning Individualized Options for Treatment (TAILORx): an update including 12-year event rates. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Accessed December 20, 2022. https://bit.ly/3GPIlpp

The TAILORx trial in over 10,000 women with early breast cancer reaches 12 years of recurrence and survival outcomes. News release. ECOG-ACRIN Cancer Research Group. December 6, 2022. Accessed December 20, 2022. 

Kalinsky K, Accordino MK, Chiuzan C, et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. 

. 2022;40(suppl 17):LBA1004. doi:10.1200/JCO.2022.40.17_suppl.LBA1004

For Kevin Kalinsky, MD, MS, director of breast medical oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia, his work on the RxPONDER trial serves as one of a few accomplishments for which he is grateful that have impacted clinical care. 

Breast Cancer Expert Focuses on Decoding Biomarkers

The treatment of patients with early-stage non–small cell lung cancer (NSCLC) is rapidly evolving across the spectrum of care, particularly in the neoadjuvant setting, where evidence in favor of systemic chemoimmunotherapy regimens is growing, according to a panel of experts.

The sharpened focus on early-stage NSCLC, defined as stages I to III, comes after a decade of expanded therapeutic options in the advanced and metastatic disease settings. Investigators are hoping that improvements can be extended to earlier stages, where the opportunities for curative therapy are greater.

Approximately 40% to 45% of patients diagnosed with lung cancer present with stages I to III disease, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program.

 The 5-year relative survival rates by stage show the comparatively better prognosis for patients with localized and regional disease vs those who are diagnosed with distant disease (Figure).

 Although surgery is a mainstay of treatment, recurrences are common, observed at a rate of more than 50% among patients with resected locally advanced (stage III) NSCLC.

The developments for patients with early-stage disease include practice- changing data involving the use of sublobar resection vs lobectomy in certain patients with stage IA disease, testing of novel techniques in radiation oncology, and “aggressive neoadjuvant approaches” with systemic regimens, according to Heather A. Wakelee, MD, who served as moderator of a recent 

 program. The panel of thoracic oncology experts discussed a broad range of topics affecting patients with stage I to IIIB NSCLC. 

"There’s just so much happening,” Wakelee said. “I worked on adjuvant therapy for many years without moving the bar too far forward. It’s really exciting now that we have to think about early-stage lung cancer the way we’ve thought about metastatic disease.” 

Evidence is growing that limited resection is just as effective as a more invasive lobectomy for certain patients with operable stage IA NSCLC. In the phase 3 CALGB/Alliance 140503 trial (NCT00499330), investigators randomly assigned 697 patients to standard lobectomy (n = 357) or sublobar resection (n = 340) via segmentectomy or wedge resection. To be eligible, participants were required to have NSCLC clinically staged as T1aN0 with tumors 2 cm or smaller, node-negative disease at level 10, and up to 2 mediastinal stations.

After a median follow-up of 7 years, sublobar resection demonstrated noninferiority to lobectomy, according to findings reported at the World Conference on Lung Cancer held by the International Association for the Study of Lung Cancer in August 2022. 

The stratified HR for disease-free survival (DFS), the primary end point of the trial, was 1.01 (90% CI, 0.83-1.24; P = .0176 for noninferiority). The HR for overall survival (OS) was 0.95 (90% CI, 0.75-1.21; P = .014 for noninferiority). The 5-year DFS rates were 64.1% in the lobectomy arm and 63.6% in the sublobar group; the 5-year OS rates were 78.9% vs 80.3%, respectively.

The findings have generated a lot of discussion among surgeons, according to panel member and thoracic surgeon Jonathan Spicer, BSc (Hon), MD, PhD, FRCS. “A lot of [providers] had already migrated toward doing more sublobar resections, but these are massive efforts—they are decades-long efforts,” Spicer said. 

However, he noted that “there are surgical implications, and probably long-term benefit implications, to what type of resection you do for which type of stage the patient has.” For example, patients with 

mutant tumors of 2 cm might experience better outcomes by receiving osimertinib (Tagrisso) therapy for 1 or 2 months before surgery. Osimertinib, a kinase inhibitor, is approved as adjuvant therapy after tumor resection for patients with NSCLC whose tumors harbor 

 exon 19 deletions or exon 21 L858R mutations.

“If you can diagnose [the mutation] up front, if we’re going to give osimertinib for 3 years [as adjuvant therapy], then why don’t we start a month or 2 early? Then that patient can have a sublobar resection,” Spicer said. “That brings a lot of quality-of-life benefit and meaning to the patient’s experience of surgery.” 

Joshua K. Sabari, MD, expressed concern that neoadjuvant osimertinib might make resection more difficult for general surgeons in community settings who would have less experience than their specialized peers in excising a more challenging “fibrosed EGFR tumor.”

There also might be a difference between sublobar resections carried out after oncologic staging and nodal sampling, which are “not the same as what have been referred to as wedge resections done by nonspecialist surgeons,” Billy W. Loo, Jr, MD, PhD, FASTRO, FACR, said. 

The treatment of patients with early-stage non–small cell lung cancer is rapidly evolving across the spectrum of care, particularly in the neoadjuvant setting, where evidence in favor of systemic chemoimmunotherapy regimens is growing.

Vol. 24/No. 2 | Oncology Live®

Frontline Pola-R-CHP, CAR T-Cell Second-line Therapies Are Not Cost-effective in DLBCL

Investigators Seek Simpler Solution to Treatment Resistance in Esophageal Cancer

MOUNTAINEER-03 Propels Progress in Metastatic HER2+ CRC

Breast Cancer Expert Focuses on Decoding Biomarkers

Neoadjuvant Therapy Helps Shape Changing Landscape of Early-Stage NSCLC

Exploring the Nuances of Regulatory Approval Vs Optimal Use of a New Antineoplastic Agent