Patients with aromatase inhibitor-resistant ESR1-positive breast cancer could be in line to gain a new treatment option outside of fulvestrant (Faslodex), according to Aditya Bardia, MD, MPH. Oral selective estrogen receptor degraders (SERDs) may be an effective treatment for patients with estrogen receptor (ER)–positive breast cancer.

In addition to discussing the potential benefit of oral SERDs in patients with ER-positive breast cancer, Bardia highlighted how the use of circulating tumor DNA (ctDNA) could help drive treatment decisions for patients with 

-mutated disease before radiographic progression is detected during presentations at the 2022 International Congress on the Future of Breast Cancer West®.

“Oral SERDs would fill an unmet need because they still work when tumors are resistant to aromatase inhibitors due to 

 mutations, because the tumor is ER dependent. They can provide a non-chemotherapy option for patients in the endocrine-resistance setting,” Bardia said in an interview with 

In the interview, Bardia, an associate professor of medicine at Harvard Medical School, and an attending physician in Medical Oncology at Massachusetts General Hospital, discussed recent and ongoing trials evaluating oral SERDs in ER-positive breast cancer, the effect of 

 mutations on treatment efficacy, and how the use of ctDNA continues to evolve across the breast cancer space.

®: What unmet needs can oral SERDs address in the treatment of ER-positive breast cancer?

: Endocrine therapy is the mainstay in the management of [localized and metastatic] ER-positive breast cancer. Right now, the only SERD that is FDA approved is fulvestrant, but that’s given as an intramuscular shot. There is a need for better therapies, including oral SERDs, and there are various oral SERDs in development.

This is particularly relevant in the metastatic setting because we know a subset of [patients with] ER-positive breast cancer can develop a mutation in the estrogen receptor, called 

 mutations, and those tumors are resistant to aromatase inhibitors. Drugs that directly bind to ER, like fulvestrant, would work, although that’s given as [an intramuscular] shot.

Oral SERDs would fulfil an unmet need [for patients with 

-mutated, ER-positive breast cancer]. That’s why there’s a lot of excitement related to these oral SERDs. [These agents] would also work in 

 wild-type [ER-positive breast cancer] in the right context in localized breast cancer and other settings. [My presentation focused on] the biology of 

 mutations and the role of oral SERDs in ER-positive breast cancer.

 mutations as drivers of resistance to endocrine therapies meant for the treatment of patients with ER-positive breast cancer?

 mutations are one of the most common mechanisms of resistance to aromatase inhibitors. If you think about their mechanism of action, aromatase inhibitors lower estrogen, but when there’s a mutation in the ER, the tumor becomes estrogen independent, [leading to resistance] to aromatase inhibitors. But a drug that can bind directly to the ER would work in that setting, and that’s why we routinely check for 

 mutations as part of comprehensive tumor genotyping via blood or tissue, because that could affect therapeutic decision making.

What efficacy have been seen with oral SERDS so far in clinical trials?

There have been a couple large, randomized, phase 2 and phase 3 trials, looking at oral SERDs vs single-agent endocrine therapy. The key is that those are trials that provide scientific proof of principle comparing a newer agent vs an existing agent. For example, the [phase 3] EMERALD trial [NCT03778931] looked at elacestrant vs standard-of-care endocrine therapy in the second- and third-line settings. [Elacestrant] demonstrated an improvement in progression-free survival [PFS] and a trend toward improvement in overall survival [OS]. But that’s in the endocrine-resistance setting.

Moving forward, there will be interest in looking at combination therapy in the endocrine-resistance setting. If a tumor has a 

 mutation, [since] the [FDA] approval of alpelisib [Piqray], we tend to use fulvestrant and alpelisib. But if you have a better endocrine backbone, like elacestrant or other oral SERDs, [those agents are] likely going to do better with alpelisib. Wherever fulvestrant is being used, if you have a better endocrine agent that would likely work, be it single-agent or combination therapy, [that would be preferable].

Oral SERDs are also being investigated in the first-line setting. For example, the [phase 3] AMEERA-5 trial [NCT04478266] is examining amcenestrant [SAR439859] plus the CDK4/6 inhibitor [palbociclib (Ibrance)] vs standard endocrine therapy plus [palbociclib]. [The phase 3] persevERA trial [NCT04546009] is looking at giredestrant [(GDC-9545) plus palbociclib vs letrozole plus palbociclib] in the first-line, metastatic setting.

Finally, there are trials looking at oral SERDs in the adjuvant setting. For example, the [phase 3] lidERA trial [NCT04961996] is looking at adjuvant giredestrant vs [physician’s choice of] endocrine therapy for patients with localized ER-positive breast cancer. There are a lot of ongoing studies [generating] excitement related to [oral SERDs].

Why is it important to evaluate oral SERDs in different settings?

If you look at endocrine therapy, we have to carefully evaluate the setting. It’s not just about the drug, but also the study population. Especially in the second- or third-line setting, a subset of tumors is estrogen receptor independent. They are dependent on other pathways. In that setting, it’s unlikely we would see benefit with single-agent endocrine therapy. [Other than] results, the context and the study population matter. We have to look at the details before drawing strong conclusions.

In another presentation, you spoke on lessons from the phase 3 PADA-1 trial (NCT03079011) and phase 2 SAFIR02 trial (NCT02299999). What did the detection of an 

 mutation and the switch from an aromatase inhibitor to fulvestrant mean for patients with metastatic breast cancer?

 mutations confer resistance to aromatase inhibitors, and that’s something that can be detected by plasma-based genotyping or ctDNA analysis. The PADA-1 trial looked at patients who were getting first-line therapy with an aromatase inhibitor plus a CDK4/6 inhibitor. They were monitored for 

 mutations. When a patient had emergence of an 

 mutation before radiological progression, they continued the same therapy or switched from an aromatase inhibitor to fulvestrant. This showed that there was an improvement in PFS with this switch. This provides proof of principle that monitoring of ctDNA and [choosing] therapy based on that might have potential clinical utility.

But I would caution [switching therapies based on ctDNA] is not ready for primetime yet. The ongoing phase 3 SERENA-6 trial [NCT04964934] is asking that question, and we need results of large, phase 3 trials before changing practice. [It is also important to look] at OS. If you make an early switch [of treatment], does it affect OS? We need to see improvement in OS before we can incorporate a switch strategy into clinical practice.

The other trial that was very insightful was the SAFIR02 trial, also in metastatic breast cancer, that looked at genotype-directed matched [targeted] therapy. The bottom line there was that it’s not just about genotype-directed matched therapy, but the level of evidence. If patients have ESCAT I/II [genomic alterations], you’re likely going to see an improvement in survival, but [in patients with] ESCAT III/IV [genomic alterations], the investigators couldn’t see much improvement. The level of evidence also matters. It is not just about selecting matched [targeted] therapy.

What did the phase 2 c-TRAK-TN (NCT03145961) trial reveal about the use of ctDNA to drive treatment decisions in breast cancer?

The c-TRAK trial was an interesting trial because it looked at [patients with] triple-negative breast cancer who had residual disease after standard therapy or after surgery [and monitored] for ctDNA. If a patient had detectable ctDNA, they could receive immunotherapy. The trial was insightful for 2 reasons. The first is that in patients who had detectable ctDNA, a large number of them already had radiologically detectable metastatic disease. This highlights that if you have ctDNA that is positive, these are patients who are at very high risk, and many of them already have metastatic disease.

The second [reason] was in terms of the effect of immunotherapy. Because only a few patients received immunotherapy, it was difficult to analyze the effect of immunotherapy in this setting. But there are other ongoing studies looking at this question. If you detect ctDNA and you add a therapy, can you prevent metastatic disease? The key there is going to be the delta between detectable ctDNA and the emergence of radiologically detectable metastatic disease. The longer the delta is, the more time you have to intervene and make an impact. But if it’s a very short delta, intervention is unlikely to be helpful.

What still needs to be learned about the utilization of ctDNA to inform treatment in breast cancer?

ctDNA is routinely being used in metastatic breast cancer for therapy selection. The things that still need to be determined include the value of serial ctDNA, be it for monitoring or, at the time of disease progression, to have another switch in therapy.

The other unmet need related to ctDNA is in the adjuvant setting. In that setting, we need sensitive assays, and we need to see what the value of ctDNA is for therapy selection. If you find detectable ctDNA, what can be done about it in terms of matched [targeted] therapy? There are ongoing studies looking at this question, so we eagerly await the results of those studies.

What are the next steps for examining the use of ctDNA in future clinical trials?

The utilization of ctDNA is increasing and will continue to increase over the years. It started with its application in metastatic breast cancer for therapy selection. Now, there’s interest in monitoring and understanding resistance in the metastatic setting. In early breast cancer [we are examining] similar principles, [including] detection, monitoring, and therapy selection.

Finally, [we can look at] early detection. Can you utilize ctDNA to detect [breast] cancer before you can see it on the mammogram? Similarly, can you detect ctDNA before a patient develops colon cancer? The use of ctDNA and similar blood-based assays for early detection is also very exciting.

Articles

Aditya Bardia, MD, MPH, discusses ongoing research with oral SERDs, such as elacestrant, and highlights what these agents could represent for patients with estrogen receptor–positive breast cancer.

Oral SERDS Open New Door in ESR1-Mutant, ER-Positive Breast Cancer

Adding a single priming dose oftremelimumab to regular interval durvalumab (Imfinzi; the STRIDE regimen) was associated with superior overall survival (OS) compared withsorafenib (Nexavar) for patients receiving frontline treatments for unresectable hepatocellular carcinoma (HCC), according to updated data from the phase 3 HIMALAYA trial (NCT03298451). The findings, resented at the 2022 ESMO World Congress on Gastrointestinal Cancer, also found the OS benefit to be consistent, regardless of a patient’s baseline albumin-bilirubin (ALBI) grade.

In patients with ALBI grade 1, the STRIDE regimen elicited a median OS of 23.43 months (95% CI, 19.19-28.75), compared with 19.02 months (95% CI, 15.67-23.16) for sorafenib (HR, 0.79; 95% CI, 0.62-1.01). In patients with ALBI grade 2/3, the STRIDE regimen produced a median OS of 11.30 months (95% CI, 9.33-14.19), vs 9.72 months (95% CI, 7.23-11.76) for sorafenib (HR, 0.83; 95% CI, 0.65-1.05).

Additionally, single-agent durvalumab produced favorable OS outcomes vs sorafenib, irrespective of ALBI grade. In patients with ALBI grade 1, the median OS for durvalumab was 21.16 months (95% CI, 17.38-25.86), compared with 19.02 (95% CI, 15.67-23.16) for soreafenib (HR, 0.91; 95% CI, 0.71-1.15). In patients with ALBI grade 2/3, the median OS for durvalumab was 12.29 months (95% CI, 9.30-16.03), vs 9.72 (95% CI, 7.23-11.76) for sorafenib (HR, 0.87; 95% CI, 0.69-1.09).

“We need to acknowledge that this was a post-hoc analysis, and all analyses that we have performed so far have been in respect to liver function, and they have never been prospectively evaluated,” said Arndt Vogel, MD, PhD. “We have a very clear picture that liver function has a strong prognostic impact, which is important when we talk to our patients.”

®, Vogel, a managing senior consultant and professor in the Department of Gastroenterology, Hepatology and Endocrinology, and the head of the GI-Cancer Center at the Hannover Medical School, discussed the post-hoc analysis from the randomized, open-label, multicenter, global HIMALAYA trial presented at the 2022 ESMO World Congress on Gastrointestinal Cancer.

®: Can you expand on the rationale of combining tremelimumab and durvalumab in the phase 3 HIMALAYA trial?

: We have seen in the past that immunotherapy has activity in HCC, but monotherapy with just a PD-1 or PD-L1 inhibitor has not been sufficient enough to achieve a positive phase 3 study. We have seen this in trials with pembrolizumab [Keytruda] and nivolumab [Opdivo].

We have seen in the past that CTLA-4 has activity in a subgroup of patients with HCC. This led to a clear rationale to combine CTLA-4- and PD-1­–targeted agents, as we have seen in other tumor types.

There were early data from the phase 3 CheckMate040 trial [NCT01658878] with nivolumab and ipilimumab [Yervoy] that suggested synergistic activity. There was a clear rationale to proceed with [HIMALAYA] in this setting.

What were the unmet needs that the trial aimed to address?

The majority of our patients are diagnosed in an advanced setting. In early HCC, we can perform resection or liver transplantation, but when the tumor gets bigger, a patient [can present] with vascular infiltration or extra hepatic metastases. We are in a palliative setting, and for many years, we had few options. The major breakthrough came with immunotherapy-based combinations, and this combination of PD-1 and CTLA-4 antibodies is now another important step for the armamentarium for advanced HCC.

What were the primary objectives of the HIMALAYA trial?

The HIMALAYA study was a 3-arm study looking at the combination of durvalumab and 1 single [dose] of tremelimumab, referred to as the STRIDE regimen. This was compared to sorafenib, with a primary end point of showing superiority [in efficacy]. Additionally, the third arm [evaluated] durvalumab monotherapy. Here, this was a key secondary end point to show noninferiority compared with sorafenib.

This was a global study for patients with unresectable HCC that were not suitable for local regional therapies.

What key findings have been found thus far, and what updates were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer?

The HIMALAYA study has been now published as a full paper, and it was a positive study. For the STRIDE regimen, there was superior activity shown in terms of OS compared with sorafenib. Additionally, [single-agent] durvalumab was noninferior to sorafenib.

In HCC, we usually have 2 diseases, including chronic liver disease in many cases, such as liver cirrhosis, and the tumor. Based on past post-hoc analyses from phase 3 studies, liver function is a very important prognostic marker. At the 2022 ESMO World Congress on Gastrointestinal Cancer, we analyzed the affect of liver function on OS for the 2 immunotherapy-based regimens. We grouped patients according to their liver function scores, which was part of the inclusion criteria.

To distinguish 2 groups of patients with different preserved liver function, we utilized the ALBI score, where half of the patients were ALBI grade1, with a good liver function, and the other half was ALBI grade 2/3.

We were able to show in the HIMALAYA study that liver function has a very important prognostic effect. The median OS was almost twice as long in patients with a more well-preserved liver function compared with those with ALBI grade 2.

In terms of efficacy, it was very evident that the STRIDE regimen specifically has clear activity in both groups of ALBI grade 1 and ALBI grade 2/3. There was almost no significant difference in terms of the hazard ratio. We can say the prognostic impact of liver function was confirmed. Importantly, the STRIDE regimen was effective independent from the underlying liver function.

What should be known regarding the safety profile and toxicities associated with the STRIDE regimen?

In the HIMALAYA study, we saw the expected adverse effect [AE] profile, though we have slightly more AEs with the STRIDE regimen compared with the durvalumab monotherapy. There were more immune-related AEs and more steroid use, but overall, there was no negative impact on the quality of life. In our analysis here, there was no impact of liver function on the safety prolie for the patients.

Based on the findings from this trial, what could this potentially mean for the treatment paradigm for patients with unresectable HCC?

We need to acknowledge that this was a post-hoc analysis, and all analyses that we have performed so far have been in respect to liver function, and they have never been prospectively evaluated. We have a very clear picture that liver function has a strong prognostic impact, which is important when we talk to our patients.

In terms of efficacy, the data are not crystal clear. But for the HIMALAYA study, we can clearly conclude that more impaired liver function of ALBI grade 2/3 has no negative impact on the efficacy of durvalumab and tremelimumab. These data need to be confirmed in a real-world setting. But it is reassuring that we do not need to select our patients based on liver function when we consider the use of durvalumab or durvalumab/tremelimumab.

Vogel A, Chan SL, Furuse J, et al. Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the Phase 3 HIMALAYA study. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022; Barcelona, Spain. Abstract O-5.

Arndt Vogel, MD, PhD, discusses a post-hoc analysis of the phase 3 HIMALAYA trial which found tremelimumab plus durvalumab to be superior to sorafenib in improving overall survival. 



Tremelimumab Plus Durvalumab Bests Sorafenib OS Rates In Frontline HCC Treatment

An assessment of patient-reported outcomes from the phase 3 SEQUOIA trial (NCT03336333) showed that patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) receiving zanubrutinib (Brukinsa) experienced improved health-related quality-of-life (HRQOL) outcomes compared with patients receiving bendamustine (Bendeka) plus rituximab (Rituxan), according to data presented at the 2022 EHA Congress.

Findings showed that patients who received zanubrutinib displayed improvements in HRQOL at both weeks 12 and 24. At week 12, patients who received zanubrutinib saw a mean change from baseline in global health status (GHS) of 2.9 (standard error [SE], 1.62; 95% CI, -0.2 to 6.1), compared with 2.2 (SE, 1.73; 95% CI, -1.2 to 5.6) for patients who received bendamustine plus rituximab. Additionally, at week 12, the mean change in physical function was 1.9 (SE, 1.19; 95% CI, -0.5 to 4.2) with zanubrutinib and 0.9 (SE, 1.26; 95% CI, -1.6 to 3.4) with bendamustine/rituximab, and the mean change in role function was 1.7 (SE, 2.00; 95% CI, -2.3 to 5.6) with zanubrutinib vs -2.8 (SE, 2.13; 95% CI, -6.9 to 1.4) with bendamustine/rituximab.

The week 24 mean change in GHS was 4.8 (SE, 1.64; 95% CI 1.6-8.0) with zanubrutinib and -0.2 (SE, 1.74; -3.6 to 3.3) with bendamustine/rituximab. The mean change in physical function was 3.5 (SE, 1.20; 1.1-5.9) with zanubrutinib and -0.3 (SE, 1.27; 95% CI, -2.8 to 2.2) with bendamustine/rituximab, and the mean change in role function was 2.1 (SE, 2.02; 95% CI, -1.9, 6.1) with zanubrutinib and -2.7 (SE, 2.14; 95% CI, -6.9 to 1.5) with bendamustine/rituximab.

“Greater improvements were observed in GHS, physical function, and role function and in symptoms of fatigue, diarrhea, and nausea/vomiting in treatment-naïve patients who received zanubrutinib compared with patients who received bendamustine plus rituximab; while the 2 arms experienced similar improvements in pain,” lead study author, Paolo Ghia, MD, PhD, deputy director, Division of Experimental Oncology, group leader, B-cell Neoplasia, unit head, Strategic Research Program on CLL, and full professor in Medical Oncology at the Università Vita Salute San Raffaele, wrote in the poster presentation.

The subpar HRQOL for patients with treatment-naïve CLL and SLL compared with the general population remains an unmet need in this space. In addition to treatment-related adverse effects, patients also suffer from chronic fatigue, pain, fever, frequent infections, night sweats, swollen lymph nodes, and enlarged spleen and liver.

BTK inhibitors, including zanubrutinib, have been shown to improve progression-free survival (PFS) and overall survival (OS) in patients. Moreover, zanubrutinib has been designed to result in less off-target effects and is now recommended as the preferred first- and subsequent-line therapy in CLL and SLL.

The open-label, randomized SEQUOIA trial, evaluated the efficacy of zanubrutinib vs bendamustine and rituximab in patients with previously untreated CLL and SLL. An interim analysis of the study showed that PFS at a median follow up of 26.2 months was significantly prolonged in patients who received the BTK inhibitor therapy vs bendamustine/rituximab. Here, HRQOL was evaluated through patient-reported outcomes from baseline through week 24.

Patients were allowed to enroll if they did not have any previous CLL or SLL treatment. Moreover, patients were required have a confirmed diagnosis of CD20-positive CLL or SLL, and ECOG performance score of 2 or less.

Once enrolled, patients were randomized 1:1 to receive either 160 mg of oral zanubrutinib twice a day, or 90 mg/m2 or intravenous bendamustine on the first 2 days of cycles 1 through 6, plus 375 mg/m2 of rituximab in cycle 1, followed by 500 mg/m2 in cycles 2 to 6. Treatment lasted until progression or unacceptable toxicity occurred in patients. Additionally, each cycle of treatment lasted 28 days.

HRQOL outcomes were assessed via patient-reported outcomes that were collected utilizing the European Organization for Research and Treatment of Cancer QLQ-C30. Patient-reported outcomes were assessed for GHS, physical function, role function, and symptoms of fatigue, pain, diarrhea, nausea, and vomiting, which were then measured utilizing a linear mixed-effects model for repeated measurements. This measurement assessed key changes from baseline in each respective arms between weeks 12 and 24.

Overall, baseline demographics and disease characteristics observed were similar between the zanubrutinib and bendamustine/rituximab arms. Patient-related outcomes were available for 92.9% of patients in the zanubrutinib arm (n = 224/241) and 84.9% of patients in the bendamustine plus rituximab arm (n = 202/238). The median age of patients across both arms was 70 years old. The majority of patients were White (89.1%) and male (62.2%). The majority of patients had an ECOG score of 1 (48.6%) and 0 (44.1%).

Additional data at week 24 showed that zanubrutinib achieved mean changes in fatigue (-7.8 [SE, 1.80; 95% CI, -11.3 to -4.2]); nausea/vomiting (-2.3 [SE, 1.06; 95% CI, -4.4 to -0.2]); and diarrhea (-1.4 [SE, 1.52; 95% CI, -4.4 to 1.6]). Those mean changes with bendamustine/rituximab were -3.3 (SE, 1.90; 95% CI, -7.0 to 0.4), 1.9 (SE, 1.12; 95% CI, -0.3 to 4.1), and 4.8 (SE, 1.61; 95% CI 1.7 to 8.0), respectively. Notably, the effects on pain were similar between zanubrutinib and bendamustine/rituximab, with mean changes of 0.7 (SE, 1.88; 95% CI, -3.0 to 4.4) and 0.3 (SE, 1.99; 95% CI, -3.6 to 4.2), respectively.

“For future analyses, examining the interaction between the patient-reported outcomes end points and broader safety assessments may be warranted,” Ghia said. “With improved selectivity and less off-target effects, zanubrutinib may improve HRQOL outcomes in treatment of patients with CLL and SLL.”

Ghia P, Barnes G, Yang K, et al. Patient-reported outcomes from a phase 3 randomized study of zanubrutinib vs bendamustine plus rituximab (BR) in patients with treatment-naive (TN) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract P662

Investigators have identified that zanubrutinib may improve the subpar health-related quality of life for patients with treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma.

Zanubrutinib Associated With Better Quality of Life Vs Bendamustine/Rituximab in CLL/SLL

Significant improvements in overall survival (OS) were observed with the addition of HER2-Vaxx vaccine to standard of care (SOC) chemotherapy in patients with HER2-neu overexpressing advanced and metastatic gastric and gastroesophageal junction cancer (GEJ).

Findings from the final analysis of the phase 2 HERIZON trial (NCT02795988),

 which assessed the regimen against chemotherapy alone, showed a 41.5% reduction in the risk of death with HER-Vaxx plus SOC chemotherapy vs SOC chemotherapy alone (HR, 0.585; 80% 2-sided CI, 0.368-0.930; 

 = .066). These results were compared with historical data from the phase 3 ToGA trial (NCT01041404), which resulted in a hazard ratio of 0.65 with trastuzumab (Herceptin) plus chemotherapy vs chemotherapy alone in the same patient population of patients included in the HER-Vaxx study.

“It has been a true pleasure to be an investigator on the HERIZON clinical trial. I have seen a positive impact on the long-term survival in my patients taking HER-Vaxx and look forward to the future development of this vaccine,” Tanuj Chawla, MD, the principal investigator of the HERIZON study, stated in a press release.

HER-Vaxx is a B-cell peptide cancer immunotherapy designed to treat tumors that overexpress the HER2-neu receptor. The immunotherapy, constructed from B-cell epitopes derived from the extracellular domain of HER2-neu, has demonstrated potent polyclonal antibody responses to HER2-neu in preclinical, phase 1, and now phase 2 trials.

“I am delighted to report that we have achieved this significant milestone for patients with advanced gastric cancer. The final analysis favored the survival outcome for HER-Vaxx and I note the Independent Data Monitoring Committee previously suggested to shorten the study by lowering the number of patients,” Leslie Chong, MD, chief executive officer of Imugene, stated in a press release.

The phase 1b/2, open-label, multicenter, dose-escalation study enrolled 36 patients with HER2-neu overexpressing metastatic or advanced stomach or GEJ adenocarcinoma.

Eligible patients were at least 20 years of age with a life expectancy of 12 weeks and an ECOG performance status between 0 and 2. Patients were required to have at least 1 measurable lesion, along with adequate left ventricular ejection function, hematologic function, liver function, and renal function. Prior chemotherapy or radiotherapy for advanced gastric or GEJ cancer within 6 months of day 0 dosing was prohibited in the phase 1b cohort. Notably, men and women were required to use contraception throughout the study.

In the phase 1b portion of the study, patients in the experimental arm received 10, 30, or 50 μg of HER-Vaxx plus 80 mg/m2 of cisplatin on the first day of each cycle and 4000 mg/m2 of 5-fluorouracil (5-FU) administered in 100 mg/m2 doses for 96 hours on days 1 and 4 of each cycle, or 2000 mg/m2 of capecitabine daily for 14 days.

In the phase 2 portion of the study, patients in the experimental arm received 50 μg of HER-Vaxx plus cisplatin and 5-FU; or capecitabine; or oxaliplatin and capecitabine. Cisplatin was administered at a dose of 80 mg/m2 on day 1 of each cycle, and 4000 mg/m2 of 5-FU was administered for 96 hours on days 1 to 4 of each cycle at 1000 mg/m2 doses each day. Treatment with capecitabine was administered at 2000 mg/m2 per day for 14 days. Patients who opted for later combination chemotherapy regimen received 130 mg/m2 of oxaliplatin on day 1 of each cycle plus 2000 mg/m2 of capecitabine per day for 14 days.

The primary end point was OS, and the secondary end point was progression-free survival. Safety, tolerability, and immune response were also analyzed.

Notably, the longest-treated patients remain alive 2.5 years after starting therapy and generated the strongest levels of anti-HER2 antibodies from their dosing schedule on HER-Vaxx.

Additionally, no difference in safety events occurred between the treatment arms.

The HERIZON-extension Cohort Review Committee announced that a new higher 100 μg dose of HER-Vaxx has been approved for use in the phase 2 nextHERIZON trial (NCT05311176) in pretreated metastatic HER2-positive gastric cancer and the neoHERIZON trial in perioperative HER2-positive gastric cancer.

The committee determined that the 100 μg dose of HER-Vaxx was safe with no dose-limiting toxicities and no serious adverse reactions. The higher dose is expected to generate improved clinical responses for HER-Vaxx.

Imugene Presents Final HER-Vaxx Overall Survival Results In Randomized Phase 2 Trial In Advanced Gastric Cancer. News release. Imugene Limited. June 27, 2022. Accessed June 28, 2022. 

A study of IMU-131(HER-Vaxx) and chemotherapy compared to chemotherapy only in patients with HER2 positive advanced gastric cancer. Updated January 20, 2022. Accessed June 28, 2022. 

https://clinicaltrials.gov/ct2/show/NCT02795988

The addition of the HER2-Vaxx vaccine to chemotherapy resulted in 41.5% reduction in the risk of death compared with chemotherapy alone among patients with gastric cancers.  

 Addition of HER2-Vaxx Vaccine to Standard Chemotherapy Prolongs Overall Survival in HER2+, Advanced Gastric/GEJ Cancer

Oncology providers can implement strategies to help improve colorectal cancer [CRC] screening rates among their patients, according to Denalee O'Malley, PhD. Structural racism, income inequality, and geographic barriers can all affect screening access, however, leveraging the provision of resources and support available to qualified health centers can be useful in combatting these barriers.

“The barriers are multilevel, but most of them can be resolved with additional resources. At the patient level, there are [barriers to] transportation, time off work, and access to appointments,” O’Malley, an assistant professor of family medicine and community health at Rutgers Robert Wood Johnson Medical School, said interview with 

®. “The centers at the clinic sites need test kits to be able to send to patients for first-line screening. They need personnel to prepare and mail them, postage, staff time to follow-up and coordinate both the abnormal and the positive results, and they need to [be able to] support patients in the transition to oncology [care].”

One strategy that is being used to improve screening rates in underserved communities is through programs such as ScreenNJ, which partners with community organizations, federally qualified health centers, and others to improve outreach and community education, support provider awareness, and strengthen peer support/patient navigation programming.

In the interview, O'Malley, who is also a member of the Cancer Prevention and Control Program and a research member of the Cancer Health Equity Center of Excellence at Rutgers Cancer Institute of New Jersey, shed light on racial and ethnic disparities in CRC screening, and strategies that can be used to address existing barriers in the clinic and beyond.

®: Please discuss the research you are currently conducting in the realm of racial disparities in CRC screening and care.

: I am currently working on a project funded by the National Cancer Institute called “Optimizing CRC Screening Among Patients with Diabetes in Safety-Net Primary Care Settings,” to target implementation approaches. This study examines differences in the types of CRC screenings utilized by patients who receive most of their care in the community health-center system, which is the primary care safety net.

The goal is to identify and overcome barriers at multiple levels—the patient, the clinic, and the health system—that can all affect optimal use of CRC screening tests, and then develop strategies that can be implemented based on context-specific needs of clinics.

How can racial disparities affect CRC screening? What are some existing barriers to testing and appropriate care?

There is structural racism embedded in the health care delivery system, and the disparities that affect CRC screening are intersectional. Racism, income inequality, geographic disparities, and how healthcare is organized and delivered all have an effect on CRC screening and care.

Multiple types of CRC screening tests [exist], which makes [this] more complicated, and they have different levels of efficacy and [need to be performed in] different intervals. For example, a FIT test needs to be administered every year. A colonoscopy, if the test comes back normal, has a 10-year interval, based on the current guidelines.

Community health centers are considered the primary care safety net. A little over 20% of community health center patient populations are uninsured, and the largest payer nationally in the community health setting is Medicaid.

When you use a first-line FIT test, there are multiple steps between an abnormal FIT test and a cancer diagnosis and transition to care. There is the screening itself, the cancer detection, the pathology report, and then, the transition to a cancer center or an oncologist. Barriers at the patient level can include not having a reliable telephone to get the [test result] information [returned to them], not being able to take off work to get a colonoscopy if the test is found to be abnormal, the inability to get an appointment that accommodates their schedule, and the need to get transportation if anesthesia is involved.

At the health-system level, there can be an insufficient number of specialists who offer the diagnostic tests at different centers. There can be there can be any constellation of these problems. In the study focused on patients with diabetes, there is also a cumulative risk involved with having another medical condition. Patients who have diabetes have a 27% greater lifetime risk of having CRC. Diabetes disproportionately affects the Hispanic and African American population, and in the in the community health center setting, we see a much larger proportion of uncontrolled diabetes than you would in a traditional primary care setting. What that means in the care space is that if a patient comes in with an acute health need, preventative health needs might take a backseat.

How can some of these barriers be addressed?

Within the medical neighborhood, the resources that the clinics need [include] receptive diagnostic centers and oncology colleagues who they can transition patients to who are in need diagnostic workups or cancer care.

What strategies are needed to help improve CRC screening in high-priority populations to prevent loss of life?

These are contextually bound strategies. The answer lies in partnering with different types of community health centers, seeing what the barriers are, and coming up with strategies that fit the needs of the context. This requires a partnership between researchers, community members, community health-center staff, and clinicians who are the experts on how their organization operates and the barriers that they face.

How can your colleagues in the community work to better address existing disparities to help close the gap?

Awareness about prevention and clear messaging is important. We are living in a time where misinformation is abundantly available. [Ensuring] that we have outlets in the community that can provide patients with reliable information about the benefits of screening is important.

[We also need] to develop creative solutions, based in the community, for the barriers that [these] populations face. [Some of these] can be universal; we [may] see [some of them] across different sites, but others may be different. Some places have an environment that has better transportation, so that may not be an issue in 1 place and a huge barrier in another.

The other piece is to be more mindful about what we accept as a normal course of business and interrogate why we do things the way we do them. [We need to ask ourselves, who] is this intervention benefiting and who is it potentially leaving out? Those are ways that we can do a better job at closing that gap.

How pivotal is screening in terms of diagnosis and outcomes in CRC?

With most prevention, the famous slogan to follow is, “An ounce of prevention is worth a pound of cure.” CRC is a clear example of that. If CRC was prevented, such as removing a polyp [prior to diagnosis], the potential life saved would be 6.5 years on average. The main takeaway is that [screening and treatment of CRC] is all connected. Our primary care system and its strength affect what we see later down the road in cancer care.

This is all connected in the sense that a patient who comes in for cancer care comes as a whole person who has other illnesses. Since cancer is generally a condition of the aging, chances of someone coming to a cancer diagnosis with chronic illness matters and affects that journey. We need to be intentional about that earlier in the care pathway because we could be more intentional about preventing what can be more cumulative risks as someone lives longer.

Exploring racial and ethnic disparities in colorectal cancer screening. Rutgers Cancer Institute of New Jersey. March 1, 2022. Accessed May 19, 2022. 

This article was originally published on 

 as “Addressing Barriers Contributing to Disparities in CRC Screening in Underserved Populations.”

Strategies to combat ethnic disparities in colorectal cancer screening are not limited to the clinic.  

How Oncology Providers Can Help Mitigate CRC Screening Disparities 

Patients with breast cancer that harbors 

 fusions achieved deep and durable responses following treatment with entrectinib (Rozlytrek), according to updated data from the phase 2 STARTRK-2 trial (NCT02568267) presented at the ESMO Breast Cancer Congress 2022.

At a median duration of survival follow-up of 35.3 months in patients with 

 fusion–positive disease (n = 7), entrectinib elicited a 71% (95% CI, 29.0%–96.3%) overall response rate (ORR); 2 patients achieved a complete response (CR) and 3 patients had a partial response (PR). Response data were missing on the other 2 patients. Both patients who achieved a CR had secretory disease, and among the 3 patients to have a PR, 2 had secretory disease and 1 had non-secretory disease. Among the 5 responders, the median duration of response (DOR) was 12.9 months (95% CI, 4.2-not evaluable [NE]).

 gene fusions are drivers in many solid tumors, including breast cancer.

 Though less than 1% of all breast cancer cases harbor 

 fusions, they are present in more than 90% of secretory breast carcinomas.

Prior data from the ALKA-372-001 trial (EudraCT 2012-000148-88), the phase 1 STARTRK-1 trial (NCT02097810), and STARTRK-2 showed entrectinib demonstrated deep and durable responses in patients with 

 Prior data from STARTRK-2 showed patients with 

 fusion–positive breast cancer achieved an ORR of 83% (n = 5 of 6), a median DOR of 12.9 months (95% CI, 4.2-NE), a median progression-free survival (PFS) of 10.1 months (95% CI, 5.1-NE), and a median overall survival (OS) of 23.9 months (95% CI, 5.1-23.9).

STARTRK-2 enrolled patients with locally advanced or metastatic solid tumors that harbored an 

 fusion–positive breast cancer. Moreover, patients were eligible regardless of central nervous system (CNS) metastases, and patients were required to be naïve to TRK inhibitors.

Enrolled patients received 600 mg of entrectinib once daily. Tumor burden was assessed following the first cycle of therapy, followed by every 8 weeks after by blinded independent central review per RECIST v1.1 criteria. Notably, regular brain scans were required for patients with baseline CNS metastases.

The primary end points were ORR and DOR per blinded independent central review. Secondary end points included PFS, OS, intracranial efficacy, CNS progression, and safety.

 fusion–positive breast cancer, all were female with a median age of 61 years (range, 36-67), and 5 patients were White. Patients had an ECOG performance status of 0 (n = 3), 1 (n = 2), or 2 (n = 2). All patients had received prior chemotherapy, radiotherapy, and hormonal therapy, and 5 patients were administered prior targeted therapy. One patient had previous radiotherapy of the brain.

Prior lines of therapy for metastatic disease included 0 (n = 3), 1 (n = 1), 3 (n = 1), and 4 or more (n = 2). Two patients presented with CNS metastases at baseline, and the median time since diagnosis for all patients was 130.1 months (range, 32.6-309.1). Histology included non-secretory (n = 2), secretory (n = 4), and not specified (n = 1).

Additional data showed the median PFS was 10.1 months (95% CI, 5.1-NE), and the median OS was 19.2 months (95% CI, 5.1–NE).

In the 2 patients with CNS metastases at baseline, the first had HER2-positive, estrogen receptor (ER)–positive, PGR-negative disease and received whole brain radiation 2-6 months prior to beginning entrectinib. This patient received no prior lines of systemic therapy for metastatic disease, and she achieved a PR and an intracranial non-CR and non–progressive disease. The second patient had HER2-negative, ER-positive, PGR-positive disease and received 6 prior lines of systemic therapy for metastatic disease. This patient did not have response data after dying 1.7 months following the first dose of entrectinib, though her death was not considered related to treatment.

Notably, no patients experienced a CNS progression event, regardless of baseline status.

Among 12 patients who received at least 1 dose of entrectinib and were evaluable for safety, 4 patients experienced a grade 3 or higher treatment-related adverse effect (TRAE). These included anemia (n = 2), fatigue (n = 1), and increased alanine aminotransferase (n = 1). There were no grade 5 TRAEs recorded. Only 1 patient had a series TRAE.

The most common TRAEs of any grade included dizziness (n = 5), nausea (n = 5), anemia (n = 4), constipation (n = 4), vomiting (n = 4), dysgeusia (n = 3), diarrhea (n = 3), increased alanine aminotransferase (n = 3), increased aspartate aminotransferase (n = 3), increased blood creatinine (n = 3), paresthesia (n = 3), and increased weight (n = 3).

Treatment-related adverse events resulted in the dose interruptions in 6 patients, dose reductions in 5 patients, and treatment discontinuations in 1 patient.

“In line with previous reports, entrectinib was associated with a manageable safety profile in patients with 

 fusion-positive breast cancer,” lead study author Min Janice Lu, MD, of USC Norris Comprehensive Cancer Center, wrote in the poster.

Lu J, Blakely CM, Barve M, et al. Entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer: updated data from STARTRK-2. Presented at: 2022 ESMO Breast Cancer Congress; May 3-5, 2022; Berlin, Germany. Poster 173P.

Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. 

. 2015;5(1):25-34. doi:10.1158/2159-8290.CD-14-0765

Wu S, Shi X, Ren X, Li K, Pang J, Liang Z. Evaluation of NTRK gene fusion by five different platforms in triple-negative breast carcinoma. 

. 2021;8:654387. doi:10.3389/fmolb.2021.654387

Demetri GD, Braud FD, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. 

. 2022;28(7):1302-1312. doi:10.1158/1078-0432.CCR-21-3597

Lu J, Blakely CM, Le Tourneau C, et al. Efficacy and safety of entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS11-28.

Basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK gene rearrangements (fusions) (STARTRK-2). ClinicalTrials.gov. Updated May 3, 2022. Accessed May 11, 2022. 

https://clinicaltrials.gov/ct2/show/NCT02568267

This article was originally published on OncLive as “Entrectinib Continues to Yield Promising Data in NTRK Fusion–Positive Breast Cancer”

Entrectinib elicited encouraging responses in patients with breast cancer that harbors NTRK fusions, according to updates from the phase 2 STARTRK-2 trial.

Entrectinib Generates Favorable Outcomes in NTRK Fusion+ Breast Cancer

Not only did ARO-HIF2, an investigational RNA interference (RNAi) therapy, reduce levels of hypoxia inducible factor-2 alpha (HIF2α) expression in patients with clear cell renal cell carcinoma (RCC), the agent was also found to have a manageable safety profile, according to data from the phase 1b AROHIF21001 trial (NCT04169711).

Findings from the trial, which were presented during the 2022 Genitourinary Cancers Symposium, showed that of 26 evaluable patients, 9 experienced a median reduction in HIF2α mRNA of 30% (range, -19% to -59%) by qPCR.

In the subset of patients who received ARO-HIF2 at 225 mg (n = 7) the median reduction in HIF2α mRNA was 46% (range, -22 to -47). In those who were administered 525 mg of ARO-HIF2 (n = 10), the median reduction in HIF2α mRNA was 27% (range, -19 to -39). In the subset of patients who were given 1050 mg of the agent (n = 9), the median reduction in HIF2α mRNA was 44% (range, -28 to -49).

Additionally, 14 patients achieved a median reduction in HIF2α protein of 26% (range, -1700 to -98) by immunohistochemistry (IHC). The HIF2α protein reduction rates in the 225-mg, 525-mg, and 1050-mg cohorts were 26% (range, -26 to -82), 47% (range, 0 to -90), and 0% (range, 1700 to -98), respectively.

“This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2α expression, as well as an acceptable safety profile in response to escalating doses of ARO-HIF2,” lead study author James Brugarolas, MD, PhD, of UT Southwestern Medical Center, and colleagues, wrote in a poster on the findings.

HIF2α is usually expressed at low levels and targeted for degradation by the von Hippel-Lindau (VHL) tumor suppressor protein. However, VHL inactivation, which is a causative event of clear cell RCC, prompts tumorigenesis through uncontrolled HIF2α accumulation. The synthetic double-stranded RNAi trigger, ARO-HIF2, which includes an alpha-v beta3 targeting ligand, was developed to silence HIF2α expression.

The AROHIF21001 trial enrolled patients with advanced or metastatic clear cell RCC that progressed during or after at least 2 prior regimens which must have included a VEGF-targeted therapy and a checkpoint inhibitor therapy.

 To be eligible for participants, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, a life expectancy that was longer than 3 months, and organ function that was considered to be acceptable at the time of the screening.

Exclusion criteria included a history of untreated brain metastases, having received prior systematic therapy or radiation therapy within 2 weeks of the first dose of study treatment, or having previously undergone solid organ or stem cell transplantation. Moreover, patients could not be receiving current treatment with immune checkpoint inhibitors, nor could they have received prior HIF2 inhibitors within 6 months before their first dose of study treatment.

Intravenous ARO-HIF2 was administered weekly at 225 mg in cohort 1 (n = 7), 525 mg in cohort 2 (n = 10), and 1050 mg in cohort 3 (n = 9). Moreover, tumor growth was evaluated by biopsy at baseline and again at 2 weeks. Additionally, patients were evaluated for safety each week. Every 8 weeks, participants were examined for tumor response by RECIST criteria.

The primary end point of the study was to evaluate treatment-emergent adverse effects (TEAEs) associated with ARO-HIF2. Secondary end points included pharmacokinetics and preliminary efficacy per RECIST v1.1 criteria.

Exploratory end points included the assessment of post-dose tumoral expression of HIF genes in response to treatment with the agent, change in tumor integrin expression, correlation of integrin expression with changes in HIF gene expression, and the examination of serum biomarkers of agent activity. The correlation of disease-related gene expression to the activity of the agent is also under exploration. Plasma and urine metabolites will also be assessed.

Spanning cohorts, the mean age was 65.1 years (range, 44-87). Seventy-seven percent of patients were male. Regarding performance status, 42.3% of patients had an ECOG performance status of 0, and 57.7% had a status of 1. Most patients (53.8%) had intermediate-risk disease per International Metastatic RCC Database Consortium criteria; 23.1% had good-risk disease and 15.4% had poor-risk disease.

Additionally, 30.8% of patients received 2 prior lines of therapy, 30.8% received 3 prior lines, and 11.5% received 4 prior lines of therapy. Notably, 26,9% of patients received 5 or more prior lines of treatment. Prior treatment included anti-VEGF therapy (100%) and checkpoint inhibition (100%). Regarding 

 mutation status, 17.6% of patients had frame shift mutations, 29.4% had missense mutations, 5.9% had in frame deletion, 11.8% had no variant, and 35.3% did not have this information available.

Prior data from the trial showcased early signals of activity with ARO-HIF2 in the 225 mg and 525 mg cohorts.

 Specifically, 7 of 9 patients who had evaluable tumor samples and received treatment experienced reductions in HIF2α per IHC H-score. Notably, these reductions ranged from -9% to -82%, with a mean reduction of -48%.

Additional data presented during the 2022 Genitourinary Cancers Symposium showed that ARO-HIF2 elicited an objective response rate of 7.7% in all patients, with 2 patients experiencing a partial response. Furthermore, 30.8% of patients achieved stable disease and 50.0% experienced disease progression. One patient was not evaluable for response, and response data were missing for 2 patients. Overall, the disease control rate with the agent was 38.5%.

At least 1 TEAE of any grade occurred in 96.2% of patients. Specifically, 57.7% of patients experienced at least 1 grade 1 or 2 TEAE, 30.8% reported at grade 3 TEAE, 3.8% experienced a grade 4 TEAE, and 3.8% experienced a grade 5 TEAE. Serious TEAEs were reported in 34.6% of patients. Moreover, treatment-related AEs of any grade occurred in 65.4% of patients. One patient discontinued treatment due to TEAEs.

TEAEs of any grade that occurred in more than 4 patients included fatigue (50.0%), dizziness (26.9%), dyspnea (26.9%), nausea (23.1%), abdominal pain (23.1%), neuropathy (19.2%), and constipation (19.2%).

Enrollment for the phase 1 trial remains open and enrollment is ongoing.

Brugarolas J, Beckermann KE, Rini BI, et al. Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001). 

 2022;40(suppl 6):339. doi:10.1200/JCO.2022.40.6_suppl.339

Study of ARO-HIF2 in patients with advanced clear cell renal cell carcinoma. ClinicalTrials.gov. Updated April 19, 2021. Accessed May 3, 2022. 

Patients with clear cell renal cell carcinoma experienced reduced levels of hypoxia inducible factor-2 alpha expression following treatment with ARO-HIF2. 

Ryan Scott

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