Jonah Feldman

Time to next breast treatment tended to vary based on HER2 status, according to a recent study.

A recent study of patients who received Enhertu (trastuzumab deruxtecan) for advanced breast cancer has revealed valuable data regarding efficacy in patients whose HER2 expression status switched during treatment.

In 191 patients with HER2-positive, HER2-low and HER2-0 status, the time to next treatment (TTNT) after receiving Enhertu was 10.4 months, 7.6 months and 3.7 months, respectively, at 10.4 months median follow-up.

However, patients whose HER2 expression changed from HER2-low to HER2-0 during the study period had a median TTNT of only three months. TTNT was 5.6 months when switching from HER2-0 to HER2-low and 9.4 months for stable HER2-low expression.

“We know that (Enhertu) is an approved treatment for HER2-positive and HER2-negative metastatic breast cancer, but we have limited real-world data with this agent, and most importantly, we don’t know the activity of this agent among patients with changes in HER2 status during the course of disease,” explained Dr. Paolo Tarantino, advanced research fellow in the breast oncology program at Dana-Farber Cancer Institute, in his presentation at the 

The investigators noted in their poster presentation that HER2-low expression is a highly unstable biomarker and no data are available on the activity of Enhertu in patients whose HER2 expression changes after a pretreatment biopsy. Additionally, data are limited on subsequent therapies after Enhertu.

Investigators in the RELIEVE study collected data on patients with advanced metastatic breast cancer who received Enhertu between July 2017 and February 2022 at Dana-Farber Cancer Institute and between March 2020 and April 2022 at Duke Cancer Center.

In addition to TTNT, the researchers analyzed progression-free survival (PFS; length of time during and after treatment when a patient lives with cancer but it does not worsen), overall survival (OS; length of time from diagnosis or start of treatment when a patient is still alive), toxicities and TTNT with post-Enhertu regimens.

Of the 191 patients, 126 had HER2-positive, 44 had HER2-low and 21 had HER2-0 expressions. The median age at metastatic diagnosis was 50.9. They had received a median of two prior lines of chemotherapy and a median of four prior lines of therapy in the advanced setting. There were 26% of patients who had de novo metastatic breast cancer and 38% had prior brain metastases, according to the study.

The median OS in the patients with HER2-positive expression was 23.1 months. For HER2-low, the OS was 14.2 months and for HER2-0, it was 9.5 months. The TTNT of the subsequent therapy after Enhertu was 4 months with HER2-positive, 3.1 months with HER2-low and 4.3 months with HER2-0 expressions, without significant difference.

Ten patients switched from HER2-low to HER-0 in the primary tumor after the pre-Enhertu biopsy, whereas 21 patients switched from HER2-0 to HER2-low and 21 had stable HER2-low expression.

“We know HER2-low is a dynamic definition,” said Tarantino. “There are primary tumors that are HER2-low that become (HER2-0) in the metastatic setting and the opposite way around, and so we decided to look at this discordance and its impact on the activity of (Enhertu).”

In five patients who switched from HER2-low to HER2-0 between the first metastatic diagnosis and the pre-Enhertu biopsy and then received Enhertu, the TTNT was 8.5 months.

The TTNT was 5.4 months in 19 patients whose expression switched from HER2-0 to HER2-low at this point, and the TTNT was 8.6 months for 25 patients with stable HER2-low status between these biopsies.

TTNT was 7.4 months for patients with hormone receptor (HR)–negative disease, compared with 10.2 months for those with HR-positive disease, which was not significantly different. There was also not a significant difference between those who received two or fewer prior chemotherapies (10.1 months TTNT) versus those greater than two (8.8 months TTNT).

At the time of follow-up, 55 patients (28.8%) continued receiving Enhertu, 108 (56.5%) had disease progression and 28 (14.7%) stopped treatment due to toxicity. Dose reduction was needed in 61 (31.9%) for side effects, including fatigue (14.7%), nausea/vomiting (9.9%) and blood toxicity (6.3%).

Interstitial lung disease (diseases causing scarring of the lungs) was reported in 22 patients (11.5%), 6.2% of which was grade 1, 3.1% was grade 2, 1.6% was grade 3 and 0.5% was grade 4. This side effect was resolved in 63.6% of cases.

DNADX, a novel machine-learning approach to sequencing, was performed with circulating free DNA from pretreatment plasmas in 81 patients, 39 with HER2-positive, 28 with HER2-low and 14 with HER2-0 status.

Fifty-one patients were found to have a tumor fraction of greater than 1%. In these 51 patients, the uppermost tertile with a high DNADX HER2 signature had a significantly longer PFS.

The respective patients also had a median TTNT of 10 months for high HER2 signature versus seven months for medium HER2 signature and five months for low HER2 signature, which was also statistically significant, according to the data. These findings were independent of their HER2 status by immunohistochemistry.

“In conclusion, (Enhertu) showed the longest TTNT in patients with HER2-positive disease or with stable HER2-low disease among the primary and metastatic setting,” Tarantino said. “Real-world TTNT remains short (post-Enhertu), and so we definitely need to study this setting more and develop novel regimens.”

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Findings were presented at the 2023 San Antonio Breast Cancer Symposium from a study investigating real-world patients who received Enhertu for advanced breast cancer.

HER2 Status May Influence Time to Next Treatment Post-Enhertu

The development of new treatment options for diffuse large B-cell lymphoma (DLBCL) traditionally has lagged behind other types of blood cancer, but the implementation of targeted therapies and other new clinical trials are starting to move the needle forward for the disease, which is the most common type of non-Hodgkin lymphoma.

Dr. Brian T. Hill, director of the Lymphoid Malignancies Program, recently discussed these exciting updates at the 2022 International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma.

One of the main struggles in treating DLBCL is how similar treatment outcomes are for patients receiving the same standard-of-care therapies, Hill said.

Various factors can indicate the level of risk for patients. International Prognostic Index (IPI) status considers risk based on age greater than 60, poor performance status, advanced stage, serum lactate dehydrogenase above normal limits (which could indicate tissue or organ damage), and at least one extranodal (beyond the lymph nodes) site. Higher IPI is predictive of worse overall survival (OS).

The standard of care for frontline therapy is R-CHOP, a drug combination of Rituxan (rituximab), cyclophosphamide, doxorubicin, vincristine and prednisone), which is typically given once a day every three weeks for six cycles. A viable alternative is dose-adjusted R-EPOCH (Rituxan, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen given as continuous infusions over four to five days every three weeks for six cycles, with dose escalation every cycle.

For double-hit lymphoma (where there are rearrangements in two genes), which is especially high-risk, data suggest that intensive induction regimens such as R-EPOCH are more effective than R-CHOP. Only 10% of patients who have double-hit lymphoma will receive R-EPOCH as opposed to R-CHOP in most cancer centers.

R-CHOP and R-EPOCH were directly compared in the A50303 trial, but the results were negative.No statistically significant difference was found in terms of OS, with a two-year OS rate of 86.5% for R-EPOCH and 85.7% for R-CHOP. Hill noted that this trial may have been influenced by factors such as having a longer period of time before patients started receiving treatment, which may have led to enrolling patients with more favorable risk.

Polivy PFS Improvement Challenges Standard of Care

One of the most important changes to standard of care in upfront therapy has been the introduction of Polivy (polatuzumab vedotin), an antibody-drug conjugate that targets CD79B, a component of the B-cell receptor signaling apparatus.

In the relapsed/refractory setting, a phase 2 trial compared Polivy with bendamustine and Rituxan versus bendamustine and Rituxan alone. Though it was a small study, Hill points out a higher number of complete responses (CR) with Polivy /bendamustine/Rituxan in the patients with ABC versus GC DLBCL. There were no differences in subgroups in the Polivy group.

Based on the positive outcomes with Polivy in the relapsed setting, vincristine was substituted from the R-CHOP regimen to create the Polivy -R-CHP regimen, and the two regimens were compared directly in previously-untreated patients in the phase 3 POLARIX trial. The two-year progression-free survival (PFS) rate, defined as the average time from treatment until patients’ disease gets worse, was 76.7% with Polivy-R-CHP versus 70.2% with R-CHOP, favoring Polivy.

Subgroup analysis showed that patients with high IPI score had better outcomes with Polivy-R-CHP, and those in the ABC group fared better with Polivy despite their expected higher risk. However, there was no OS advantage in this trial.

Based on the subsequent treatments received by the patients in each arm of POLARIX, Hill suggested that in approximate terms, several times as much money was spent to prevent relapse in those who received R-CHOP versus those receiving Polivy-R-CHP, which could warrant more investigation of costs and benefits of treatment.

In his presentation, Hill proposed the development of five new comparison trials for patients with each of 5 molecular subtypes that would compare Polivy-R-CHP plus a targeted inhibitor versus Polivy-R-CHP alone. If these trials show differences in outcomes due to the targeted therapy, patients could be treated more effectively upfront based on the results of genetic testing.

“DLBCL is not a single entity but largely approached this way clinically in 2022. While in general GC-derived tumors have better outcomes than those derived from ABCs, there is a heterogeneity which can be explained in the subgroup analysis,” Hill concluded. “Future clinical trials should be based on integration of multiomic biomarkers to test precision medicine with specific pathway inhibitors for individual subtypes of DLBCL.”

An expert gives an overview of current standard of care and what’s coming down the pipeline in terms of treatment options for diffuse large B-cell lymphoma. 

Targeted Therapies Shake up the DLBCL Treatment Paradigm, Expert Says

In a clinical trial evaluating Tecentriq (atezolizumab) in patients with advanced squamous cell carcinoma of the penis, the immunotherapy agent failed to meet its survival goals — regardless of whether it was given with or without radiotherapy, according to data presented by Dr. Hielke Martijn de Vries, of Netherlands Cancer Institute, at the 2022 ASCO Genitourinary Cancers Symposium.

The phase 2 PERICLES trial of Tecentriq with or without radiotherapy in patients with stage 4 cancer did not meet its primary end point of one-year progression-free survival (PFS; meaning that patients were able to live for one year without their disease getting worse). At an average follow-up of 22 months, only 12.5% of patients had a PFS of one year or more.

The PERICLES trial investigated whether immunotherapy would be effective against advanced squamous cell carcinoma of the penis based on preclinical data suggesting patients had high rates of intratumoral CD8 T cells and 40% to 60% PD-L1 positivity. Patients in one of the two arms of the study were also to receive radiotherapy to control locoregional lymph node disease, which is disease that stayed within the original area.

“Advanced penile cancer has a very poor prognosis, especially for those patients with stage 4 disease, and these patients have limited options,” said de Vries in his presentation.

According to de Vries, his institution ran two previous studies in this setting. A trial of neoadjuvant chemotherapy with docetaxel, cisplatin and 5-fluorouracil was judged to have high toxicity and early relapses, with 23% of patients discontinuing treatment. A trial of chemoradiation resulted in fewer side effects and better PFS than the chemotherapy, but this study was not restricted to advanced-stage disease.Neither trial included patients with metastases that have spread to distant parts of the body.

In the PERICLES trial, patients in both arms received 1,200 mg of Tecentriq every three weeks, while the radiotherapy arm also received 33 fractions of 1.5 Gy (locoregional affected lymph nodes) and 1.8 Gy (macroscopic tumor and margin) irradiation. There were 12 patients in the Tecentriq arm and 20 patients in the Tecentriq plus radiotherapy arm.

All patients had stage 4 disease with an inoperable primary tumor and a World Health Organization performance status of 0 or 1, meaning that their disease resulted in little to no restrictions to their daily life. Patients were allowed to have received any previous treatment besides immunotherapy; only 25% had no prior treatment. The percentage of patients with distant metastases was 59%.

In addition to the primary end point of PFS of 35% or greater at one year (to exclude 15%), there was a secondary end point of two-year overall survival rate in both groups combined.

The median PFS was 2.5 months with no significant difference between the treatment groups.Patients with PD-L1 positivity, as well as those who were positive for human papilloma virus (HPV), showed slightly higher PFS.

“It’s interesting here to notice that the two patients in arm B who responded well to treatment were both PD-L1 positive and high-risk HPV-positive,” de Vries said in his presentation.

The average overall survival (OS) was 12 months, and the one-year OS rate was 43.4%, though further follow-up is needed, according to de Vries.

Response to treatment was evaluated with 12-weekly scans of the abdomen and thorax. While some durable responses and complete responses (CRs; where there is no detectable traces of cancer) were observed, including two patients with pulmonary metastases achieved CRs, overall response rates were low.

Out of 30 evaluable patients in both groups, there were seven (23%) partial responses (PRs) and three (10%) CR. In the radiotherapy groups (18 patients), there were six PRs and two CRs, while there was only one PR and one CR in the arm that received atezolizumab (12 patients).

In terms of side effects, 20 patients (63%) across both groups experienced any grade of immunotherapy-related side effects while three (9.4%) experienced severe (grade 3 or 4) side effects. In the radiotherapy arm, 18 patients (90%) experienced radiotherapy-related side effects, with 13 (65.0%) being grade 3 or 4.

Despite some evidence of antitumor activity from Tecentriq in this patient population, the trial did not meet its goals. The combination with radiotherapy did not improve outcomes of immunotherapy, though de Vries noted that a more optimal radiotherapy schedule might increase efficacy. De Vries suggested that further investigation could assess not only the biomarkers associated with improved response but those linked to resistance to the treatment.

“We also saw in this trial an incomplete immunological activity and early resistance to (Tecentriq) … and we’re currently looking at pre- and on-treatment biopsies to see if there are other biomarkers for response and which combination therapies would be best to overcome this resistance,” de Vries said. “So while there is still a lot of work to be done, we’re quite enthusiastic about immunotherapy for the treatment of advanced penile cancer.”

This article was originally published on Urology Times as, “Atezolizumab Fails to Improve PFS in Advanced Squamous Cell Penile Cancer.”

Tecentriq failed to meet the progression-free survival goal in a trial analyzing the immunotherapy agent in advanced squamous cell carcinoma of the penis.

Jonah Feldman

HER2 Status May Influence Time to Next Treatment Post-Enhertu

Targeted Therapies Shake up the DLBCL Treatment Paradigm, Expert Says

Immunotherapy Agent Misses Study Survival Goal in Advanced Penile Cancer

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