Jessica Hergert

Average progression-free survival (PFS), which is the time a patient survives before their disease gets worse, was doubled in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer with rising ESR1 mutations who were treated with an aromatase inhibitor plus Ibrance (palbociclib) and then switched to Faslodex (fulvestrant) plus Ibrance before their disease progressed, according to findings from the phase 3 PADA-1 trial.

, showed that at an average follow-up of 26 months, the median PFS was 11.9 months in patients who switched to Faslodex compared to 5.7 months in patients who remained on treatment with an aromatase inhibitor.

Notably, no new side effect concerns emerged, and approximately 35% of patients in each group experienced severe (grade 3 or 4) neutropenia, a condition where there is a decrease in neutrophils, which are a type of white blood cell.

“PADA-1 is the first trial to demonstrate that, in most patients, resistance-associated mutations in the estrogen receptor (ER) gene can be detected and targeted before tumor progression,” said lead study author Dr. François-Clément Bidard, a professor of medical oncology and co-coordinator of breast cancer research at the Institut Curie and Paris-Saclay University in Paris. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”

ESR1 mutations are known to cause resistance to aromatase inhibitor-based therapy in patients with HR-positive, HER2-negative metastatic breast cancer. While the mutation is only found in less than 5% of patients at metastatic relapse, about 30% to 40% of patients present with ESR1 mutations after they progress on first-line aromatase inhibitor-based treatment.

The PADA-1 trial is a randomized, UCBG-GINECO, precision endocrine therapy study evaluating a novel “1.5th-line” treatment for patients with HR–positive metastatic breast cancer with the goal of delaying tumor progression in patients receiving the first-line combination of an aromatase inhibitor and Ibrance.

In the first part of the trial, patients with HR–positive, HER2-negative, aromatase inhibitor-sensitive metastatic breast cancer received aromatase inhibitor-based therapy plus Ibrance in the frontline setting. Patients provided blood samples for 

 mutation screening at inclusion, then every month, then every two months until progression.

In the second phase of the trial, patients with rising 

 mutations and no synchronous progressive disease were randomized to continue with aromatase inhibitor/Ibrance or switch to Faslodex/Ibrance until progression.

An optional third step of the study made it possible for patients who were randomized to and progressed on aromatase inhibitor therapy/Ibrance to cross over and receive Faslodex/Ibrance.

The main goals of the study were investigator-assessed PFS in the second phase and safety (grade 3 or higher hematologic side effects). Additional outcomes included investigator-assessed second PFS after crossover and serious or severe (grade 3 or greater) nonhematologic side effects. Other goals included measuring overall survival, PFS from inclusion in the first portion, time to strategy failure, chemotherapy-free survival and patient-reported outcomes.

Randomization was stratified based on time from inclusion to rising ESR1 mutation detection (less than or at least 12 months) and presence of visceral metastases (yes or no).

Overall, 1,017 patients with ER-positive, HER2-negative breast cancer were enrolled to the first portion of the PADA-1 trial. At a cut-off date of July 31, 2021, 407 patients (40%) had an 

 mutation–negative PFS event. Of the 279 patients (27.4%) who had detectable rising 

 mutations, 219 had no synchronous progressive disease and 172 were randomized in the second portion. Of these patients, 84 received an aromatase inhibitor plus Ibrance (standard treatment group) and 88 received Faslodex plus Ibrance.

In the standard treatment group, patients were a median age of 60 years and 63% (53 patients) did not receive prior adjuvant aromatase inhibitor-based therapy. In the experimental treatment group, patients were a median age of 62 years and 66% did not receive prior adjuvant aromatase inhibitor-based therapy.

Across both groups, most patients had visceral sites of metastasis (occurring in the soft internal organs) and at least 12 months of time to rising 

Notably, the results did not show any significant interactions with patient subgroups.

As of July 31, 2021, 69 patients who received an aromatase inhibitor plus Ibrance developed progressive disease and 47 patients crossed over to the Faslodex plus Ibrance treatment group.

In the cross-over cohort, and with a median follow-up of 14.7 months, the average PFS was 3.5 months in the third portion.

Bidard noted that the observed clinical benefit may be underpinned by a lower burden of 

 mutation tumor cells at initiation of Faslodex. The benefit may also not be equalized with standard second-line Faslodex-based therapy.

“This targeted approach, after the start of the first-line endocrine therapy but before the second line, yields a statistically and clinically significant gain in PFS,” Bidard said. “That benefit might not catchup when you wait, which might justify the adoption of the PADA-1 treatment strategy as a valid option in routine care.”

Moreover, monitoring the rise of resistance-associated mutations opens new opportunities for patients with metastatic breast cancer with novel agents, such as oral SERDs, as well as in other clinical settings beyond 

Additionally, the phase 2 INTERACT and phase 3 SERENA-6 trials are ongoing to further evaluate the efficacy of switching therapy after detection of an 

A version of this article originally appeared on OncLive as, “

Fulvestrant/Palbociclib Following AI/Palbociclib Doubles PFS in HR+/HER2- Metastatic Breast Cancer

For more news on cancer updates, research and education, don’t forget to 

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Ibrance plus Faslodex improved progression-free survival in certain patients with metastatic breast cancer, compared with those who continued to receive an aromatase inhibitor.

Novel Drug Combo Doubles Progression-Free Survival in HER2-Negative Metastatic Breast Cancer

Elderly patients with previously untreated chronic lymphocytic leukemia (CLL) and other health issues had longer remissions when they were given a fixed-duration combination of Venclexta (venetoclax) plus Gazyva (Obinutuzumab), compared to those given chemoimmunotherapy, according to findings from the phase 3 CLL14 trial.

The long duration and high rates of minimal residual disease (MRD) negativity – which describes the small number of cancer cells left after treatment – may point toward Venclexta plus Gazyva being a first-line treatment for this patient population, said Dr. Othman Al-Sawaf, a physician at the University Hospital of Cologne in Germany.

During the EHA 2021 Virtual Congress, long-term findings from the CLL14 trial were presented, revealing that 74% of patients treated with Venclexta/Gazyva did not have their CLL progress, even after three years since the end of treatment.

No late-onset side effects were observed in the Venclexta/Gazyva –treated group, and the rate of secondary malignancies was similar with the fixed-duration approach compared with Leukeran (chlorambucil)/ Gazyva.

Notably, the benefit was observed across all evaluated subgroups, including patients with 

. Additionally, undetectable MRD remissions were found to be deeper and more sustained with Venclexta/Gazyva vs Leukeran/ Gazyva in this patient population.

“The fact that we see such deep remissions and MRD-negativity rates that are higher than 70% in this elderly patient population [with CLL] is highly suggestive of similar efficacy in younger, fitter patients,” said Al-Sawaf. “Therefore, we can recommend—and most of the treatment guidelines that exist at the moment reflect this—this treatment for all patients with previously untreated CLL.”

In an interview with CURE®’s sister publication, 

, Al-Sawaf discussed the long-term follow-up data from the CLL14 trial, the lack of long-term toxicity with the fixed-duration treatment of Venclexta/Gazyva, and ongoing research efforts that have the potential to further the clinical utility of this treatment approach in treatment-naïve CLL.

: What did the initial findings from the CLL14 trial show?

: CLL14 was a randomized phase 3 study that was started several years ago. (The investigators) aimed to enroll patients with previously untreated CLL with co-existing conditions. The patients were randomized to receive 12 cycles of chlorambucil [plus] (Gazyva) or 12 cycles of (Venclexta) [plus] (Gazyva). The primary end point of the study was progression-free survival.

The primary read out of the study showed a significant advantage in terms of PFS with the novel BCL-2–targeting treatment of (Venclexta) plus (Gazyva). The main aim of these ongoing follow-ups is to better understand what the long-term outcome of this fixed-duration approach is, and how and when disease progression eventually occurs. We don’t expect that this treatment is curative for most patients.

Basically, that is why at this EHA meeting (we presented) new data with longer follow-up. All patients in this study have been off treatment for more than three years. This allows us to understand long-term toxicities and efficacy, as well as the durability of the remissions in both arms.

What methods were employed to evaluate this regimen? What patients were eligible for enrollment?

The study population in CLL14 is relatively special in that all patients had co-existing conditions, which was the main inclusion criteria. This was assessed by the Cumulative Illness Rating Scale [CIRS], in which all patients had to have more than six points, such as a clinically relevant burden of co-existing conditions. Additionally, (patients had to have) impaired renal function with a creatinine clearance below 70 mL/minute, as this is a good surrogate for patient fitness.

We can see in the baseline characteristics of the patients that the median age was 72 to 73 years, so this was an elderly patient population. Also, the median CIRS was 9 points, suggesting that this was a patient population with relevant co-existing conditions. This is important to bear in mind when looking at the long-term data because we can control the disease quite well with our BCL-2–targeted treatments. However, we do have a strong competing risk in all our survival analyses because of the co-existing conditions. Therefore, it is important to [note] that our patient population is quite vulnerable and is at risk of having cardiac events and other sorts of complications from their co-existing conditions.

How did the findings of the long-term analysis advance the initial results from the study?

With this long-term analysis we can see that most patients who received (Venclexta) plus (Gazyva) remain in remission. Although all patients have not received any sort of treatment for more than 3 years after (Venclexta) plus (Gazyva), over 70% of patients remain without disease progression. Only 35 disease progression have been observed in the (Venclexta) /(Gazyva) arm; of those, only 17 have required the next line of treatment.

The majority of PFS events in the (Venclexta) arm were driven by deaths related to the co-existing conditions or the older age of patients rather than the CLL. This suggests that we are now able to control the disease quite well with a fixed-duration approach so that patients do not [have poor] quality of life. The survival of the patients is not dependent on the cancer anymore, but rather the co-existing conditions. That is a huge advancement for our field. We are now able to control the effects of CLL on survival by choosing a limited-duration approach to treatment in the frontline setting.

Were any long-term or late-onset side effects observed? How did the rates of secondary malignancies compare between the arms?

We showed that a big advantage of the fixed duration is that virtually all toxicity occurs while patients are on treatment. After treatment, no toxicity was observed, so we don’t see any long-term hematologic toxicities or late-onset neutropenia. Those are [toxicities] that we might have seen in the era of more intensive chemoimmunotherapies. We do see that(Venclexta) /(Gazyva) is quite well tolerated in the long term, particularly when patients come off treatment.

Also, in previous follow-ups, we looked at secondary neoplasms. We know that patients with CLL have a higher risk of developing secondary malignancies. We also know that some intensive chemoimmunotherapies increase the risk of specific malignancies, such as secondary acute myeloid leukemia after an FCR [fludarabine, cyclophosphamide and Rituxan (rituximab) treatment, so we have a particular focus of looking at secondary malignancies.

In initial follow-ups [of the CLL14 trial], we observed a slight discordance in favor of chlorambucil plus (Gazyva) where there was a numerically lower number of secondary malignancies. Now with longer follow-up, we see that this has pretty much evened out and there is no statistically significant difference between both arms regarding secondary malignancies. This suggests that the previous observation was by chance; this doesn’t substantiate with longer follow-up.

We do see that, overall, the number of secondary malignancies is higher than what we would expect in an aged-matched population that doesn’t have CLL. This confirms our previous observations that we have seen for over a decade that patients with CLL have a higher risk of secondary malignancies. We don’t see that any type of treatment is increasing or decreasing this risk in a meaningful way.

What do these data suggest in terms of the clinical utility of venetoclax/

The data suggest that a frontline approach with (Venclexta) and (Gazyva) is very feasible and effective for an elderly patient population [with CLL]. We are in an interesting situation because the treatment in Europe and the United States is approved for all patients with previously untreated CLL, whereas this study was strict and only enrolled elderly and unfit patients [with previously untreated CLL]. There are ongoing studies that also enrolled fit patients that compared this treatment with more intensive chemoimmunotherapies than chlorambucil. We expect the first read outs [of these studies] within this year or early next year.

We also looked at different subgroups and see, overall, that the treatment is better for all biological and clinical subgroups compared with chemoimmunotherapy. Therefore, we can recommend it for all patients with previously untreated CLL irrespective of low- or high-risk disease.

What are the next steps of this research?

We are eagerly awaiting the data from studies that are enrolling fit patients, particularly the CLL13 trial, which is also conducted by our study group in collaboration with many other European study groups. The trial design will investigate the benefit of (Venclexta) in younger patients [with CLL], so it will be a very important practice-informing study.

On the other hand, we still need to see a head-to-head comparison between this fixed-duration approach and other existing targeted approaches, particularly the continuous BTK inhibitor approach. We are seeing a lot of activity with the BTK inhibitors now, but we do not know whether the continuous single-agent therapy is superior or noninferior to the fixed-duration approach. This is something that we are addressing with the CLL17 study that has recently started enrollment several weeks ago. In this study, we are comparing Venclexta plus a CD20-directed antibody or BTK inhibitor to continuous treatment to compare not just targeted therapy with chemoimmunotherapy, but also with other targeted treatments. Hopefully this will further inform our practice and our treatment stratification for patients.

This article was originally published on OncLive as, “

Long-Term Data Showcase the Clinical Utility of Fixed-Duration Venetoclax/Obinutuzumab in Treatment-Naïve CLL

Fixed-duration Venclexta plus Gazyva produced longer remissions than chemoimmunotherapy in elderly patients with chronic lymphocytic leukemia and other comorbidities.

Drug Duo Boosts Outcomes in Elderly Patients With CLL

Mobocertinib performed well and had a favorable safety profile in patients with platinum-pretreated EGFR exon 20 insertion–positive metastatic non-small cell lung cancer and could serve as a possible treatment in this patient population, according to findings presented at the virtual 2021 ASCO Annual Meeting.

In the platinum-pretreated patient cohort (114 patients), the confirmed overall response rate (the rate of a measurable response to treatment) assessed by an independent review committee was 28%, and all responses were partial responses. By investigator assessment, the confirmed overall response rate was 35%; the complete response rate was less than 1%, and the partial response rate was 34%.

The median duration of response (length of time a tumor continues to respond to treatment without growing or spreading) was 17.5 months by independent review committee and 11.2 months by investigator assessment. The confirmed disease control rate (percentage of patients who have achieved complete response, partial response and stable disease) was 78% by independent review committee and investigator assessment.

The median overall survival (time from diagnosis or treatment start when patients are alive) was 24 months, and the median progression-free survival (time during and after treatment when the patient lives without disease progression) was 7.3 months.

“Based on these data, we believe that mobocertinib is a potential treatment option for patients with EGFR 20 insertion mutations,” said lead study author Dr. Suresh S. Ramalingam, a professor in the Department of Hematology and Medical Oncology and director of the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine, during a virtual presentation of the data.

“Mobocertinib is an orally administered tyrosine kinase inhibitor that is specifically being developed for the treatment of (patients with) EGFR (exon) 20 insertion mutations,” added Ramalingam, who is also deputy director and director of the Lung Cancer Program of Winship Cancer Institute of Emory University. “Among EGFR mutations, the insertion 20 mutations account for approximately 10%.”

In this study, researchers assessed the effects of a 160-mg dose of mobocertinib once per day on two groups:

patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy and no active or measurable central nervous system metastases (114 patients; median age, 60 years; 66% women; 59% received two or more prior systemic anticancer lines)

patients with EGFR exon 20 insertion–positive metastatic non-small cell lung cancer (96 patients, of whom 86 received prior platinum-based chemotherapy; median age, 59 years; 65% women).

The median follow-up time was 14.2 months in the platinum-pretreated patient group and 13 months in the EGFR exon 20 insertion–positive metastatic group.

For patients without measurable central nervous system metastases, the majority of patients were never smokers (71%). The median number of prior anticancer regimens was two; 100% of patients received prior platinum-based chemotherapy, 43% received prior immunotherapy, and 25% received prior EGFR tyrosine kinase inhibitors. Finally, 35% of patients had brain metastases at the start of the study.

For those with EGFR exon 20 insertion-positive metastatic disease, most patients were never smokers (73%). The median number of prior lines of anticancer therapy in this group was one; 90% of patients received prior platinum-based chemotherapy, 34% received prior immunotherapy, and 31% received prior EGFR TKIs. Finally, 34% of patients had brain metastases at the beginning of the study.

In this cohort, the confirmed overall response rate by the independent review committee was 25%, and all responses were partial responses. The confirmed overall response rate by investigator assessment was 32%; 1% of patients achieved a complete response and 31% achieved partial responses.

The median duration of response was not evaluable by independent review committee and 11.2 months by investigator assessment. The confirmed disease control rates were 76% and 75%, respectively.

In the EGFR exon 20 insertion–positive group, 60% of patients experienced progressive disease by investigator assessment. The brain was the first site of progressive disease in 38% of patients. Of these patients, 23% continued on mobocertinib for at least three months after initial progressive disease. The median time on treatment beyond initial progressive disease was 1.6 months.

Additionally, in the remaining 62% of patients who experienced progressive disease in initial sites other than the brain, 6% continued on mobocertinib for at least three months after initial progressive disease. The median time on treatment beyond initial progressive disease was 0.1 months.

In the EGFR exon 20 insertion–positive group, 33 patients had brain metastases at the beginning of the study. Of these patients, 76% developed progressive disease, 68% of which reported the brain as the first site of progressive disease.

Additional results indicated that 23% of patients in the platinum-pretreated patient group and 26% of patients in the EGFR exon 20 insertion–positive group remained on mobocertinib at the time of the data cut-off. The median time on treatment was 7.4 months and 6.8 months, respectively.

“Nearly 85% of patients in this study had some level of tumor shrinkage (with mobocertinib) … and nearly 50% of patients with an objective response still have an ongoing response at the time of data cut-off for this presentation,” said Ramalingam.

Notably, in the platinum-pretreated patient cohort, responses were observed in all evaluated subgroups irrespective of prior EGFR tyrosine kinase inhibitor treatment, prior immunotherapy, or EGFR exon 20 insertion mutation variant.

Additionally, the safety profile observed with mobocertinib was consistent with the known profiles of EGFR tyrosine kinase inhibitors.

Regarding safety in the platinum-pretreated patient cohort, all patients reported any-grade side effects, and 99% of patients reported any-grade treatment-related side effects. Of these, any severe or worse side effects were observed in 69% of patients and any severe or worse side effects related to the treatment were observed in 47% of patients.

Serious side effects were noted in 49% of patients; 46% of these were severe or worse. A quarter of patients (25%) experienced a side effect that led to dose reduction and 17% experienced a side effect that led to treatment discontinuation.

The most commonly reported side effects that led to treatment discontinuation in this cohort included diarrhea (4%), nausea (4%), vomiting (2%), decreased appetite (2%), and inflammation of the mouth and lips (2%). Other common any-grade side effects included rash, inflammation of skin around the nails, dry skin, increased creatinine and itchy skin.

In the EGFR exon 20 insertion–positive group, side effects of any severity were reported in 100% of patients, 66% of which were severe or worse. Nearly all patients (99%) reported any-grade treatment-related side effects, 42% of which were severe or worse. Serious side effects were observed in 47% of patients, of which 44% were severe or worse. Additionally, 22% of patients experienced a side effect that required dose reduction, and 10% of patients experienced a side effect that required treatment discontinuation.

Nausea and diarrhea were the most frequently reported side effects that required treatment discontinuation in the EGFR exon 20 insertion–positive group. Other side effects included rash, skin infection around fingernails and toenails, decreased appetite, dry skin, increased creatinine, inflammation of the mount and lips, vomiting, acne-like bumps on certain areas of the body, itchy skin and increased amylase (which potentially indicates pancreatitis).

Of note, one treatment-related death from cardiac failure occurred in the EGFR exon 20 insertion–positive group in a platinum-pretreated patient.

Mobocertinib showed clinically meaningful benefits in patients with EGFR exon 20 insertion–positive metastatic non-small cell lung cancer with a manageable safety profile.

Novel Tyrosine Kinase Inhibitor Shows Promise for Metastatic Non-Small Cell Lung Cancer With Specific Genetic Mutation

Targeted drugs known as Bruton’s kinase inhibitors (BTKs) are important treatments for many patients with blood cancers that invade the B immune cells, whose job is to create antibodies that fight infection.

In fact, some large clinical trials indicate that BTK inhibitors should be considered the go-to initial treatment for patients, according to Dr. Ian Flinn, director of lymphoma research and principal investigator at Sarah Cannon Research Institute, and director of the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center.

But what happens if a patient has to stop taking one of these drugs because it causes intolerable side effects?

A next-generation BTK, Brukinsa (zanubrutinib), may be easier to tolerate for patients who have stopped receiving Imbruvica (ibrutinib) or Calquence (acalabrutinib) because of side effects, Flinn said, and an ongoing clinical trial will test that hypothesis. Flinn presented information about the trial in a poster during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Brukinsa was approved by the Food and Drug Administration (FDA) in November 2019 as a therapy for previously treated mantle cell lymphoma, a B-cell malignancy.

The phase 2 trial, known as BGB-3111-215, is evaluating the side effect profile of Brukinsa in a broader group of patients with B-cell malignancies who stopped taking Imbruvica or Calquence because of side effects.

®, is to measure the recurrence and change in severity of treatment-emergent side effects with Brukinsa and compare them with those that arose when the patients received Imbruvica and/or Calquence. Enrollment, which is underway, will take place at 30 community medical centers across the United States.

Investigators plan to enroll approximately 60 patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma or marginal zone lymphoma whose disease was intolerant of prior BTK inhibition and whose treatment-emergent side effects resolved to mild or lower before they started treatment with Brukinsa.

While Flinn doesn’t think Brukinsa would be an effective treatment for patients whose cancers progressed during treatment with a previous BTK, he believes “there’s good rationale to think that patients who are intolerant to (Imbruvica) or (Calquence) might tolerate (Brukinsa).”

“Zanubrutinib is a specific inhibitor of BTK,” he explained. “It has less inhibition of off-target kinases (meaning it precisely targets and disables the proteins that drive the cancer without affecting others that aren’t involved in the cancer process). As a consequence, the hypothesis is that it will have less of these (side effects), such as arthralgias, atrial fibrillation and bleeding.”

The most common reason patients stop taking Imbruvica, he said, is that they develop arthralgias (joint pain or other aches and pains); this occurs in about 40% of patients. Abnormal heart rhythms and atrial fibrillation occur in up to 15% of patients treated with Imbruvica, and bleeding is another major reason for discontinuation, he said.

In the study, intolerance to a previous BTK is defined as bad joint pain, cardiac arrhythmia or bleeding to the point where a patient’s physician does not think they can remain on the drug, Flinn said. “If the patient has to come off therapy,” he said, “they may be eligible for this trial.”

Once the patient’s side effects subside enough to be considered mild, they can start the study drug, with the goal of testing whether they will develop the same intolerance while taking Brukinsa, Flinn said.

“The hypothesis is that these (side effects) will not reoccur, which will allow patients to continue on “Brukinsa,” he said.

Those interested in participating in the trial can learn more by contacting BeiGene, the pharmaceutical company developing the drug, at 

There are also other trials in progress that are testing Brukinsa and other BTK inhibitors, Flinn noted.

“The biggest issue we have currently in these diseases is: ‘Which BTK inhibitor is better?’” he said. “There are head-to-head trials comparing (Brukinsa plus Imbruvica) and (Calquence plus Imbruvica) to better understand how the efficacy and (side effect) profiles line up. Many people think that these drugs are fairly similar in their efficacy, but because some patients have to come off treatment — most prominently with (Imbruvica) &mdash; that cuts into the efficacy, because patients are no longer on therapy. Perhaps that is where the differences will be (most evident).”

A version of this article originally appeared on OncLive

Ongoing Trial Evaluates Zanubrutinib in BTK-Intolerant B-Cell Malignancies

A clinical trial of Brukinsa (zanubrutinib) is open to patients with B-cell blood cancers and will determine whether the side effects re-emerge with Brukinsa.
 

Jessica Hergert

Novel Drug Combo Doubles Progression-Free Survival in HER2-Negative Metastatic Breast Cancer

Drug Duo Boosts Outcomes in Elderly Patients With CLL

Novel Tyrosine Kinase Inhibitor Shows Promise for Metastatic Non-Small Cell Lung Cancer With Specific Genetic Mutation

Brukinsa May Cause Fewer Side Effects Than Other BTK Inhibitors for Patients with B-Cell Malignancies

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