Camizestrant: Results of the Randomized Phase 2 SERENA-2 Trial (with slides)
Thank you, Carlos. Thank you, everyone, for the opportunity to be here and present the firsthand results of the tool trial. So these are my disclosures. Camizestrant is a oral selective ER, degrader, and antagonist that has been tested in a phase 1 study, across a range of doses and has shown a very good profile of inhibition of the ER, and we designed SERENA-2 to assess different doses of Camizestrant in comparison with the standard of care with Fulvestrant in patients progressing to prior endocrine therapy. So in SERENA-2, 240 patients postmenopausal with ER positive (breast cancer) HER2- advanced breast cancer (ER positive HER2 negative breast cancer) candidates to receive Fulvestrant monotherapy in the advanced setting were included. Additional key inclusion exclusion criteria included recurrence or disease progression on at least 1 line of endocrine therapy. No prior Fulvestrant or oral CERTs. For advanced disease and no more than 1 line of endocrine therapy or chemotherapy in the advanced setting as long as the presence of measurable or non-measurable disease.
So these patients were stratified according to treatment with prior CDK4/6 inhibitors, and with the presence of lung or liver metastasis, and were randomized 1 to 1 to receive 3 different doses of Camizestrant 75 m. 1 50 milligrams, 300 milligrams, and for all the standard of careful vest, the arm of Camizestrant 300 milligrams was discontinued after 20 patients were included because of a strategic reason. In the absence of toxicity concerns, and I will show those data later on. The primary endpoint for SERENA-2 was PFS. According to investigator assessment, the secondary endpoint was the clinical benefit rate at 24 weeks. Overall response rate, overall survival, and, of course, safety. And we also have a number of translational endpoints, including serial CT analysis and measurement of the CT of ctDNA, including ESR1 mutations.
How Many Patients Were Included In The Camizestrant Trial?
So, as I said, 240 patients were included in this trial. Median age of the patients were 60. Most of the patients had ECOG 0 and all of the patients a spare inclusion criteria had ER positive (ER positive HER2 negative breast cancer) disease. We planned in advance to include 50% of patients with prior treatment with the CDK4/6 inhibitors, and that’s exactly what you can see here. Also, a stratification factor, as you remember, was the presence of Longo metastases, which were present in 58% of the patients. 37% of the patients had a detectable esr, 1 mutation at baseline. 20% of patients had received chemotherapy in an advanced setting, and all of the patients received it and progressed to prior endocrine therapy.
What Was The Progression Free Survival (PFS)?
In the adjuvant setting, this number was 60 at 7%. And in the advanced setting 70% of the patients had progressed to endocrine therapy in this setting. So these are the primary endpoints results of the SERENA-2 trial in the overall population. Camizestrant produces a statistically significant and clinically meaningful improvement in PFS. For both 75 milligrams and 150 milligrams over Fulvestrant. It is important to note that the trial was powered to detect differences between the two Camizestrant doses and Fulvestrant. So Camizestrant 75 of Fulvestrant and Camizestrant 150 of Fulvestrant, but not between Camizestrant 75 of Fulvestrant and 150. As you can see here, Camizestrant 75 in comparison with Fulvestrant reduced the risk of disease progression or cancer related deaths by 42% at a dose of 150.
This was a 33% reduction. The median PFS for the 3 arms were 7.2 months for Camizestrant (75), 0.7 months for Camizestrant (150), and 3.7 months for Fulvestrant. We also conducted a blinded central review of PFS as a sensitivity analysis, which also showed a statistically significant benefit in PFS at both doses of Camizestrant over Fulvestrant, which was consistent with the investigator’s assessment. Now we will go over some of the important subgroups because these are subgroups of unmet clinical need. And to see the activity of Camizestrant over the standard of careful Fulvestrant. First, the group of patients that had received prior CDK4/6 inhibitors. So in these patients, with prior treatment with CDK4/6 inhibitors and endocrine therapies, as well as in those patients with lung or liver metastases, Camizestrant at both doses produces a clinically meaningful improvement in PFS over Fulvestrant. You can see the hazard ratios there, a reduction in 51% in the risk of progression or death with Camizestrant (75) and a reduction of 32% with Camizestrant (150) in patients that had received prior CDK4/6 inhibitors and similar hazard ratios.
Also for the subgroup of patients with lung early metastasis. There was also activity of Camizestrant over Fulvestrant in the breast cancer group of patients with no prior CDK4/6 inhibitors. Although the activity in the group of patients with no lung or test was less clear from this study. Another two important groups are the group of patients with ESR1 mutations. And you can see that graph on the left. So in the subpopulation of patients with detectable ESR1 mutations at baseline, Camizestrant at both doses produces a clinically meaningful improvement. EPFS overflow reins reduction of progression or death. Was 67% for Camizestrant, 75 and 45% for Camizestrant 150 with median PFS (progression free survival) values of 6.3, 9.2 compared to 2.2 months with Fulvestrant, also in patients with evidence of ER driven disease.
And this definition is according to the ABC5 definition of secondary endocrine resistance, just shifting to 12 months. The limit for patients receiving prior CDK4/6 inhibitors, and here in these patients with driven disease, Camizestrant at both doses showed a very consistent benefit compared to standard of care Fulvestrant.
We also looked at changes in the ESR1 mutation and ctDNA variant frequency in the 3 treatment arms, and, as you can see depicted here, treatment with Camizestrant (75) and 150 milligrams reduced the level of ESR1 mutation and ctDNA to undetectable or near undetectable. Cycle to day 1 and maintain this to cycle 7, day 1, and Fulvestrant also reduces the level of ESR1 mutation, but not to the same extent as Camizestrant.
Regarding objective response rate and the clinical benefit rate at 24 weeks, Camizestrant at both doses increases these two efficacy parameters over Fulvestrant. And of note, the clinical benefit rate at 6 months in the Camizestrant arms is 50%, meaning that half of the patients included were still deriving benefit from these treatments at 6 months time.
Regarding safety, treatment related adverse events of grade 3 or higher. And treatment related adverse events leading to discontinuation were infrequent across treatment arms, as you can see in the table. And also infrequent were the treatment related adverse events leading to those interruptions.
And were a very short duration, so median duration of drug interruption was 1 week, 7 days, and all Camizestrant are well tolerated. What are the most common adverse events with this drug? So you can see here all treatment emergent adverse events independent of causality, and the most common and most frequent adverse events with Camizestrant are alopecia, visual flashes, sinus bradycardia, fatigue, anemia, asthenia, and arthralgia. But I would like to call your attention to this important column that is about events of grade 3 or higher. And as you can see, the proportion of grade 3 or higher events with Camizestrant is extremely low. So in summary, SERENA-2’s primary objective chemist at both 75 and 1 50 milligram doses improves PFS over Fulvestrant in postmenopausal women with ER+ HER2- advanced breast cancer.
Camizestrant delivers statistically significant and clinically meaningful PFS benefits at both 75 and 150 milligram doses over for Fulvestrant in the overall population. And the clinically meaningful PFS (progression free survival) benefit was observed across the pre-specified subgroups of unmet medical need, like patients progressing after CDK4/6 inhibitors, patients with lung or lymphoma metastases where there is an emergence of SR1 detected, and also those patients with evidence of ER driven disease. Both Camizestrant doses are well tolerated, with infrequent grade 3 or higher treatment related adverse events, dose reductions, and discontinuations. So in conclusion, the results of SERENA-2 support a further development of Camizestrant in ER+ breast cancer.
What Other Studies Include Camizestrant in ER Positive HER2 Negative Breast Cancer?
And now currently 2 phase 3 studies of Camizestrant in advanced breast cancer. SERENA-4 and SERENA-6, are ongoing. So with that, I’d like to thank the patients and all their families for participating in this trial. All the investigators and site staff for their contribution AstraZeneca for support supporting the study.
And there in the QR you can find a link to a plain language summary with the SERENA-2 results. Thank you so much for your attention.
Watch and Share the Video Here: https://oncologytube.com/v/41469
Q&A For the Camizestrant Trail With Dr. Mafalda Oliveira
Thank you. Thank you very much. You can stay there for questions. So moving forward, what’s going to be the dose?
Yes, so the dose that was chosen to SERENA-4and SERENA-6 is the dose of 75 milligrams.
I think that SERENA-2 results show consi consistently that Camizestrant, that this both doses is superior to the standard of care. But again, It was not designed to compare both doses.
Thank you. Question?
Neil Oster Wild with MD Edge Hematology Oncology. I noticed for your primary endpoint for the 150 dose you’ve got a PFS of median PFS (progression free survival) is 7.7 months, and then for the 75 dose, a 7.3 months hazard ratio for the 150 milligram doses higher. I know you’re not comparing the two, but why? What would the adjustments be?
Yes, that’s an excellent question. And the question here is whether hazard ratios are adjusted for the prior certification factors. Prior CDK4/6 inhibitors and presence of liver lung metastasis, the Kaplan Meyer Curves and the medians are not adjusted for this factors.
And this is why it seems that it goes otherwise, but the adjusted hazard ratio gives us a more realistic and more measure of the magnitude of benefits.
And Dr. Arteaga or the other columnists. Would you mind commenting on your impression, I know it’s an early and, but your impression of this agent versus Fulvestrant.
Where is a clear suggestion that this might be better? Also looking at the effect on the SR1 mutations. I think also they appear to be better, better at reducing that ti in the plasma of the ESR1 mutations. And that is based on basic science that supports that. Again, these mutations may respond better to these new CRTs, but obviously this is a small study.
But direction seems to be consistent. You know what the science has told us. Next question.
Thank you. Caroline Helwick, ASCO Post: So what are the differences between Camizestrant and Elestrin, which is, we’re more familiar with, it’s further along. They’re both thirds, but can you tell us if there’s something that distinguishes yours.
So they both have the same mechanism of action. They are surges, they antagonize the ER receptor, and they degrade the ER receptor. They belong to the same class unlikely Fulvestrant that is in intramuscular injection. These are also pills, so I think that now we have two very interesting pieces of evidence that this new class of drugs may be superior to the current standard of care.
Do you want to comment on that doctor?
No, I was just asking her about the photopsia. Okay and whether that was a surprise and whether there’s an explanation for it.
Yeah. That’s a very important question because this is an adverse event that we started to see in the phase 1 trial.
And it seems dependent of the dose. So at higher doses, it seems to occur more frequently, but it is extremely important to note that these are great 1 event. So this light flashes that patients experience more in the morning or in at evening, but do not interfere with their daily practice activities so they can keep driving and reading, watch tv, et cetera. Regarding the mechanism for now, it is unclear. In all the SERENA studies, a thorough ophthalmologic evaluation for all these patients. And we have found no structural alterations in the eye or other structural things that could explain photopsia.
So this is currently ongoing , so that’s one differentiating factor of this CRTs that toxicity appears to be a little bit different. Toxicities are different.
Albeit mild, unfortunately, so it’s like Pepsi Cola and Coca-Cola kind of.
So photopsia is not really seen with the Elestrin that we know of?
No, not at all. Thank you.
We have two questions from the webcast.
The first is from Jean-Claude La Marre from Media Scoop. He asks if you could please clarify why the 300 milligram dose was discontinued.
Yes. Excellent question. Thank you. When we looked at data from the Serena 1 trial where we escalated dose until 450 milligrams, we saw that there was a relatively flat exposure, efficacy relationship from 75 to 300 milligram.
By doing that, AstraZeneca decided to go with 75 milligrams for the SERENA-4 and SERENA-6 trial, and 300 milligrams was actually 4 times the dose that was selected for the phase 3 trials. And for that reason, the arm was discontinued. It is important to note that patients that were already randomized to that arm were allowed to continue treatment at 300 milligrams.
Or they could reduce the dose to 150 or 75 according to protocol guidelines. But there was no there were no toxicity issues about the 300 dose that made made us discontinue that term.
What is the second question?
The second question is from Lyn Brook with Oncology Data Advisor. She says, with these results, are there any plans in the works for clinical trials to further measure the efficacy and safety of other potential orals?
For Camizestrant, there are two ongoing trials right now. SERENA-4 testing Camizestrant in combination with Palbociclib versus the standard of care AI plus palbociclib first line and the SERENA-6 study that is addressing the emergent, the SAR 1 mutations during the first line treatment. And now these are the current trials that are ongoing. Thank you.
Mafalda Oliveira, MD, PhD – About The Author, Credentials, and Affiliations
Since 2011, Mafalda Oliveira, MD, PhD, has been a medical oncologist at the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO) in Barcelona. She graduated from the Universidad Autónoma de Barcelona with a Master’s in Clinical Research in June 2013 and a Ph.D. in Medicine in July 2017, both in the field of medicine.
Dr. Oliveira’s research focuses on the molecular alterations and evolution of metastatic breast cancer, the clinical development of new drugs (especially through the design of clinical trials with innovative biological hypotheses), and the application of liquid biopsies as diagnostic, predictive, and prognostic tools in breast cancer. She is the Principal Investigator for a number of phase I, phase II, and phase III breast cancer clinical trials with medications that target the PI3K/AKT/mTOR system, CDK4/6 inhibitors, (next generation) oral SERD, novel epigenetic therapies, ADCs, and cancer immunotherapy agents.
She is also a member of ASCO, ESMO, SEOM, and AACR, as well as the Executive Board and Scientific Committee of SOLTI-Breast Cancer Research Group (a Spanish academic cooperative research group).