I will go through what are the unmet needs in patients with advanced endometrial cancer and talking about the current landscape in the treatment of advanced and metastatic or recurrent endometrial cancer.

[00:20:50]

Molecular Classification of EC

As you know, a few years ago, the Cancer Genome Atlas taught us that endometrial cancer was not 1 disease, not 2 diseases, as we thought many years ago, but at least 4 different diseases, probably 5, as you can see here. We now talk about the POLE pathogenetic subgroup, the POLE wild-type, which could be mismatch repair proficient or deficient. Of course, we also have the p53 mutated or wild-type subgroups.

This is very important because we should take into consideration these different subgroups in order to decide the best treatment for our patients, both in the adjuvant setting and in the metastatic setting.

[00:21:42]

GOG-209 Phase III Trial: OS With Carboplatin and Paclitaxel in Advanced EC

Until few years ago, we only had carboplatin and paclitaxel to treat our patients with advanced or recurrent endometrial cancer. As you know, this was a very important GOG trial, GOG-209, which compared the 2-drug regimens with platinum and paclitaxel compared to the 3-drug regimens, including also anthracycline.

It was clear that the 2 regimen was the best because it was similar in efficacy but with less toxicity. This has been our standard treatment for many, many years for patients with endometrial cancer.

[00:22:20]

Algorithm of 1L Therapy in Unresectable Stage III/IV or Recurrent EC With No Prior CT, Except Adjuvant Setting 

Now the situation, as you can see here, is much more complex. This is the very recent update of the ESGO-ESTRO-ESP guidelines published in Lancet Oncology at the end of August. Here you see what is the current algorithm for the first-line treatment of advanced and recurrent endometrial cancer.

As you can see, it is very important to differentiate the mismatch repair deficient status. For patients with mismatch repair deficient tumor chemo plus IO is the standard treatment. For the non-mismatch repair deficient tumors, then you have several options.

First of all, you should consider endocrine therapy in case of slowly an indolent tumor. But for the others with symptomatic advanced disease, then chemotherapy is your choice. And you can add to chemotherapy the ICI or ICI plus PARP inhibitor.

But also we are offering 2 other choices, as you can see here. One is for patients where chemotherapy is contraindicated, we indicate the possibility to use the combination of pembrolizumab and lenvatinib. On the other hand, if you have a tumor with HER2 3+ expressing tumors, then the addition of trastuzumab to chemotherapy may be considered.

Let me go through more deeply into these recommendations.

[00:23:56]

Recommended Treatment for 1L Systemic Therapy

First of all, I want just to say that the NCCN guidelines are very similar. They look much simpler, I must say. But at the end of the day, if you go through the indication, you will see very similar options for your patients.

[00:24:12]

Integrated Genomic Characterization of EC

Now, this is what the Cancer Genome Atlas told us. As you see, there are 4 different subgroups, and 2 of them, the POLE ultra-mutated and MSI hypermutated are considered hot tumors. These hot tumors may respond very well to immunotherapy to immune checkpoint inhibitors.

[00:24:37]

Immune Checkpoint Inhibitor + Chemotherapy in 1L Endometrial Cancer: PFS in dMMR Tumors

That is what we have done during the past years. You see here 4 randomized trials, very similar in their design because they investigated whether the addition of immune checkpoint inhibitor to chemotherapy may provide a benefit.

Here you see the results in the dMMR population, where it is quite clear. These are the PFS, the progression-free survival. You see that by adding dostarlimab or pembrolizumab or durvalumab or atezolizumab in patients with dMMR tumor, you may achieve incredible results.

Also I want you to notice the flattening of these curves after 1 year, more or less indicating a very long lasting benefit with the addition of immune checkpoint inhibitors in frontline in patients with dMMR tumor.

[00:25:34]

Immune Checkpoint Inhibitor + Chemotherapy in 1L Endometrial Cancer: PFS in Non-MMRd Tumors

The situation is a little bit different in the non-dMMR population, as you can see. You can still see a benefit for some of these drugs, such as dostarlimab in the RUBY trial or pembrolizumab in the NRG-GY018 study. Also some benefit with durvalumab, no benefit with atezolizumab. So this population is clearly more difficult. In the guidelines we indicate the possibility to use immune checkpoint inhibitors.

[00:26:11]

RUBY/ENGOT-en6: OS With Dostarlimab for Advanced or Recurrent EC

This is mainly based on the results on overall survival. These are the overall survival of the RUBY trial. As you can see here in the overall population. So not only the dMMR but the intention-to-treat population, you see a benefit in overall survival by adding dostarlimab to chemotherapy.

Also, even though it is not analytical, you see a trend for a benefit in the non-mismatch repair deficient population.

[00:26:40]

Rationale for Combining PARPi and Anti–PD-1/PD-L1

This has led to approval of this combination also in the intention-to-treat not only in the dMMR. But there are other combinations that we may consider. First of all, why do not we add a PARP inhibitor to the combination of chemo plus immune checkpoint inhibitors?

In fact, there is a strong rationale, as you know, because first of all, some endometrial cancer have high PARPi expression. PARP inhibition may increase the generation of neoantigens and also increase the expression of PD-L1 and decrease the Tregs.

[00:27:24]

DUO-E: Durvalumab in Newly Diagnosed Advanced EC

There is a strong rationale for this combination, and this has been investigated in the DUO-E trial, where the patients were randomized to receive either the control arm or 2 experimental arms, one only with durvalumab added to chemotherapy and as a maintenance, and the other one adding also olaparib in the maintenance phase.

[00:27:45]

DUO-E Subgroup Analysis: PFS by MMR Status

This trial showed us that, of course, there is a benefit, particularly in the population with non-mismatch repair deficient tumor, even though the trial was not designed to test the superiority of the 2 experimental arms each other, but only in relation to the control arm. You see that in the dMMR population, the addition of olaparib does not add anything.

In the non-mismatch repair, it may add something, even though we cannot say for sure, because again, there was no direct comparison between the 2 experimental arms.

[00:28:26]

DUO-E Subgroup Analysis: OS by MMR Status

Now, if you look at the overall survival, again, you do not see any benefit in the dMMR population. In the pMMR population, you still see a trend. But these results are still immature because the number of events are not enough to conclude on the overall survival data.

[00:28:48]

DUO-E: PFS by Biomarker Subgroup

Now, if you look at the forest plot, you see that the benefit of adding durvalumab to chemotherapy is very consistent across different subgroups. The same is true if you look at the addition of olaparib. I want just to notice that maybe in the olaparib comparison, the presence of a p53 mutation may indicate more benefit in this population. But of course, overall, we may say that the benefit is seen across all the different subgroups analyzed.

[00:29:23]

Rationale for Combining TKI and Anti–PD-1/PD-L1 Therapies

There is another combination that was investigated, and this is the combination. I would call this like a chemo-free regimen because in fact chemo is not included in this combination. It is the combination of a TKI, lenvatinib, and an anti-PD-1 drug.

The rationale is that lenvatinib, this TKI agent:

• Increases CD8-positive T-cell function;
• Increases cytotoxicity of NK cells;
• Decrease the expression of PD-1, CTLA-4, and TIM3 in T cells; and
• Inhibits T-cell exhaustion.

[00:30:06]

ENGOT-en9/LEAP-001: 1L Lenvatinib + Pembrolizumab vs Chemotherapy for Advanced EC

The combination of lenvatinib and pembrolizumab was investigated in the LEAP-001 trial in frontline. This was a very ambitious trial. I think the investigators were very brave because they compared this chemo-free regimen, which is lenvatinib and pembrolizumab with the standard of care, which is carboplatin and paclitaxel. So the bar was very high because as you know, carboplatin/paclitaxel in frontline is quite effective.

The trial was designed to show the superiority of this combination compared to the standard of care.

[00:30:48]

Non-MMRd: PFS and OS Similar Between Lenvatinib + Pembrolizumab and Carboplatin + Paclitaxel

As you know, the results of the trial were, in a way disappointing because the trial was not positive. They could not demonstrate the superiority of pembrolizumab/lenvatinib compared to carboplatin and paclitaxel. Here you see the progression-free survival and the overall survival.

[00:31:08]

dMMR: PFS and OS Improved With Lenvatinib + Pembrolizumab vs CT in the dMMR Subgroup

However, we may look at some different subgroups. First of all, in the dMMR population, the combination of pembrolizumab/lenvatinib is better than chemotherapy. We do not know if it is better than chemo plus immune checkpoint inhibitor, of course, because the control arm was only chemo. But still, you see a very interesting PFS and also OS in the dMMR population by using this chemo-free regimen.

[00:31:37]

ENGOT-en9/LEAP-001 PFS Improved With Len + Pembro vs CT in Prior Neoadjuvant/Adjuvant CT Subgroup

Particularly, it was interesting to see the benefit for this combination compared to chemo in the population who had received prior adjuvant treatment with chemotherapy. As you know, chemotherapy now is given quite often in high-risk patients after surgery.

So you may have a population who already receive chemotherapy in the adjuvant setting, they relapse. If you look at this specific population, you see that pembrolizumab/lenvatinib is more effective both in terms of progression-free survival. This is true in the non-mismatch repair deficient population and also in the all-comers.

That is why in the guidelines now we included a possibility in patients for whom chemotherapy is contraindicated, we included the possibility to use pembrolizumab/lenvatinib instead of chemotherapy.

[00:32:39]

ENGOT-en9/LEAP-001: 1L Lenvatinib + Pembrolizumab vs CT for Adv/Recurrent EC: Additional 1-Yr Follow-up

Of course, this is a recent update of this study, the LEAP-001, showing again very important results in terms of overall survival in the pMMR population and also in the dMMR population.

[00:32:58]

Treatment Options for Endometrial Cancer: Second Line and Beyond

This combination, of course, has been also used in second-line. And very briefly, I just want to mention what is our possibility in second-line. As you see the NCCN guidelines, actually they are listing a lot of agents. But the reality that the efficacy of second-line is not very striking with all these drugs. The most effective regimen right now is the combination of lenvatinib and pembrolizumab.

[00:33:31]

KEYNOTE-775: Survival With Lenvatinib + Pembrolizumab After Platinum in Advanced EC

This is based on the results of the KEYNOTE-775 trial. Here you see the survival with lenvatinib plus pembrolizumab compared to standard of care. This is a second-line. What I show you before was frontline. This is second-line. The control arm was weekly paclitaxel or anthracycline.

You see that the combination of pembrolizumab/lenvatinib is more effective compared to standard of care second-line chemotherapy. That is why it is the preferred regimen now in second-line after platinum failure.

[00:34:07]

Lenvatinib + Pembrolizumab in Advanced/Recurrent EC: AEs Require Careful Management

Of course, you have to be aware of the toxicity of this combination because this is a chemo-free regimen, but the toxicity is still there. You have to learn how to use this combination and these drugs. You see the most frequent side effects and also when they may occur. Some of them occur quite early, some others occur later.

It is very important to become familiar with all these side effects and learn how to manage in order to keep your patients on treatment, because this, again, is a very effective treatment in second-line compared to chemotherapy.

[00:34:48]

What Has The TCGA Taught Us?

There are other possibilities to treat our patients with endometrial cancer. Remember the subgroup of copy number low where endocrine therapy may be effective.

[00:35:00]

EC: Aromatase Inhibitors and CDK4/6 Inhibitors

Also in this respect, besides the classical progesterone agents or aromatase inhibitors, there are other trials indicating some possible advantage by combining, for instance, everolimus with letrozole. This is the GOG-3007 trial, or in the PALEO trials where the CDK4/6 inhibitors was combined with letrozole, showing an increase in response rate compared to letrozole alone.

[00:35:33]

CDK4/6i + Endocrine Therapy in ER-Positive Endometrial Cancer (NSMP)

Again, in a similar way, there are other trials looking at this combination of CDK4/6 inhibitor with endocrine therapy. These are quite promising. Hopefully, we will soon have a phase III randomized study looking at this combination.

[00:35:50]

Tumor Suppressor p53

The other interesting target is, of course, the serous-like tumors, where p53 is very often mutated. In this population, besides the PARP inhibitors, which I mentioned before, there is another class of agents which may be very interesting.

[00:36:13]

Adavosertib (AZD1775) Inhibits WEE1 and May Be Most Active in p53-Mutant Background

These are the DNA damage regulator. As you know, the cell cycle have several checkpoints, which are very important because they slow down the cell cycle when in order to allow the repair of damaged DNA.

Now, in the patients or in the tumors where p53 is lost, this is one of the important checkpoints of the cell cycle, you may act by inhibiting another checkpoint such as WEE1. In this case, you will cause mitotic catastrophe and the cells death. This is the principle to use this WEE1 inhibitors such as this drug which is called adavosertib.

[00:36:56]

ADAGIO: Deep and Sustained Responses Observed in Some Patients Treated With Adavosertib

As you can see, this was tested in patients with recurrent endometrial cancer, provide a very good results in terms of response rate. But unfortunately the toxicity profile was too high. Therefore, the development of this drug was stopped.

[00:37:17]

Phase III XPORT-EC-042: Selinexor in Maintenance Therapy for Non-MMRd Advanced/Recurrent EC

There is another way of looking at p53, and this is the other phase of the coin as I say. You can look not at p53 mutated as a target, but p53 wild-type. This is the case of this drug which is called selinexor because this drug basically keeps the p53 wild-type inside the nucleus, so that can continue to work as a checkpoint of the cell cycle.

This trial showed that the use of selinexor as a maintenance after chemotherapy can lead to an improvement in progression-free survival, but this is a subgroup analysis looking only at patients with p53 wild-type tumor. That is why a phase III is currently ongoing.

[00:38:12]

2L Systemic Therapy in Unresectable, Recurrent Disease After 1L Platinum-Based CT

To sum up, these are the guidelines in terms of second-line treatment. The bottom line of course, for patients with dMMR, who did not receive immunotherapy in frontline, they can receive immunotherapy. But for all the others, of course, you can use pembrolizumab and lenvatinib. But if you have used already immune checkpoint inhibitor in frontline, there are very few options available or at least very few effective options. This represents an incredible unmet need. Here is where we need different targets and different drugs.

I leave you to Ketta to describe what are the options for the future.

Emerging Therapies for Progressive Advanced EC: Antibody–Drug Conjugates, Small-Molecule Inhibitors, and Other Novel Approaches

Dr. Domenica Lorusso (Humanitas University): Thank you, Nicoletta. Thank you so much. Really interesting meeting.

[00:39:04]

Antibody–Drug Conjugates: Key Elements and Target Antigens

The option of the future. There is no doubt that antibody drug conjugate will play a role in the future treatment of endometrial cancer, exactly as they are doing in so many solid tumor. You know exactly what an antibody drug conjugate is. It is made by 3 different part:

• The monoclonal antibody that recognizes a well-defined target on solid tumor;
• A payload that is basically represented by the cytotoxic agent. You know that we have basically 2 type of FDA-approved cytotoxic agent: Topo I inhibitor and microtubule interfering agent; and
• Last, the linker, which is not a negligible part. This is very important because we have 2 types of linker: cleavable and uncleavable.

The cleavable linker allow the payload penetration through the target cell membrane and allow the so-called bystander killing effect. We will speak about this effect.

The non-cleavable linker remain intact and do not release the payload until the ADC is degraded within the tumor cell. This limits the diffusion and the bystander effect. But what is important is that the cleavable and non-cleavable linker should be absolutely stable in the plasma because the drug should not be released in the plasma.

[00:40:58]

ADC Mechanism of Action for Use in EC

The mechanism of action of ADC is really fascinating. They remember the Trojan horse. The ADC moves in the circulation. They reach the tumor cell, the antibody linked to the target entities internalize with the process of endocytosis.

In the cell, the endocyte merge with the liposome and the drug is released inside the cell. The free drug is also able to go down and have this kind of bystander effect, that is the capability for the free drug to kill also the surrounding cell regardless the expression of the target.

This is a very important effect, but unfortunately this may increase the toxicity.

[00:42:00]

ADCs Under Investigation in Endometrial Cancer

Endometrial cancer is a lucky disease because we have at least 4 target of interest. For each of these target, at least 2 or 3 ADC are now in clinical development. These ADC are different to each other with respect to the linker but also with respect to the payload. We will go a little bit more in detail in speaking about ADC.

[00:42:29]

Factors Influencing the Toxicity of ADCs

This variability makes us very lucky because we have several opportunities and we will have in the future several opportunities for our patients. In particular, the next big question will be how to choose. For sure, we will take into account the target. We will take into account the efficacy. But there is another aspect that will play, in my opinion, a major role when we will choose one treatment over another, and it is the toxicity.

Toxicity may differ from ADC to ADC, and toxicity may be different also because it is related to any single part of the antibody drug conjugate. There are some toxicity that are typical of some ADC targeting the specific target. In this moment, I am thinking about TROP-2 inhibitor, in which typically we see mucositis or HER2 inhibitor, in which typically we see cardiotoxicity or ILD, while for instance for folate receptor, we see some kind also of immune-related side effect.

The toxicity also may be different according to the payload. The microtubule inhibitor payload like BMI, for instance, have typically thrombocytopenia or hepatotoxicity. While for Topo I inhibitor, for instance, we see much more gastrointestinal toxicity like diarrhea and nausea and also neutropenia.

Do not forget the major role that is played by the linker. As I told you, the cleavable linker facilitate the bystander effect.

[00:44:29]

ADC Mechanisms of Toxicity: Bystander Effect

The bystander effect increase the toxicity. For sure, increase the efficacy, no doubt, but also increase the toxicity because allow the free drug to move in the bloodstream to kill also other cells, but unfortunately to exert a larger toxicity. That is typically an off-target toxicity just because the drug is free to move.

[00:45:02]

ORR of Antibody–Drug Conjugates in Endometrial Cancer

There we have several drugs with the different efficacy and different toxicity profile. If we want to roughly summarize, we can say that the ADC targeting HER2 has a reported response rate up to 50%. Why so high? Because HER2 is an oncogene. It is not only a protein target, but it is an oncogene. That is the reason why the ADC targeting HER2 has reported the higher overall response rate right now.

Then we have a group of ADC targeting folate receptor. In this setting, the response rate is around 25% to 30%. Then we have at least 3 drug targeting TROP-2, where also around 30% overall response rate has been reported.

Finally, we have 2 drug targeting B7-H4, which is another interesting target with the response rate between 35% and 40%.

[00:46:19]

Strong Scientific Rationale for Targeting TROP-2 in EC

Let us go more in detail of this target. There is a strong scientific rationale in targeting TROP-2. TROP-2 is overexpressed in more than 80% endometrial cancer, and in about 50% we have a high strong overexpression of TROP-2.

It is interesting, because it seems that the dMMR status does not impact on TROP-2 expression, and neither the histology play a role. It just seems that carcinosarcoma may have a lower overexpression of TROP-2, but these data are really preliminary and need to be confirmed.

TROP-2 is important because promote cell growth, proliferation, metastatic and regulate calcium ion signaling pathway and cyclin overexpression.

[00:47:21]

Anti–TROP-2 Antibody–Drug Conjugates

We have 3 drugs in this moment, 3 ADC targeting TROP-2. They are a little different with each other. They have also some common characteristics. The payload, for instance, is the same is a Topo I inhibitor. The ratio between the drug and the antibody, we call this DAR, is different. It is 4 for Dato-DXd, and it is 7.6 and 7.4 for sacituzumab govitecan and sacituzumab tirumotecan.

The efficacy is very similar. We are around 30% of all of this drug. Also I have to say the toxicity profile have some elements in common and some difference. For instance, for Dato-DXd, stomatitis were reported in 52% of the patient, then nausea in 37% and alopecia in 25%, while for sacituzumab govitecan, for instance, gastrointestinal toxicity seem to be dominant with diarrhea reported in 56% of patients and nausea in 53%, and fatigue in 51% of patients.

For sacituzumab tirumotecan, nausea was reported in a range between 40% and 86%, alopecia in up to 70% of patients and anemia in up to 80% of patients. Maybe there is a dose-dependent effect.

[00:49:02]

Sacituzumab Govitecan: TROP-2–Targeted ADC

Sacituzumab govitecan is an ADC targeting TROP-2. As I anticipated, here the payload is SN-38, which is a potent Topo I inhibitor, and the linker is represented by a cleavable linker, very sensitive, made to provide a rapid release inside the tumor.

This drug has a DAR higher than more than 7 and has also a potent bystander effect.

[00:49:41]

ASCENT-GYN-01: Sacituzumab Govitecan vs TPC in EC Post Platinum-Based CT and PD-1/PD-L1 Therapy

The drug is actually in clinical development in recurrent endometrial cancer patients who have failed 1 prior line of platinum and immunotherapy. The trial design is simply a comparison between sacituzumab govitecan vs physician's choice chemotherapy between doxorubicin and weekly paclitaxel.

The trial has a co-primary endpoint PFS by BICR and overall survival, and has already concluded the recruitment. So very anxious to see the data.

[00:50:14]

Sacituzumab Tirumotecan

Sacituzumab tirumotecan is another ADC targeting TROP-2. Also in this case, the payload is represented by a Topo I inhibitor. The DAR is quite high, also in this case 7.4, and this condition and high bystander effect.

The linker is a cleavable linker, stable in the bloodstream but that provides immediate release in the cell.

[00:50:47]

TroFuse-005: 1L Sacituzumab Tirumotecan After CT and PD-(L)1 Treatment in EC

Also in this case, we have a trial ongoing. The TroFuse-005 has also concluded recruitment. It is very similar to the ASCENT trial. It is targeting a population with recurrent endometrial cancer who have failed at least 1 prior line of chemo in combination with immunotherapy.

It is a randomized trial, sacituzumab tirumotecan vs physician's choice chemotherapy. The dosage being reduced to 4 milligrams per kg to increase the tolerability of the drug.

Also, in this case, a co-primary endpoint, PFS by RECIST by BICR, and overall survival. The trial has concluded recruitment.

[00:51:37]

TroFuse-033: 1L Sacituzumab Tirumotecan + Pembro vs Pembro Alone in pMMR EC

Another trial is ready to start with the same drug moved in an earlier setting. The setting is the front-line setting of patients with advanced stage III/IV or recurrent endometrial cancer. This patient can never receive chemo only in the adjuvant setting not for metastatic disease. The trial is a randomized trial in the maintenance setting after induction carboplatin/paclitaxel/pembrolizumab.

The patient in complete or partial response are randomized to proceed pembrolizumab alone or pembrolizumab in combination with sacituzumab tirumotecan.

[00:52:23]

FRα Expression in Endometrial Carcinoma

Folate receptor is another very interesting target. We know that more than 50% of endometrial cancer patients present overexpression of folate receptor and 22%, a very high expression of folate receptor.

[00:52:41]

FRα-Directed ADCs Under Investigation for EC

We have 4 drugs that has produced preliminary data of efficacy in endometrial cancer, ranging between 25% and 50%. Different payload, in this case, some as maytansinoid DM4, which is a microtubule interfering agent. Some other as a Topo I inhibitor. So a lot more drug and more possibility for our patients.

This obviously conditionate the toxicity profile that, as you can see here for mirvetuximab, for instance, involve ocular toxicity as we have seen also in ovarian cancer, while for Rina-S for instance is more hematological toxicity.

[00:53:36]

RAINFOL-01: Rina-S in Patients With Heavily Pretreated EC (Dose Expansion Cohort B2 of GCT1184-01)

In particular, Rina-S seems to be a very interesting drug. In this phase I/II study, which was a dose optimization study comparing the dose of 100 milligram for microsphere every 3 weeks, or 120 milligram per microsphere every 3 weeks, an interesting 50% overall response rate was reported, with the disease control rate up to 100%.

[00:54:07]

RAINFOL-03: Rina-S in Patients With Recurrent or Progressive EC Following Prior Therapy

Now, based on these preliminary results, the RAINFOL-03 trial is ready to start comparing Rina-S 100 milligram per meter square to physician's choice chemotherapy, either weekly paclitaxel or doxorubicin in patients with recurrent endometrial cancer who have received up to 3 prior lines of therapy, including immunotherapy. Also, in this case, progression-free and overall survival are the primary endpoint.

[00:54:31]

HER2-Targeted ADC: Trastuzumab Deruxtecan

HER2 seems to be a very interesting target. It is an oncogene, as I told you. This explains, in my opinion, the higher responses reported here. We know that trastuzumab deruxtecan is an antibody drug conjugate with a very high DAR of 8 targeting HER2. The payload here is a topoisomerase inhibitor.

[00:55:04]

HER2 Expression Across Solid Tumor Types

We know that up to 30% of endometrial cancer patients present high expression, with the 50% of endometrial cancer patients presenting HER2 expression regardless intensity.

[00:55:22]

Rationale for Targeting HER2 in Endometrial Cancer

We know that this is an interesting target. We already have information about that. Few years ago, the colleagues of GOG published a randomized phase II trial reporting that the addition of trastuzumab to platinum/paclitaxel chemotherapy in HER2-positive tumor increased the survival.

[00:55:41]

Trastuzumab Deruxtecan in Previously Treated Advanced/Recurrent Endometrial Cancer

Now the evolution of trastuzumab deruxtecan. There were 40 patients with HER2-positive endometrial cancer in the DESTINY-PanTumor, where an impressive 85% overall response rate with the median PFS not reached was reported by our colleagues. Thanks to this data, FDA provide agnostic approval of trastuzumab deruxtecan for HER2-positive 3+ tumor.

But this drug provided preliminary efficacy data also in one of the most aggressive endometrial histotype, which is carcinosarcoma, where an impressive 50% to 70% overall response rate was reported, regardless HER2 expression.

[00:56:35]

DESTINY-Endometrial02: Trastuzumab Deruxtecan vs SoC CT ± Adjuvant RT for HER2+ Tumors (EC Cohort)

The clinical development of this drug is moving on and trastuzumab deruxtecan is part of this DESTINY-Endometrial02 trial in comparison to standard of care chemotherapy in patients with stage II and III endometrial cancer ineligible for curative treatment, HER2-positive, where HER2-positive means 2+ and 3+.

[00:57:06]

NRG-GY026: CT + Trastuzumab ± Pertuzumab vs CT in Newly Diagnosed HER2+ Endometrial Cancer

But also other trials ongoing are addressing this target. This is another NRG trial, very interesting in patients with stage I/IVB all patient, chemo-naïve, carcinosarcoma and serous tumor, HER2-positive by local test, randomized to receive carboplatin/paclitaxel or carboplatin/paclitaxel/trastuzumab/pertuzumab or carboplatin/paclitaxel/trastuzumab followed by maintenance.

[00:57:38]

DESTINY-Endometrial01: 1L T-DXd + Pembro or Rilvegostomig (BiSpAb PD-1 + TIGIT) in HER2+ pMMR EC

Lastly, there is another trial assessing randomized phase III in patients with stage III measurable disease, stage IV or recurrent HER2-positive in pMMR endometrial cancer. The randomization here is carboplatin/paclitaxel/pembrolizumab vs trastuzumab/deruxtecan/pembrolizumab vs trastuzumab deruxtecan/rilvegostomig, which is a bispecific antibody targeting immune system.

[00:58:10]

Detecting and Managing T-DXd–Related Interstitial Lung Disease: The 5 “S” Rules

New drug, new toxicity profile. We need to learn how to manage the new toxicity of our patient. In particular, trastuzumab deruxtecan is under observation for the high incidence up to 10% of interstitial lung disease. Nothing that we cannot be able to manage, but we need to learn.

We need to learn how to screen the patient, to scan the patient where there is any symptom. But in particular, we need to learn to work with our pneumology colleagues in a multidisciplinary setting to provide the best treatment to our patient.

[00:58:52]

Targeting B7-H4 in Endometrial Cancer

Lastly, very quickly B7-H4. This is interesting target to me, because this target not only is involved in apoptosis and metastasis, but also is a part of the immune system promoting T-cell proliferation.

[00:59:12]

ADCs Targeting B7-H4 in Clinical Development

Up to 80% of endometrial cancer patients overexpressed B7-H4. We have 3 drugs in clinical development targeting. For some of them, we have preliminary results.

[00:59:25]

Bluestar-Endometrial01: Safety and Preliminary Efficacy of P-Sam in Patients With A/R EC

This is the Bluestar-Endometrial01 trial with the P-Sam in a population of patients who have already received immunotherapy to those were compared.

[00:59:37]

Bluestar-Endometrial01: Efficacy of P-Sam

And 34% and 38% overall response rate were reported with a quite long duration of response.

[00:59:47]

Bluestar-Endometrial01: Safety of P-Sam

The toxicity profile seems to be manageable. Nausea and anemia and neutropenia were the most frequently reported toxicity, but at the higher dose also, an ILD pneumonitis was reported.

[01:00:05]

Puxitatug Samrotecan (AZD8205) vs CT in B7-H4 EC Post Platinum-Based CT + PD-1/PD-L1 Inhibitor

This drug now is in clinical development in comparison to physician's choice chemotherapy in platinum paclitaxel and immunotherapy recurrent ovarian cancer patient.

[01:00:17]

Phase I Dose Escalation of GSK5733584/HS-20089 in Patients With Advanced Solid Tumors

Another drug targeting B7-H4 is arriving. There were a cohort of endometrial cancer patients in the BEHOLD program. We do not have still data on this cohort, but looking what the drug has given in breast and ovarian cancer, it seems very, very promising.

[01:00:37]

Sapanisertib and Serabelisib (PIKTOR)

ADC are interesting, but not the only one. Nicoletta already mentioned how is important for us, the group of NSMP patients. I just want you to remember that up to 40% of these patients present PI3K mutations. So drug targeting the TORC complex are very important in endometrial cancer, particularly in this patient.

[01:01:02]

GOG-3111: Sapanisertib and Serabelisib (PIKTOR) + Paclitaxel in Advanced/Recurrent EC

A trial is ongoing exploring a combination of PI3K inhibitor and TORC inhibitor in patients with recurrent endometrial cancer who have received up to 4 prior lines of therapy, suggesting that this target is also very important.

[01:01:28]

Provider-Level Strategies for Supporting Equitable Access to New Therapies and Clinical Trials

Dr. Colombo: That is so exciting. I mean, it is incredible to see how many trials are ongoing in endometrial cancer. You know that I call this the Cinderella disease. Now it is more than a princess. It is really a queen because we have so many new interesting drugs with increased activity and also incredible results and trials ongoing.

[01:01:53]

Provider-Level Strategies for Supporting Access to New Therapies and Clinical Trials

The problem is, how can we be sure that patients can get access to these clinical trials? What are the main barriers that you would see in order to more and more patients having access to these trials with such a huge opportunity and offer that we have right now? What is your experience? Yes.

Dr. Lorusso: That is very important question. It is absolutely necessary to make this trial available for the larger number of patients. It is obvious that we can report what is our experience. We are quite lucky in Italy, we have this possibility for our patient, but we work in 2 direction to get the trial available.

You know that in Italy we have 2 cooperative group working on gynecological cancer research. When we distribute the trial across the group, we try to select the centers that are more or less spread in all the country in order to reduce what is called the health mobility and make for the patient easy to get a closer center to receive a drug in a clinical trial. That is the first point, try to spread as much as possible the trial along all over the country.

The second, because we work with the same patient advocacy group, it is important to sensitize the patient and to explain the importance of a clinical trial, which is more difficult for a patient. It is more difficult also for us, as clinicians, obviously, and also for the patient, but they have to understand the importance and the advantage that came from that.

You know Nicoletta, how many educational sessions we had with patient advocacy group to explain, for instance, the mechanism of randomization that is very difficult for the patient to understand and to accept. But now I have to say the uptake to the trial in Italy is quite high. We sensitize the patient and now the patient move to such a clinical trial and not the opposite as a few years ago as it happened.

Dr. Colombo: Yes, you are right. It is just a matter of education. But also there are of course some cultural barriers sometimes. Of course, not all patients are ready and knowledgeable enough to understand the huge advantage of being a role in clinical trials.

I think we do have some minutes to go through the question. I do not know, Mandi.

[01:04:48]

          Poll 1

Mandi Murph: Yes. Thank you so much for this excellent presentation, doctors Colombo and Lorusso. Before we go into our Q&A session, let us quickly revisit our questions. Do you plan to make any changes in your clinical practice based upon what you learned in today's program?

Okay, let us go ahead and close out this poll question and bring up the next one.

[01:05:16]

          Poll 2

Please take a moment to text in one key change that you plan to make in your clinical practice based on this education?

Okay. Let us go ahead and close out this poll question.

[01:06:00]

          Posttest 1

Our first post-test question, which you're seeing for the second time. What is the primary clinical implication of identifying an MMR-deficient tumor in endometrial cancer? Please go ahead and take a moment to answer.

Okay. Let us go ahead and close out this question and go on to the next.

[01:06:33]

          Posttest 1: Rationale

Okay. I do not know if the faculty would like to.

Dr. Colombo: Yes, I think it is excellent. The response is absolutely correct. Yes.

[01:06:53]

          Posttest 2

Mandi Murph: Okay. The next post-test question. A patient with rapidly progressing stage III to IV recurrent endometrial cancer has a non-MMRd tumor that is unresponsive to treatment with chemotherapy. Which option below is most appropriate for this patient.

All right, let us go ahead and close out this poll and see how the audience did on the answer to this question.

[01:07:38]

          Posttest 2: Rationale

Dr. Colombo: Yes, Ketta, you want to comment on that?

Dr. Lorusso: That is pretty interesting. I mean, I agree with the 66% of our colleagues in a patient progressing rapidly after chemotherapy non-dMMR, also in my mind the best option is Lenvatinib/pembrolizumab. Yes, we can discuss on the concept of rapidly. But for sure there is a signal here that chemotherapy probably is not the best option. We have an alternative, as Nicoletta reported during her talk. We have a good alternative in lenvatinib/pembrolizumab.

It is obvious that the combination with the chemo may have a role, again, depending on the concept of rapidly. What I would not so much agree is dostarlimab plus pembrolizumab that I guess is dostarlimab or pembrolizumab. That means immunotherapy single agent.

This is a non-dMMR patient. Immunotherapy single-agent in this situation provide 13% overall response rate. We think that immunotherapy alone is not enough in this patient. That is the reason why we try to combine with TKI inhibitor or chemotherapy or chemotherapy plus PARP.

In this patient, I would really move with lenvatinib/pembrolizumab.

Mandi Murph: Okay. Excellent. All right. Let us go on to the next question and see how our audience did.

[01:09:08]

          Posttest 3

For the third question, which of the following toxicities are most commonly associated with sacituzumab govitecan? Please go ahead and answer this question.

Okay. Let us go ahead and close out this poll and see how the audience responded.

[01:09:35]

          Posttest 3: Rationale  

Dr. Lorusso: Yes, they did very well. It is typical of this drug. Nicoletta has led the trial. So very much experienced with this drug. The diarrhea and neutropenia is the right answer.

Dr. Colombo: Yes, it is right. You have to prevent diarrhea is very important to know and to watch carefully the patients. Of course, this is related to the irinotecan, the toxicity of the payload. It is very important to watch this patient to prevent the diarrhea, which can be quite serious sometimes.

But of course, again, it is a matter of knowledge and understanding how to treat, how to prevent. Then of course, it becomes feasible for sure. Yes.

[01:10:27]

          Posttest 4

Mandi Murph: Okay. Our last question, and this is just open answer. Please rate your confidence at applying patient-healthcare provider level strategies to improve access to investigational therapies available through clinical trials among underserved patients with endometrial cancer.

[01:10:46]

Q&A

With that, I encourage you to submit your questions, and we have time for a question or 2. I will throw this out to both of our faculty members.

One question is, are there any antibody drug conjugates in development, or ADCs, that are approved that would appear more favorable than another because of the expression of targets across gynecological tumors?

Dr. Lorusso: Well, that is a very interesting question. According to the preliminary data we have, which are very preliminary, most of the data that I did show you came from phase IB trial. So very preliminary data. The overall response rate is in the range of 30% for anti-TROP and anti-folate receptor. Around maybe a little bit more for anti-folate receptor Rina-S, about 50%.

It is about 30% for B7-H4, and it is around 70% to 80% for HER2. But in my opinion, this apparently higher efficacy in HER2 is related to the fact that the HER2 is not only a target, but it is an oncogene. These are very, very preliminary data, but we do not know in the future what will be the role of the target.

Our colleagues asked if one ADC can be more interesting, maybe because the target is widely expressed. In the reality, unfortunately, we do not know what will be the role of the target in the development, approval and reimbursement of this drug. Because most of the trials that I did show you enroll the patient regardless the target, some of them stratify for the target, but we do not know what will be the results and if the results will be different according to the level of expression of the target.

So it is very difficult in this moment to answer your question. In additional for sacituzumab govitecan, you saw the data a few days ago at GCS[?]. It seems that there is no correlation between the target expression and the and the efficacy of the drug. So really, in this moment, the data are so many preliminary that it is impossible to answer your question, but it remains a very good question.