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The Wee1 inhibitor adavosertib, either alone or in combination with the PARP inhibitor olaparib (Lynparza), demonstrated promising efficacy in patients with PARP inhibitor–resistant ovarian cancer, according to Shannon Westin, MD, MPH, who added that additional efforts are underway to make the approach more tolerable in this population.

Results from the phase 2 EFFORT trial (NCT03579316), which were presented during the 2021 ASCO Annual Meeting, showed that adavosertib monotherapy induced an overall response rate (ORR) of 23% (95% CI, 12%-38%) and a clinical benefit rate (CBR) of 63% (95% CI, 48%-76%). When the agent was paired with olaparib, it resulted in an ORR of 29% (95% CI, 14%-44%) and a CBR of 89% (95% CI, 76%-96%). Notably, the benefits achieved with these approaches were observed, irrespective of 

However, although toxicities reported with these agents, such as diarrhea, neutropenia, and thrombocytopenia, were determined to be manageable with supportive treatment, dose reductions and interruptions may be necessary for certain patients.

“[Although these data are] very exciting, we want to ensure that we [make this approach] as tolerable as possible [for our patients],” Westin said. “To this end, we have an ongoing study that is examining the sequential dosing of adavosertib and olaparib to see whether…[it will result in] less toxicity and make it easier for our patients to tolerate.”

,Westin, an associate professor in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at The University of Texas MD Anderson Cancer Center, discussed the key takeaways from the EFFORT trial, future research direction with adavosertib, and the characteristics of PARP inhibitor resistance in patients with ovarian cancer.

:To date, what is known about PARP-resistant ovarian cancer?

: Now that PARP inhibitors are accepted in almost every piece of the ovarian cancer journey—up-front maintenance, second-line maintenance, and even treatment—we are seeing more and more people [receiving treatment with] PARP inhibitors. With that, we are also seeing more resistance to [these agents]. There are several different mechanisms of PARP resistance, and one area we are still struggling with is how to know what patient has which mechanism of resistance, and what [is needed] to target that. Right now, we are trying to tackle common mechanisms of resistance, or common pathways that may be involved [in this process].

One pathway that we have seen is involved is the cell cycle. Specifically, when we treat patients with PARP [inhibitors], we can see upregulation of different cell-cycle regulators, indicating that the tumor is becoming dependent on them. As such, in the EFFORT study, we [set out to] target a specific regulator of the cell cycle, Wee1, and the drug that does that is adavosertib. What is interesting about this study is that, not only did we explore adavosertib on its own, but we also combined it with [another] PARP [inhibitor] to see whether that would help to overcome PARP resistance in this population.

What was the rationale to explore adavosertib in this patient population?

Some early phase 1 and 2 data demonstrate that adavosertib appears to have activity. What we were not sure about, however, [what] the best potential population [is to receive this drug]. Several ongoing studies are looking for predictors of response to adavosertib and utilizing molecular factors [to figure this out]. However, we thought it might be worthwhile to explore [the agent] specifically in a PARP-resistant population.

Furthermore, [we know that] Wee1 acts along the cell cycle. 

 is involved in that same cell cycle, and high-grade serous ovarian cancer has a high proportion of these mutations. When [those mutations occur], the cell becomes extremely dependent on the G2-M [DNA damage] checkpoint, which is what Wee1 regulates. As such, [with Wee inhibition,] we are hitting the cancer cell in a couple of different ways. We are tackling this potential mechanism of PARP resistance, and we are tackling a potential area of injury to the cell already with that 

 mutation. We were hoping that a 2-hit [strategy] would lead to better outcomes for our patients.

Could you expand on the design of the study? What were the key objectives of this research?

The study was [comprised of] 2 parallel arms. [Although this] was a randomized study, the arms were not comparative. [Patients] either [received] adavosertib alone, or adavosertib plus the PARP inhibitor olaparib.

This was an open study [in the sense that] patients could have any recurrent ovarian, fallopian tube, or peritoneal cancer. We did not restrict [enrollment] based on histology or 

 status. Patients [were also able to] have [received] unlimited prior therapies. The only real [eligibility] requirement was that they must have had progressive disease on a single-agent PARP inhibitor, and they could not have come off of that agent because of toxicity; it needed to be [because of] progressive disease. That PARP inhibitor could have been given for maintenance or for treatment; no selection was based on that.

The primary end point [of the trial] was to look at the efficacy in both arms. Again, we were not comparing [the efficacy in these arms], we were just reporting the data for adavosertib alone and the combination.

Would you say that the population included in the trial was reflective of the patients you typically see in practice who develop PARP resistance?

Overall, yes; the population was very representative of our general patient population with ovarian cancer. We had many patients with high-grade serous [disease]. The median prior lines of therapy was 4, so this was a heavily pretreated group. The bulk of the patients had platinum-resistant disease, which is of course a worse population for outcomes. Most patients did have some benefit from their prior PARP inhibitor—either they had reduction of disease or stable disease, and were able to stay on it for a significant amount of time. This is a good population and is very reflective of the population we see that is developing PARP resistance.

What were the key results from the study?

We saw activity in both arms of the trial. With adavosertib alone, the ORR was 23% and the CBR, which included not just objective response, but also those who were able to achieve stable disease for more than 4 months, was 63%. Thus, this [approach] was very active [as a monotherapy]. The adavosertib/olaparib arm also demonstrated activity. Here, the ORR was 29% and the CBR was 89%. [Thus, these data showed that] most patients derived benefit from these regimens.

We were also interested to see whether the response [to treatment] could be predicted, whether it was associated with the presence of a 

 mutation, or whether better activity [would be observed] in tumors that were 

 wild-type. Interestingly, we found that patients who had 

 mutations seemed [to have] lower levels of response; [the ORRs were] 20% in the adavosertib-alone arm and 19% in adavosertib/olaparib arm. The [CBRs in this subgroup] were similar to [those seen in the] group as a whole, at 67% with adavosertib alone and 81% with the combination.

 wild-type subgroup, we saw higher levels of response, with [an ORR of] 31% in the adavosertib-alone arm and a [CBR of] 69%; with the combination, the ORR was 39% with a CBR of 94%. [Those are] exciting numbers, [although] we always have to be careful because the samples are getting smaller. Regardless, [we] definitely [saw] a hint that there is something going on here.

One thing we were missing, that we are obtaining now, is the homologous recombination deficiency [HRD] status of these patients. [This information will help us tease out whether] that clinical benefit in the wild-type group is driven by an HRD tumor, or whether it is in a truly wild-type tumor that we are seeing activity. [We are] very excited to generate those data so we can understand this a little bit more.

Could you expand on some of the next steps for research with adavosertib?

Adavosertib alone, and in combination with the PARP inhibitor, [has shown] impressive activity. There are a few things that we want to tease out. First, we want to [really understand] who is benefiting [from these approaches]. To this end, we are doing a deep [molecular] dive [into these data], and we are starting with the low hanging fruit of looking at HRD. Then, we want to expand that [exploration] to other potential markers of response and resistance to therapy. This effort is being made as we speak, and we are excited about where that [research] might lead us.

The other thing that is important to note, is that there are toxicities with these agents. As such, we really do need to explore different dosing strategies. Adavosertib alone is tolerable, although [we know that there] are several AEs [with this agent]. Ninety-seven percent [of patients on the trial experienced] a treatment-related AE, but only 5% required discontinuation because of toxicity. The AEs that we see very commonly with this drug [as a monotherapy] include nausea, vomiting, fatigue, diarrhea, and bone marrow issues. [These are] standard toxicities that can be mitigated but we need to prepare for.

The combination is a little trickier. Most patients are able to stay on the [regimen], but 56% of patients needed a dose reduction, 85% had to have a dose interruption, and 10% discontinued [treatment] due to AEs. Similar types of AEs [were reported with the doublet] in that [patients experienced] gastrointestinal, fatigue, and bone marrow issues.

[To make these approaches easier to receive, we are] figuring out whether sequential administration is better tolerated. After this, we will move forward to tease out who needs the single agent and who needs the combination.

From a multidisciplinary care standpoint, what should be taken away from this trial?

Similar to what we have seen with other combination strategies, it is important to engage the patient, your pharmacist, and your nursing staff to ensure that everyone is aware of the potential AEs, as well as set expectations to make sure patients know. We may start on 1 dose, but there may be a need to hold, and to reduce as needed to make this tolerable. That would be the major thing. As far as where this is going, scientifically, this is very exciting. Clinically, we are seeing the benefit we need, but it is not quite ready for primetime. We need to do a little bit more study before it is going to be in the hands of clinicians in practice.

Westin S, Coleman R, Fellman B, et al. EFFORT: EFFicacy Of adavosertib in parp ResisTance: A randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer. 

. 2021;39(supp 15):5505. doi:10.1200/JCO.2021.39.15_suppl.5505

Articles

Shannon Westin, MD, MPH, discusses the key takeaways from the EFFORT trial, future research directions with adavosertib, and the characteristics of PARP inhibitor resistance in patients with ovarian cancer.

Adavosertib, With or Without Olaparib, Showed Promising Efficacy in PARP-Resistant Ovarian Cancer

Although the combination of regorafenib (Stivarga) and nivolumab (Opdivo) was found to elicit responses in patients with mismatch repair–proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC), a subgroup of patients with liver metastases were not found to respond to the regimen, according to Marwan Fakih, MD. As such, the absence of liver metastases may be indicative of a better response with the VEGFR/PD-1 combination.

Results from a single-arm, phase 2 study (NCT04126733) presented during the 2021 ASCO Annual Meeting showed that 5 patients who did not have liver metastases at baseline experienced a durable partial response with the regimen, translating to an overall objective response rate (ORR) of 7% in all patients (n = 70).1 Moreover, 31% of all patients achieved disease stability, and the disease control rate was 39% with the doublet.

In patients without liver metastases (n = 23), the ORR achieved with the combination was 22%; the ORR in those with liver metastases (n = 47) was 0%. Moreover, the median progression-free survival was found to be longer in the patient subgroup without liver metastases vs that seen in those with liver metastases, at 3.5 months vs 1.8 months, respectively.

“The patients with liver metastases unfortunately did not respond [to the combination],” said Fakih, a professor in the Department of Medical Oncology & Therapeutics Research and the associate director for Clinical Sciences at the Comprehensive Cancer Center. “That tells us that there is a lot of work that needs to be done for [those with] liver metastases. It also tells us that maybe the combination of VEGFR inhibitors plus PD-1 inhibitors may not be as effective in patients with CRC who have liver metastases.”

, Fakih, who is also the medical director of the Judy & Bernard Briskin Center for Clinical Research and co-director for the Gastrointestinal Cancer Program at the City of Hope Comprehensive Cancer Center, discussed the efficacy of regorafenib plus nivolumab in patients with pMMR/MSS CRC, the potential for VEGFR/PD-1 inhibitor combination regimens in this population, and future directions for research.

: Why is there an unmet need to evaluate the role of immunotherapy further in mismatch repair and MSS CRC?

: Historically, many studies have looked at the role of PD-1 targeting in patients with MSS, and the results have been disappointing. In addition, a randomized phase 2 trial [NCT02870920] looked at combining a CTLA-4 inhibitor with a PD-L1 inhibitor vs best supportive care and showed no improvement in progression free survival [PFS] or responses with [the immunotherapy combination] in this population.

As such, for the longest time, we have deemed these patients to be immunotherapy resistant, and we are trying to figure out ways to overcome that resistance. Several reports show that the combination of a VEGFR TKI [and a] PD-1 [inhibitor] may, indeed, be associated with activity.

Why is this important for this patient population? Once first- and second-line therapy [fails], they do not have good options [available to them]. The treatment options after first-, second-, and in some patients, third-line [failure]…include regorafenib alone or trifluridine/tipiracil [TAS-102] alone [depending on what was received in the first line].

Although these [agents] are important in [terms of] improving survival, the improvements are modest, and the response rates are very low, so we need better options for our patients. If we can make pMMR tumors immune responsive, and [achieve] significant benefits, then that [will be] great for our patients; it is very much needed.

What prompted the evaluation of nivolumab plus regorafenib in this population?

Approximately 2 years ago, a Japanese research group evaluated the addition of regorafenib to nivolumab in patients with MSS CRC. Some preclinical data suggested that regorafenib may have some beneficial impact as far as altering regulatory T cells in tumors, [as demonstrated in] in vivo models. Preclinically, [we have seen] some synergy between VEGF targeting, VEGFR targeting, and PD-1 targeting. [We] also [have] evidence from other tumor types that when we combine bevacizumab[Avastin], for example, with a PD-1 [inhibitor] we may also improve outcomes. [By combining] VEGFR-targeting agents with PD-1 inhibitors in renal cell carcinoma, [we saw] a high response rate.

There is plenty of clinical and preclinical rationale for targeting the VEGF pathway in combination with PD-1. The Japanese group evaluated the combination of regorafenib and nivolumab in 25 patients with metastatic CRC, 24 of whom had MSS [disease] and had initially shown a very robust response rate of 30% and a PFS exceeding 6 months. This created a buzz about 2 years about the [possibility of that]. This research prompted several groups to look at VEGFR inhibitors in combination with PD-1 inhibitors.

How do immunotherapy and TKI agents synergize? What are some of the findings reported in the phase 2 study of regorafenib plus nivolumab in MSS CRC presented during the 2021 ASCO Annual Meeting?

We have not reached a consensus as to how they really synergize fully. It is not easy to obtain serial biopsies in patients who undergo these treatments. When you do, [we are] quite limited with the amount of tissue that we get. As I mentioned earlier, at least one of the paths [forward] that is believed to be associated with this is the impact of VEGFR inhibitors on regulatory T cells, which are inhibitory to the immune response or immune activation. In addition, there may be an impact on the tumor microenvironment and other ways that may make the response to immunotherapy more favorable.

Last, VEGFA has been shown to be immunosuppressive through binding to VEGF receptors and it is possible that it may be another way [in which] this is working. The definitive pathway of synergy, frankly, is not fully elucidated, at this point. What we know is that we are seeing definitive clinical signals because the response rate with regorafenib in patients with advanced CRC is expected only to be 1%, and the response rate with nivolumab alone is expected to be nonexistent; it is rarely described and only anecdotally.

The fact that we are seeing a 7% objective response rate [ORR] in an unselected patient population with regorafenib plus nivolumab on our study, and even more importantly that we are seeing an ORR of 22% in [those with] non-liver metastases, tells us that there is some form of synergy with this combination. Interestingly, this synergy appears to be more prevalent and noticeable in patients without hepatic metastatic disease. Not only do we see synergy, but it seems like there is a clinical biomarker [that can indicate which] patients [will] respond better to this combination.

What were the key takeaways of this trial? Was there anything surprising?

The discordance in clinical responses [observed] in patients with pMMR, metastatic CRC between [those with] liver metastases and non-liver metastases was very noticeable here. This is a 70-patient clinical trial, and 23 patients did not have liver metastatic disease; 47 patients had liver metastases. We saw no responses [with the combination] in those with liver metastases. However, 5 out of 23 patients without liver metastases had an ORR, and an additional 35% had stable disease. This means that more than half of the patients had a clinical benefit [with the regimen], with a median PFS of 3.5 months in the non-liver metastases cohort [that] was [determined to be] clinically significant.

[These findings raise several questions]. Should we start thinking about targeting our patients without liver metastases with immunotherapy, and specifically with a PD-1 inhibitor plus a VEGFR inhibitor? For the sake of this study, specifically nivolumab plus regorafenib? Should we be designing different combinations for patients with liver metastases? That is [where] the field should be moving.

It is important to note that our study was with regorafenib plus nivolumab. Other combinations are being investigated, and other [studies] have looked at PD-1 inhibitors plus TKI inhibitors. Not all those studies have reported based on the pattern of metastatic disease, and we await those data because it would be important to see whether this is a class effect of the combination of PD-1 and VEGFR inhibitors, or whether this is seen specifically more with the combination of regorafenib plus nivolumab. I do suspect that it may, to a certain point, be somewhat of a class effect. However, this should be confirmed through other studies.

That is basically where we are right now. We do see a signal of benefit in pMMR non-liver metastases that we believe is clinically significant, although it is not as robust as described in the Japanese data. The reason for that is unclear. It could be related to the pattern of metastatic disease, or it could be the burden of disease. Regardless, a lot of work still needs to be done in this area.

How are immunotherapy/TKIs moving forward in the paradigm?

There is a study of lenvatinib [Lenvima] plus pembrolizumab [Keytruda]. Some studies have also been conducted in China, [that have combined] fruquintinib [Elunate] with a PD-1 inhibitor. The good thing is that whatever has been reported so far, has been [found to be] associated with clinical responses. Not every single study stratified like we did, by liver metastases vs non-liver metastases to see whether there is a clinical subgroup who would respond more than others.

We have previously reported on 95 patients with MSS CRC who were treated with immunotherapy [and] findings were similar to what we had reported during the 2021 ASCO Annual Meeting. [We saw a] lack of benefit [with the regimen] in patients with liver metastases. Clinically, to the medical oncology community, there is some hope that our pMMR patients will benefit from such combinations.

Right now, the question remains as to what the degree of benefit is and which patients should be elected for this treatment? We cannot say we have a winner combination among what has been reported so far. The reason I say that is because even with regorafenib and nivolumab, we have seen a huge discrepancy in response rates [with regard to] what has been reported in Japan and what we reported in the United States.

We can see that patient selection does matter, the burden of disease probably does matter, oligometastatic disease does matter, and liver metastases probably does matter. Those are not the same across the different studies [that have been done]. As such, [we are unable] to say that one combination is superior to another. Moving forward, we have to start thinking about randomized studies more and more so that [we can] better discern what is predicted, what the impact of therapy is, and what is related to a patient prognosis.

Fakih M, Raghav KPS, Chang DZ, et al. Single-arm, phase 2 study of regorafenib plus nivolumab in patients with mismatch repair-proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC). 

. 2021;39(suppl 15):3560. doi:10.1200/JCO.2021.39.15_suppl.3560

Marwan Fakih, MD, discusses the efficacy of regorafenib plus nivolumab in patients with pMMR/MSS CRC, the potential for VEGFR/PD-1 inhibitor combination regimens in this population, and future directions for research.

Regorafenib/Nivolumab Elicits Better Responses in pMMR/MSS CRC Without Liver Metastases

Tucatinib (Tukyska) and ONT-993 were found to be detectable in the cerebrospinal fluid (CSF) of all patients with leptomeningeal metastases from HER2-positive metastatic breast cancer who received treatment with tucatinib plus trastuzumab (Herceptin) and capecitabine (Xeloda), according to data from the phase 2 TBCRC049 trial (NCT03501979).1

This is the first documented evidence of tucatinib distribution into the CSF in this patient population, according to Debu Tripathy, MD, and this finding could have potential clinical implications for other cancer types with HER2 positivity.

Data from a pharmacokinetic analysis of the first 15 patients included in the investigator-initiated phase 2 trial showed that tucatinib and ONT-993 concentrations within the expected range and had high interindividual variability, following receipt of 300 mg of tucatinib. Moreover, CSF concentrations in cycle 1 ranged from 0.57 ng/mL to 12 ng/mL for tucatinib and from 0.28 ng/mL to 2.0 ng/mL for ONT-993. In cycle 2, these concentrations ranged from 0.94 ng/mL to 25 ng/mL for tucatinib and 0.31 ng/mL to 4.7 ng/mL for ONT-993.

Tucatinib concentrations in the CSF per time point following 300 mg of the agent were not found to significantly fluctuate with time. Moreover, these concentrations in the CSF were found to fall within a similar rang to plasma tucatinib concentrations over time. The median ratios for cycle 1 and cycle 2 were 0.60 (range, 0.17-2.0) and 0.83 (range, 0.19-2.1), respectively.

“This is a unique study, as we not only looked at the efficacy of this novel combination, which already has shown activity in [patients with] brain metastases, but we also performed pharmacokinetic studies, which are generally very difficult to do,” Tripathy said. “We wanted to see whether the drug enters the CSF, what its time course was in the blood, and what percentage of it makes it into the CSF.”

®, Tripathy, professor and chairman in the Department of Breast Medical Oncology, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, further discussed the pharmacokinetic findings of tucatinib plus trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer with leptomeningeal disease and future directions for research.

®: What was the rationale for the TBCRC049 study?

: Patients with metastatic HER2-positive breast cancer have a fairly high incidence of developing brain metastases. As many as 50% of these patients, over some course of their treatment, [will] experience [these] metastases. In some cases, this involves a particularly aggressive form of [disease] known as leptomeningeal disease; this involves the meninges and typically, one sees positive cancer cells in the CSF. This [disease] tends to have an even worse prognosis than intracranial metastases.

In the phase 2 HER2CLIMB trial [NCT02614794], which led to the approval of tucatinib, the addition of the agent to the backbone of capecitabine and trastuzumab was tested in patients with metastatic breast cancer. [The trial] even allowed [the enrollment of] patients with untreated brain metastases who did not receive local treatment but had minimal symptoms.

Overall, about half the patients in that study had brain metastases. The results did show that the addition of tucatinib improved progression-free survival [PFS] and overall survival, and it improved these outcomes particularly in those with brain metastases. [Additionally], responses were also observed in the patients who had untreated brain metastases. That study, as well as studies that had preceded it—the phase 1 study of tucatinib showed that patients with brain metastases [responded to treatment]—led to [the launch of the] TBCRC049 study to test [the regimen] in a smaller group of patients with leptomeningeal disease that is HER2 positive.

Could you expand on the design of this study?

The study design was to enroll patients with newly diagnosed leptomeningeal disease. These patients were diagnosed and confirmed, either by imaging or by CSF positivity, to have leptomeningeal involvement. Those patients underwent complete neuroimaging. They [also] underwent examination, both for standard-of-care, as well as research studies, including drug levels of their CSF. They were treated with capecitabine, tucatinib, and trastuzumab, according to the FDA-approved [label]. Patients received treatment if they did not have clinical or radiographic progression or intolerable adverse effects [to the] therapy.

What were the key takeaways from this study? Were there any that surprised you?

The study primarily looked at concentrations in the blood and in the CSF. [At the 2021 ASCO Annual Meeting] we reported [information on] the CSF concentrations. The results of the primary outcomes, which are overall response rate and time to progression, will be reported later, because patients are still being followed. 

We showed that patients did achieve [CSF] concentrations that were in the range of [0.57 ng/mL to 12 ng/mL with tucatinib], which is an active range; [tucatinib concentrations in the CSF] were maintained over time. These types of numbers really have not been described over time, with many drugs. The [CSF] concentrations range from 0.28 ng/mL to 4.7 ng/mL [for ONT-993, tucatinib’s predominate metabolite].

We also looked at the CSF to plasma ratios, and what percentage of the drug is getting through. The [median] CSF to plasma ratios in cycles 1 and 2, ranged from 0.60 ng/mL to 0.83 ng/mL, [respectively, with tucatinib and 0.66 ng/mL to 1.0 ng/mL, respectively, for ONT-993]; these [concentrations] did not really appear to fluctuate very much over time.

Do you believe that this study could be applied to other cancer types?

Yes. [Ongoing] studies [are being done] in other types of cancers that are HER2 positive. For example, gastric cancer is known to have a 20% to 25% positivity of HER2, and HER2 agents are approved [for use] in [patients with] gastric cancers. Now that we are doing next-generation sequencing on a broader number of patients, we are finding that either amplification or activating mutations can be found in HER2 in a very broad range of tumors. We are seeing [these alterations] in lung cancer, in colorectal cancer, bladder cancer. Even in [patients with] hormone receptor [HR]–positive, HER2-negative cancers, we are starting to see some who develop mutations in HER2—particularly those who have been exposed to endocrine therapy. That seems to be an escape mechanism for endocrine therapy.

We now test patients for mutations in HER2, because these are cases where the standard HER2 amplification and immunohistochemistry are negative; although it is not present in high amounts, the small amount that is present is mutated and turned on. We now know that these cases can respond to kinase inhibitors like neratinib [Nerlynx]. More recently, [it has been] shown that if [patients have] HR-positive [disease], we get better results if we combine [neratinib] with endocrine therapy like fulvestrant [Faslodex]. Most recently, [we saw even] better results if we combined [the agent] with trastuzumab.

As such, the way we approach multiple diverse tumors that are HER2 positive, either based on amplification or mutations, is changing. [Many of these] patients can stand to benefit from HER2-targeted agents. Similarly, for those who develop brain metastases from these tumors, they may benefit from the drugs that are known to cross the blood–brain barrier.

What are the next steps for research with this combination?

We want to complete this study so we can define what tucatinib-containing regimens can do for [patients with] leptomeningeal disease. Other studies [are] looking at [how these combinations can help those with] brain metastases, as well.

We are looking at different ways to treat [patients with] HER2-positive breast cancers based on mutations, using agents like antibody-drug conjugates [ADCs]. That is another area where we've seen major improvements in the treatment of HER2-positive disease. For example, the ADC known as trastuzumab deruxtecan [Enhertu], has shown dramatic results—not only in [those with] HER2-positive disease, but [also in those] with HER2-low disease who are technically HER2 negative but express it at a level of 1 to 2+, but without amplification of the gene. This is a very exciting area where we can treat HER2-low disease. Some patients with central nervous system disease have responded to this agent, even though it is an antibody-based agent; [these agents] are not thought to penetrate the blood­–brain barrier very well. Regardless, we are seeing responses [with this approach]. Several studies are now looking at this ADC, as well as others, [in the treatment of those with] HER2-positive brain metastases.

One of the big controversies in the field, because patients with advanced HER2-positive breast cancer develop brain metastases at such a high rate, is whether they should be screened automatically for brain metastases if they are not symptomatic. We do not typically obtain a brain MRI unless we see symptoms, and we do not even know if it is helpful to pick patients up early before they need treatment, because it is possible that some may do fine with systemic therapy. Once we know they have brain metastases, we monitor them, and we treat everything that shows up with stereotactic radiation, or even whole brain radiation. We may be over treating these patients.

However, on the other hand, it is very disturbing when you have a patient who has advanced breast cancer, and they present with a seizure as their first manifestation of a brain metastases. Many of them ask whether they should have had their brain [screened] and we say no, because that is not the standard of care. It really begs the question of whether we should be doing it. Some ongoing pilot studies are [exploring] going ahead and getting a brain MRI and then following the outcomes of these patients so we can better characterize this. It may very well be that these kinds of studies will lead to a change in this paradigm.

Stringer-Reasor E, O’Brien B, Topletz-Erickson A, et al. S Pharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer. 

. 2021;39(suppl 15):1044. doi:10.1200/JCO.2021.39.15_suppl.1044

Tucatinib and ONT-993 were found to be detectable in the cerebrospinal fluid of all patients with leptomeningeal metastases from HER2-positive metastatic breast cancer who received treatment with tucatinib plus trastuzumab and capecitabine. 

Tucatinib Detectable in CSF of HER2+ Metastatic Breast Cancer With Leptomeningeal Disease

The combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) is not only efficacious but has also proven to improve health-related quality of life (HRQoL) vs sunitinib (Sutent) in the first line treatment of patients with advanced renal cell carcinoma (RCC), according to Robert J. Motzer, MD, who added that the regimen represents a “standout” option for this setting.

Results from the phase 3 CLEAR trial (NCT02811861) presented during the 

 showed that the median progression-free survival (PFS) with lenvatinib/pembrolizumab was 23.9 months (95% CI, 20.8-27.7) vs 14.7 months (95% CI, 11.1-16.7) with lenvatinib and everolimus (Afinitor) and 9.2 months (95% CI, 6.0-11.0) with sunitinib.

 The stratified hazard ratio with lenvatinib/pembrolizumab vs sunitinib was 0.66 (95% CI, 0.49-0.88; 

Lenvatinib plus pembrolizumab was also found to showcase similar or improved HRQoL

 and disease-related symptom scores compared with sunitinib, and lenvatinib plus everolimus was found to have similar or worse HRQoL and symptom scores vs those observed with sunitinib.

“The quality-of-life assessments are the perception of a patient. The HRQoL assessments are filled out by the patient on how they perceive their tolerability to the regimen, and how they feel about being on the regimen,” Motzer said. “They are an extraordinarily important metric that needs to be considered seriously when interpreting results of trials, and choosing a regimen.”

Earlier data from the trial supported the submission of a biologics license application for pembrolizumab and a supplemental new drug application for lenvatinib for the frontline treatment of patients with advanced RCC. In May 2021, the 

, Motzer, medical oncologist, Kidney Cancer Section head in the Genitourinary Oncology Service, and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, discussed the efficacy and HRQoL benefits of lenvatinib/pembrolizumab in patients with advanced RCC, and projected where the regimen might fit into the treatment paradigm.

: Could you speak to the rationale of conducting the HRQoL analysis of the CLEAR trial?

: CLEAR was a 3-arm trial that compared pembrolizumab plus lenvatinib with everolimus plus lenvatinib, and [then compared] both of those arms with sunitinib in patients with clear cell RCC as a first-line therapy.

Results showed that both lenvatinib-containing arms met their primary end point, showing improvement in progression-free survival [PFS] compared with sunitinib. [However,] only the lenvatinib/pembrolizumab [arm] showed an increase in overall survival [OS]; the results for lenvatinib plus everolimus compared with sunitinib were similar.

The efficacy observed in this trial was quite striking—particularly for the lenvatinib plus pembrolizumab arm, with a very high response rate of over 70%, a 16% complete response rate, and a median PFS of approximately 24 months. The safety profile was as anticipated for both arms compared with sunitinib. The results presented during the 2021 ASCO Annual Meeting [focused on] HRQoL [outcomes].

What is your expectation for where the combination of pembrolizumab plus lenvatinib will fit into the RCC treatment landscape? How will this regimen impact subsequent treatment use?

We have been successful in the past few years, in terms of developing better regimens [for the] first-line treatment [of patients with] RCC. [This success is] largely based on the [emergence of] newer TKIs, [such as] axitinib [Inlyta], lenvatinib, cabozantinib [Cabometyx], and the use of immunotherapy. [This includes] both immunotherapy combinations, such as ipilimumab [Yervoy] and nivolumab [Opdivo], and more recently, TKI/immunotherapy combinations. Results [with these combinations] have been very striking. [These regimens] have come about in a very short time, but clearly, all these options are better than a single-agent TKI.

However, we are still sorting out whether there is a role for one vs the other, or which regimen might be best or particularly useful for a community oncologist to administer. We studied lenvatinib plus pembrolizumab at our center in a large, single-arm trial of over 140 patients and I had personal experience with that regimen. It really appeared to be an excellent regimen in terms of efficacy and manageable safety.

What I was most impressed with in the phase 3 trial is the magnitude of efficacy that we saw, coupled with manageable toxicity. It is a standout [option] for use in first-line therapy, and certainly, along with the others, it should be a choice [in this setting].

Do any subgroups appear to derive more benefit with this treatment regimen than others?

With the lenvatinib/pembrolizumab regimen, one of its best features are that it seems to be effective across the board. [We see efficacy] in patients, regardless of risk group. The favorable-risk patients did very well with [this approach], as well as the intermediate- and the poor-risk patients. Those who had sarcomatoid elements also did very well [with the doublet]. It is a very reliable regimen, [for which we know that] we are going to see a positive effect.

What were the key findings from the HRQoL analysis of the trial?

We performed several analyses. In a mixed-model analysis, we looked at longitudinal changes from baseline to [time] on study. In the other [analysis], we looked at time to deterioration, which was one end point [of the trial], as well as time until definitive deterioration, which served as another end point. [Results from the] QoL studies suggested that [these end points] were either similar or better with some scales with [regard to] lenvatinib plus pembrolizumab compared with sunitinib.

The time until definitive deterioration was the standout [finding because it was] in favor of lenvatinib plus pembrolizumab. The hallmark of that analysis is that it looks at QoL, by these scales, over time. As such, patients who continue on the trial, even those who were treated beyond progression or those with a [long] PFS, appear to, over time, have a better QoL.

In general, I would say that the scores were the same, or better, with lenvatinib plus pembrolizumab. On the other side of the coin, when we looked at lenvatinib plus everolimus, for the most part, the scores were either the same or worse [than what we saw with sunitinib]. This makes sense because the combination is comprised of 2 targeted therapies, and there is a fair amount of toxicity that has been associated with it. The results were quite fitting with what we have seen in terms of efficacy and safety for both of these regimens [in the past].

What is the take-home message from this research?

The standout from the overall trial was the efficacy gain [observed with] lenvatinib plus pembrolizumab. Those results were extremely impressive, and [demonstrate that this regimen] is a good choice for the first-line treatment [of patients with] RCC. The toxicity was certainly manageable with lenvatinib plus pembrolizumab. In my own experience, is that over time, the toxicities are quite manageable with dose reduction, as needed. Patients can stay on treatment for long periods of time. I have patients who were treated on this program for years. Those metrics are assessed by clinicians and research staff.

[However, we always need to ask ourselves,] how does the patient feel about [the regimen]? I was quite impressed that this [efficacious] combination had either similar or better scores than what we have seen with sunitinib, which has been our standard of care for more than a decade.

Motzer RJ, Porta C, Alekseev B, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). 

. 2021;39(suppl 15):4502. doi:10.1200/JCO.2021.39.15_suppl.4502

Merck and Eisai receive priority review from FDA for KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) applications for advanced renal cell carcinoma and for advanced endometrial carcinoma. News release. Merck. May 6, 2021. Accessed July 9, 2021. https://bit.ly/2PYnqtM

Robert J. Motzer, MD, discusses the efficacy and health-related quality of life benefits of lenvatinib/pembrolizumab in patients with advanced RCC, and projected where the regimen might fit into the treatment paradigm.

Ryan Scott

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