CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 23, 2023
Expiration: March 22, 2024
Christopher H. Lieu, MD:
We begin our discussion with an exciting study presented at ASCO GI 2023 that assessed a targeted therapy for advanced gastric/GEJ cancer. Zolbetuximab is a monoclonal antibody that targets CLDN18.2.1 CLDN18.2 is a tight‑junction protein normally expressed in gastric mucosa cells, but if those cells become malignant, then CLDN18.2 may become exposed on the surface of those cells, making CLDN18.2 a promising target. In a prior randomized phase II study, FAST, zolbetuximab in combination with chemotherapy improved both PFS and OS vs chemotherapy alone for patients with advanced CLDN18.2 positive gastric or GEJ adenocarcinoma.2
SPOTLIGHT was a randomized, double-blind phase III trial in which 565 patients with previously untreated, unresectable, metastatic gastric or GEJ adenocarcinoma that was HER2 negative and CLDN18.2 positive were treated with zolbetuximab plus mFOLFOX6 vs mFOLFOX6 alone (NCT03504397).3 CLDN18.2 positivity was defined by moderate to strong staining in 75% or more tumor cells. The primary endpoint was PFS, and the secondary endpoint was OS.
Christopher H. Lieu, MD:
Approximately 40% of the patients who were screened for this study and had assessable disease had CLDN18.2-positive cancer, which is an important fact to be cognizant of when screening patients with this disease.3 This is a significant proportion of our patient population.
It is also important to note that most patients had gastric cancer, with approximately 25% having GEJ cancer.
Christopher H. Lieu, MD:
Primary endpoint results demonstrated that the combination of zolbetuximab plus FOLFOX was associated with a median PFS of 10.61 months, which was a significant improvement compared with the median PFS of 8.67 months associated with FOLFOX alone (HR: 0.751; P = .0066).3
Zolbetuximab plus FOLFOX was also associated with a median OS of 18.23 months vs a median OS of 15.54 months with FOLFOX alone (HR: 0.75; P = .0053).
Christopher H. Lieu, MD:
Zolbetuximab plus FOLFOX was associated with a similar overall response rate (ORR: 60.7%) and median duration of response (DoR: 8.51 months) compared with FOLFOX alone (ORR: 62.1% and DoR: 8.11 months).3
Christopher H. Lieu, MD:
The combination of zolbetuximab plus FOLFOX was associated with significant increases in nausea and vomiting compared with FOLFOX alone.3 Nausea and vomiting are known to be on‑target effects associated with zolbetuximab. Nausea and vomiting occurred predominantly in the first 2 cycles and then, during subsequent cycles, mirrored what was observed in the FOLFOX alone treatment group.
Christopher H. Lieu, MD:
Overall, the SPOTLIGHT trial demonstrated that first-line zolbetuximab plus FOLFOX significantly improved PFS and OS compared with FOLFOX alone for patients with advanced gastric or GEJ adenocarcinoma that was HER2-negative and CLDN18.2-positive gastric or GEJ adenocarcinoma.3 It is important to note that the median OS observed with zolbetuximab plus FOLFOX is one of the longest seen in phase III studies investigating this disease. The study also demonstrated that the safety profile associated with the zolbetuximab plus FOLFOX combination is consistent with what was seen previously with zolbetuximab—specifically, nausea and vomiting were the most frequently observed on‑target effects.
This is a practice‑changing trial. Based on these data, we can expect to see the FDA grant zolbetuximab approval in combination with chemotherapy for treating patients with previously untreated, unresectable, metastatic gastric or GEJ adenocarcinoma that is HER2 negative and CLDN18.2 positive.
This trial significantly changes the landscape of this disease in that there is now a new targeted therapy available for these patients. Before this, the only available targeted therapy for patients with advanced gastroesophageal cancers was anti‑HER2 therapy. In the future, I think the treatment landscape will be the following: Patients who have HER2-positive cancer will continue to receive chemotherapy in combination with trastuzumab and immune checkpoint therapy; patients who have a high combined positive score (CPS) score will receive FOLFOX chemotherapy in combination with immunotherapy; and patients with low CPS scores and cancer that is HER2 negative and CLDN18.2 positive may receive a combination of zolbetuximab plus FOLFOX.
We do not currently know the impact of adding immunotherapy to a regimen of zolbetuximab plus chemotherapy. Studies examining this are ongoing.
Finally, it is important to note that CLDN18.2 is currently not a biomarker that is necessarily assessed as a standard of care. This will need to change in the near future, and this biomarker needs to be considered in all newly diagnosed patients with metastatic gastric cancer.
Rachna Shroff, MD, MS:
I completely agree with you. I think that the results from this trial are clearly practice changing. Since several anti-CLDN agents are in development, the definition of CLDN positivity is an important question. Your point about the percent of patients who were CLDN18.2 positive in SPOTLIGHT, such that there was a moderate to strong signal in at least 75% of tumor cells, is an important one. There are other anti‑CLDN18.2 agents for which trials have different cutoffs for defining CLDN18.2 positivity, and as more data become available, it will be interesting to see how “CLDN positivity” is defined.
I agree that another big question that remains includes how zolbetuximab will be integrated into the current armamentarium, including checkpoint inhibitors, that is available for treating patients with HER2-negative cancer.
Patients with this type of cancer often do not have a lot of time to wait before initiating therapy. Therefore, in the reality of the clinical practice, determining how to quickly acquire all of the necessary biomarker data and then integrate these data into a treatment plan will be important.
Christopher H. Lieu, MD:
I think that your point about testing for these biomarkers early and as quickly as possible is well said. It is easy to see the buckets this is going to create in the untreated or frontline setting. We will be looking at microsatellite instability, HER2 status, CPS scores, and, because of the development of anti-CLDN agents, CLDN status. We will require a lot from our biopsy specimens, and efficiently obtaining information about all these biomarkers will become very important in the future.
Christopher H. Lieu, MD:
Let us switch gears now to look at another important study presented at ASCO GI 2023, this one focused on later-line treatment for mCRC. Trifluridine plus tipiracil (TAS‑102) is approved by the FDA for mCRC that has been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti–vascular endothelial growth factor (anti-VEGF) biologic therapy, and if RAS wild-type mCRC, an anti–epidermal growth factor receptor therapy.4 This approval was based on data from the phase III RECOURSE trial comparing TAS‑102 with the placebo. Several phase II trials have suggested that adding bevacizumab to TAS-102 prolongs OS and PFS in refractory mCRC.5
The phase III SUNLIGHT trial was designed to confirm the efficacy of TAS‑102 with or without bevacizumab in this patient population. Patients with refractory mCRC (2 prior treatment regimens with disease progression or intolerance; N = 492) were randomized to TAS-102 plus bevacizumab or TAS-102 alone.6 The primary endpoint was OS.
Christopher H. Lieu, MD:
This trial demonstrated that the combination of TAS-102 plus bevacizumab was associated with a median OS of 10.8 months, a significant improvement compared with TAS-102 alone (median OS: 7.5 months; HR: 0.61; P <.001.6
Christopher H. Lieu, MD:
SUNLIGHT also demonstrated that the combination of TAS-102 plus bevacizumab was associated with a significantly improved median PFS of 5.6 months compared with the median PFS of 2.4 months observed with TAS-102 alone (HR: 0.44; P <.001).6
Christopher H. Lieu, MD:
With regard to ORRs, it is well known that agents typically used for treating refractory mCRC (eg, TAS-102 and regorafenib) have a very low response rate. The SUNLIGHT trial demonstrated that among patients receiving a combination of TAS-102 plus bevacizumab, an ORR of approximately 6% was observed, an improvement compared with approximately 1% ORR among patients receiving TAS‑102 alone (P = .004).6
In addition, the combination of TAS-102 plus bevacizumab was associated with a significantly higher disease control rate (76.6%) compared with TAS‑102 alone (47%; P <.001).
Christopher H. Lieu, MD:
The OS and PFS data were supported by data demonstrating an improvement in the time to deterioration in the global health status. The time to global health score deterioration was 8.5 months with the combination of TAS-102 plus bevacizumab compared with 4.7 months with TAS-102 alone (HR: 0.50; P <.001).6
Christopher H. Lieu, MD:
The combination of TAS-102 plus bevacizumab was also associated with improvements in the time to worsening performance status. Among patients receiving TAS-102 plus bevacizumab, the time to worsening performance status was 9.3 months compared with 6.3 months among those receiving TAS‑102 alone (HR: 0.54; P <.001).6
Christopher H. Lieu, MD:
Treatment‑related adverse events (TRAEs) were similar in both treatment groups, with expected bevacizumab-associated AEs being observed in TAS-102 plus bevacizumab group. These included hypertension, which occurred in 10% of patients receiving the TAS-102 plus bevacizumab combination and 2% of patients receiving TAS-102 alone.6
Christopher H. Lieu, MD:
In the phase III SUNLIGHT trial, adding bevacizumab to third-line TAS-102 significantly improved OS, PFS, and disease control in refractory mCRC. The investigators noted that this was the first trial in the refractory mCRC setting to demonstrate an improvement in OS when the comparator was an active control as opposed to the placebo. Also, this regimen appears to be safe.6
I agree with the investigators that the combination of TAS-102 plus bevacizumab represents a new standard of care for patients with refractory mCRC. I think that this regimen, based on the phase II data, has been used frequently in the United States before the data from SUNLIGHT being presented. In fact, only 3% of the patients enrolled on the study came from North America. I am convinced that this regimen represents the new standard of care and preferred treatment option in the third‑line setting for patients eligible to receive bevacizumab.
Rachna Shroff, MD, MS:
I completely agree, and I have already seen this regimen being implemented in the United States. Clearly this study has changed the paradigm. One question that I have is regarding the diminishing returns of receiving bevacizumab therapy in the third-line setting. What I am referring to is illustrated by approximately 75% of patients in both treatment groups in the trial who had previously received bevacizumab therapy. In clinical practice, most patients, probably more than 75% in the United States, will have received bevacizumab and multiple lines of therapy before receiving the TAS-102 plus bevacizumab regimen as a third-line therapy. What are your thoughts on the diminishing returns of receiving bevacizumab in the context of this third-line regimen?
Christopher H. Lieu, MD:
I think that is a wonderful point. The data show that approximately 72% of the patient population had prior bevacizumab exposure. This begs the question of the effect that receiving bevacizumab for the first time had on the remaining 28% of patients. The trial results may be somewhat attenuated because the majority of the population had previously received bevacizumab, which reflects treatment practices in the United States. I am certain that a subgroup analysis based on prior bevacizumab exposure may be available in the near future.
Before we move on, let’s return to a question we asked earlier in the program.
Rachna Shroff, MD, MS:
We now look at an important study in pancreatic cancer that was presented at ASCO GI 2023. Frontline therapies for metastatic pancreatic cancer include leucovorin/5-FU/irinotecan/oxaliplatin (FOLFIRINOX) and gemcitabine plus nab‑paclitaxel, which have not been compared in a randomized, phase III trial.7 Liposomal irinotecan is used in combination with 5‑FU and is approved in patients with metastatic pancreatic cancer after gemcitabine‑based therapy, that is, as a second-line therapy.7,8
The NAPOLI 3 trial was a randomized, open‑label phase III study in which 770 patients with previously untreated metastatic pancreatic adenocarcinoma were treated with NALIRIFOX or gemcitabine plus nab-paclitaxel.9 Data from a phase I/II trial examining NALIRIFOX as a first-line therapy for treating metastatic pancreatic cancer suggested that it may be efficacious for this population.10
The primary endpoint of NAPOLI 3 was OS. Key secondary endpoints included PFS and ORR by investigator using RECIST.
Rachna Shroff, MD, MS:
Similar to some of the other trials we have mentioned, most patients in this global trial, approximately two thirds, were from outside North America.9
Of note, only approximately 40% of patients had pancreatic head tumors. This is an important point because FOLFIRINOX is commonly associated with hematologic toxicities, and pancreatic head tumors have a potential for biliary obstruction.
Rachna Shroff, MD, MS:
Results for the primary endpoint demonstrated that NALIRIFOX significantly improved median OS to 11.1 months compared with 9.2 months observed with gemcitabine plus nab-paclitaxel (HR: 0.83; P = .04).9 All of the prespecified subgroup analyses for OS favored NALIRIFOX.
Rachna Shroff, MD, MS:
NALIRIFOX was also associated with an improved median PFS compared with gemcitabine plus nab-paclitaxel (7.4 vs 5.6 months; HR: 0.69).9
Rachna Shroff, MD, MS:
The ORR was 41.8% among patients receiving NALIRIFOX and 36.2% among patients receiving gemcitabine plus nab‑paclitaxel.9
In both treatment groups, approximately 50% of patients required subsequent lines of antineoplastic therapy. This is an important consideration when thinking through OS.
Rachna Shroff, MD, MS:
Rates were of grade ≥3. TEAEs were relatively similar between the treatment groups (87% among patients receiving NALIRIFOX and 86% among those receiving gemcitabine + nab‑paclitaxel).9 The frequency of serious TEAEs was also relatively similar between the treatment groups.
Rachna Shroff, MD, MS:
With regard specifically to hematologic toxicities, the frequencies of grade 3/4 neutropenia and febrile neutropenia were numerically higher in the gemcitabine plus nab‑paclitaxel compared with the NALIRIFOX group. Grade 3/4 neutropenia occurred in 24.5% of patients receiving gemcitabine plus nab-paclitaxel compared with 14.1% of patients receiving NALIRIFOX.9
NALIRIFOX was associated with higher incidences of grade 3/4 diarrhea, nausea, vomiting, and hypokalemia compared with gemcitabine plus nab-paclitaxel.
Of importance, the incidences of peripheral neuropathy and sensory neuropathy were not dramatically different between the treatment groups.
Rachna Shroff, MD, MS:
The investigators concluded that the NAPOLI 3 trial demonstrated that NALIRIFOX provided a significant, clinically meaningful improvements in median OS and PFS compared with the combination of gemcitabine plus nab‑paclitaxel for patients with previously untreated metastatic pancreatic adenocarcinoma.9 Of importance, the safety profile of NALIRIFOX was manageable, and there no new safety signals emerged. Overall, the trial supports the use of NALIRIFOX as a new reference regimen for the frontline treatment of metastatic pancreatic cancer.
There are several important takeaways from this trial. First of all, I do not necessarily think that the trial results were surprising. We know that FOLFIRINOX is a very active first-line treatment regimen. However, because no randomized phase III trials compare frontline FOLFIRINOX with gemcitabine plus nab-paclitaxel, we do not know the relative efficacy of these regimens. The NAPOLI 3 trial was the first time that any sort of 5‑FU–based regimen had been compared head to head with gemcitabine plus nab‑paclitaxel. Although NALIRIFOX definitely improved median OS relative to gemcitabine plus nab-paclitaxel, and it also absolutely creates a new benchmark for frontline therapy, it should be noted that the median OS of 11.1 months reported in NAPOLI 3 is very similar to that observed in trials of FOLFIRINOX, with the caveat that cross-trial comparisons can be problematic.
Although NALIRIFOX was relatively well tolerated, the burning question is whether this regimen will supplant FOLFIRINOX. Key questions also arose during the question and answer portion of the oral abstract session at ASCO GI 2023 related to financial toxicity and the cost of liposomal irinotecan vs FOLFIRINOX.
Overall, I think although NALIRIFOX provides an additional option for treating newly diagnosed metastatic pancreatic cancer, it will not replace FOLFIRINOX in the treatment armamentarium.
Christopher H. Lieu, MD:
I agree with you that NALIRIFOX provides an additional option; however, I also think that FOLFIRINOX will still be used extensively, despite the data supporting the use of NALIRIFOX.
I do think the data from this trial represent some of the best data we have seen and definitely show that NALIRIFOX is an alternative option to FOLFIRINOX. I also agree that it is good to finally see a 5‑FU–based regimen compared with something other than just single‑agent gemcitabine, which has been the comparator in other key phase III studies of frontline therapy for metastatic pancreatic cancer. It would be very interesting to see a trial assessing how FOLFIRINOX compares with NALIRIFOX in this setting; however, I doubt we will ever get an answer to this.
Another point to mention is that historically we have considered gemcitabine plus nab‑paclitaxel to be better tolerated than FOLFIRINOX or NALIRIFOX. However, given that the TRAE profiles were fairly similar between the treatment groups, I think the data from this trial dispute that notion to some extent.
Finally, I am intrigued by the response rate observed in the NAPOLI 3 trial, mainly because these data could be extrapolated to the neoadjuvant setting. Response rates over 40%—such as the 41.8% ORR observed with NALIRIFOX represent some of the best rates we have seen.
Rachna Shroff, MD, MS:
I completely agree with that. I also agree with your point about historical misconceptions about the tolerability of the gemcitabine and nab‑paclitaxel combination. I think that the data from the NAPOLI 3 trial silence the argument that gemcitabine and nab‑paclitaxel are supposedly “easier” than FOLFIRINOX or NALIRIFOX.
Rachna Shroff, MD, MS:
Gemcitabine and cisplatin‑based regimens have formed the standard of care in advanced biliary tract cancers (BTCs) for over a decade.11 Data that were presented at ASCO GI 2022 from the phase III TOPAZ‑1 study established gemcitabine plus cisplatin plus durvalumab as a new standard of care.12 However, even with the addition of immunotherapy to gemcitabine plus cisplatin, the median OS for advanced BTC is still only approximately 12 months.
In a single‑arm phase II trial of gemcitabine/cisplatin/nab‑paclitaxel (GAP), the triplet regimen showed promising efficacy, with a median OS of 19.2 months in 60 patients.13 Following this trial, the outstanding question was how the GAP triplet regimen would compare with gemcitabine plus cisplatin alone.
This question was addressed by the phase III SWOG 1815 trial, in which patients with newly diagnosed, untreated advanced cholangiocarcinoma and gallbladder cancer were randomized to GAP or gemcitabine plus cisplatin.14 SWOG 1815 was the first randomized phase III trial in advanced biliary tract cancers in the United States. The primary endpoint was OS, and the study was powered to 90% (target HR: 0.7), which resulted in a target of 441 planned patients.
Rachna Shroff, MD, MS:
Among enrolled patients, approximately two thirds had intrahepatic cholangiocarcinomas. Among the remaining one third of patients, equal numbers had gallbladder cancer or extrahepatic cholangiocarcinomas.14 This was somewhat different from the patient populations in previous trials establishing frontline standards of care for advanced BTCs; for example, in the TOPAZ-1 study, the population comprised a slightly lower percentage of patients with intrahepatic cholangiocarcinomas, closer to the 55% range.12
Approximately three quarters of the enrolled patients had metastatic cancer at the time of enrollment vs locally advanced cancer.14
Rachna Shroff, MD, MS:
Results for the primary endpoint demonstrated that, although not statistically significant, the GAP regimen was associated with a numerically improved median OS of 14 months vs a median OS of 12.7 months with gemcitabine plus cisplatin (P = .65).14
The GAP regimen was associated with a median PFS of 8.2 months, which was a numeric but not statistically significant improvement vs gemcitabine plus cisplatin of 6.4 months (P = .43).
The results of the disease site subgroup analysis provided some potentially interesting signals. Although there were no statistically significant survival differences between the GAP group and the gemcitabine plus cisplatin group, there were trends toward improved survival with the GAP triplet regimen among patients with gallbladder cancer compared with gemcitabine plus cisplatin (median OS: 17 vs 9.3 months; median PFS: 9.6 vs 5.6 months).
It is important to point out that the number of patients in this subgroup analysis was small because most of the patients in the trial, approximately two thirds, had intrahepatic cholangiocarcinomas and, of the remaining one third, only approximately one half of those had gallbladder cancer.
Similar trends were observed in the disease stage subgroup analysis. Among patients with locally advanced cancer, those who received GAP had a median OS of 19.2 months compared with a median OS of 13.7 months among patients who received gemcitabine plus cisplatin.
Rachna Shroff, MD, MS:
The ORR for the entire population was not significantly different between the treatment groups (31% among patients receiving GAP and 22% among those receiving gemcitabine + cisplatin).14
Disease control rates were 77% among patients receiving the GAP triplet regimen and 69% among those receiving gemcitabine plus cisplatin.
Rachna Shroff, MD, MS:
About ORRs in the subgroup analyses, among patients with gallbladder cancer, GAP was associated with a numerically higher 44% ORR compared with a 22% ORR with gemcitabine plus cisplatin. Among patients with extrahepatic cholangiocarcinomas, the GAP triplet regimen was associated with a 34% ORR vs a 21% ORR with gemcitabine plus cisplatin.14
Rachna Shroff, MD, MS:
As for the safety profile, it is not surprising that the GAP regimen was associated with a significantly higher incidence of grade ≥3 AEs compared with the gemcitabine plus cisplatin regimen; however, there was not a significantly higher discontinuation rate among patients receiving GAP compared with patients receiving gemcitabine plus cisplatin.14
Rachna Shroff, MD, MS:
The investigators concluded that the addition of nab‑paclitaxel to gemcitabine and cisplatin did not improve OS as frontline therapy for patients with advanced BTC. Although the GAP regimen was associated with a numerically higher ORR compared with the gemcitabine plus cisplatin regimen, the difference was not significant.14
The exploratory subgroup analysis data suggesting the GAP regimen was associated with a higher ORR and OS in patients who had gallbladder cancer or locally advanced cancer are interesting and may warrant further evaluation. There are also ongoing biomarker analyses that may identify additional subsets of patients who might benefit from the GAP regimen. This has immense potential, and we should be carefully considering how to most effectively collect bispecimens to maximize the information we can obtain. This includes examining not just tissue but also blood and, with regard to analysis techniques, thinking beyond just the basic next-generation sequencing.
As the lead author of this study, I obviously agree with the conclusion that GAP triplet regimen is not appropriate for all patients. Providers who have used this triplet regimen for a longer period of time are aware of the associated hematologic toxicities and have developed ways to mitigate some of these, such as administering the regimen every 14 days, as we do in my practice.
Based on the observed response rates on the order of 30% (higher in some subgroups), I think several areas merit further exploration, including the potential use of the GAP regimen in the perioperative/neoadjuvant setting. The NEO‑GAP trial, which was a single-arm prospective phase II trial examining the use of GAP in patients with resectable high-risk intrahepatic cholangiocarcinomas, demonstrated the feasibility of administering the GAP regimen to these patients.15
Christopher H. Lieu, MD:
I agree. First of all, I think it is exciting to see that this trial could be designed and conducted fairly quickly because it is extraordinarily difficult to design and complete these studies.
Data from the adjuvant setting and this trial support that more chemotherapy is not always better when treating biliary cancers. This is a biologically complex and heterogeneous disease, as demonstrated by data from this trial showing different response rates in gallbladder vs biliary cancers. However, we treat them all the same, even though it is clear that subgroups of this disease may respond differently to different treatments.
I agree with your point about extrapolating these trial data into the perioperative space. To downstage a patient so that they are surgically resectable requires the highest response rates possible. As you said, the GAP regimen is associated with some of the highest response rates we have ever encountered with this disease, and using this regimen in the perioperative space may definitely be something to consider and implement in the future.
Additional studies of interest in gastroesophageal cancers included the following:
Additional studies of interest in colorectal cancers included the following:
Christopher H. Lieu, MD:
I would like to conclude by discussing an FDA approval that occurred during ASCO GI 2023. Tucatinib, a selective tyrosine kinase inhibitor of HER2, received accelerated FDA approval in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal CRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.20 This regimen represents a new treatment option for a small but critically important subset of patients with mCRC.
A small but important subset of patients with mCRC, approximately 3%, have HER2-positive cancer, meaning that HER2 is amplified or overexpressed. The landscape for HER2‑positive mCRC has changed dramatically in the past few years. The NCCN guidelines have incorporated multiple trastuzumab combination regimens, as well as trastuzumab deruxtecan, which is an antibody–drug conjugate targeted against HER2.7
The approval of tucatinib was based on data from the open-label, randomized phase II MOUNTAINEER trial, which examined the combination of tucatinib plus trastuzumab in patients with HER2-positive, RAS wild-type mCRC that progressed on ≥2 prior treatment lines including fluoropyrimidines, oxaliplatin, irinotecan, and a VEGF antibody. No prior HER2-targeted treatment was permitted.21
The MOUNTAINEER trial population included 84 heavily pretreated patients who received a combination of tucatinib plus trastuzumab. The ORR was 38%, with a disease control rate of 60%.
Among the 38% of patients who had confirmed objective responses, the median DoR was 12.4 months. The tucatinib plus trastuzumab combination was also associated with a median PFS of 8.2 months and a median OS of 24 months.
The most common TRAE associated with the combination of tucatinib plus trastuzumab included diarrhea, fatigue, and nausea. The most common grade 3 toxicity was hypertension, which only occurred in 7% patients. Overall, it appears that the combination was well tolerated.
I think that with the accelerated approval of the combination of tucatinib plus trastuzumab, we will have another option, in addition to the continued use of trastuzumab deruxtecan, for patients with HER2-positive disease who have progressed on previous therapies.
Rachna Shroff, MD, MS:
With all of the HER2-targeted treatment options currently available, I think that we now have better options for patients who have HER2-positive mCRC than we have had in the past. As we learn more about the clinical applications of the various treatment options, it will be important to determine optimal treatment sequencing, where each treatment fits into the overall treatment of mCRC, and when and how patients will tolerate the various options.
Christopher H. Lieu, MD:
The sequencing issue is going to be huge because after frontline therapy, chemotherapy is the current second-line strategy. However, I think that practitioners are going to start opting for targeted therapies, namely the tucatinib plus trastuzumab combination, in the second-line setting.
Trastuzumab deruxtecan is available, although not currently approved by the FDA for colorectal cancer. However, providers may hold that in reserve as a subsequent option after patients progress on a second-line anti-HER2 therapy such as tucatinib plus trastuzumab. This will be part of ongoing discussions as new agents become available for the patient population with HER2-positive mCRC.
Let’s now return to a few questions from earlier in the activity.
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