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Jun 9, 2020

Dr. S. Lindsey Davis, medical oncologist and assistant professor at the University of Colorado Cancer Center, highlights key abstracts on GI cancers that were featured at the #ASCO20 Virtual Scientific Program.



ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Lindsey Davis to the podcast today. She's a medical oncologist and assistant professor at the University of Colorado Cancer Center, where her clinical focus is gastrointestinal tract cancers.


She joins me today to discuss key abstracts in the GI field that were featured at the ASCO20 Virtual Scientific Program. Dr. Davis reports no financial conflicts of interest relating to the issues discussed in this podcast. Full disclosures relating to all daily news podcasts can be found on our episode pages. Dr. Davis, it's great to have you on the podcast today.


Dr. Lindsey Davis: Thank you, Geraldine. I am excited for the opportunity to discuss some of the key abstracts related to GI malignancies with you today. I must say the virtual scientific program was a bit of a different ASCO experience than we're accustomed to. However, the high quality of the data and presentations we expect at the annual ASCO meeting was really beautifully maintained in the virtual sessions.


ASCO Daily News: Well, what are the abstracts, Dr. Davis, that really caught your attention in the GI field this year?


Dr. Lindsey Davis: To me, the results from the KEYNOTE-177 study, abstract LBA4, which was presented at the plenary session, is really the standout in terms of GI malignancies from this ASCO meeting. KEYNOTE-177 is a randomized, open label, phase III study, comparing pembrolizumab to standard of care chemotherapy as first-line treatment for microsatellite instability-high and mismatch repair deficient metastatic colorectal cancer.


With a median follow-up of 32 months, the primary progression-free survival endpoint was met, with a median PFS in the pembrolizumab group of 16.5 months, as compared to 8.2 months in the chemotherapy group. So that's a doubling of PFS and a hazard ratio of 0.6.


In addition, and as expected, the toxicity rates were significantly lower in the pembrolizumab versus chemotherapy arms, with grade 3 or higher events occurring in only 22% of patients treated with pembrolizumab. And that's compared to 66% of patients treated with chemotherapy. This, of course, provides us the best case scenario of a treatment that is more effective, but also less toxic.


And though the MSI high population represents a relatively small proportion of our patients with metastatic colorectal cancer, this study is still clearly practice changing, making pembrolizumab the first-line treatment of choice for patients with metastatic MSI high disease.


In addition, I think this object is also important, as it provides further direction toward the biomarker-driven treatment of metastatic colorectal cancer. So I would encourage our listeners to look at abstract 4000, the DESTINY-CRC01 study.


There are a couple of additional biomarker-based trials in colorectal cancer that I wanted to touch on as well. The first is the PANDA study. This is abstract 4002. This is a randomized phase II trial, evaluating 185 patients aged 70 and above. The median age in this study was actually 77.


These patients had untreated RAS and BRAS wild-type metastatic colorectal cancer and were treated with FOLFOX plus the EGFR inhibitor panitumumab, or with 5-fluorouracil plus leucovorin and panitumumab for up to 12 cycles, followed by panitumumab maintenance. So really, the key difference between the arms here is that oxaliplatin was not included in the second arm.


Interestingly, approximately 20% of patients treated in each arm on the PANDA trial had right-sided primary tumors, which we now have data to suggest in a general population, not specific to age, would be less likely to benefit from EGFR inhibitor therapy in the first-line setting.


The primary endpoint for this study was progression-free survival in each arm, with no direct comparison made between the arms in this trial. The median PFS was 9.6 months in the FOLFOX panitumumab arm and very similar at 9.1 months in the 5-fluorouracil leucovorin panitumumab arm.


This was accompanied by a significant decrease in grade 3 and greater toxicity, including, of course, neurotoxicity-related to oxaliplatin as well as neutropenia and diarrhea. In general, these results are promising for our elderly patients with RAS and BRAF wild-type metastatic colorectal cancer and warrant further assessment in a phase III study for formal comparison of the arms.


And importantly, I'll say in clinical practice, we do encounter elderly patients who are not candidates for oxaliplatin or who are unlikely to tolerate intensive chemotherapy due to competing medical risks. So this data provides us some evidence for proceeding with 5FU and EGFR inhibitor therapy in this population.


That said, given the data regarding the decreased benefit of EGFR inhibitor therapy as part of first-line treatment for RAS wild-type right-sided colorectal cancer, I would limit the use of this strategy to elderly patients with left-sided tumors that are RAS and BRAF wild-type.


I would also like to just briefly mention a third biomarker-based abstract for metastatic colon cancer, abstract 4001, which detailed the updated survival results from the phase III BEACON CRC trial. And I wanted to mention this study because these results are the basis for the recent FDA approval of the encorafenib cetuximab doublet for the treatment of BRAF V600E mutant metastatic colorectal cancer beyond first-line.


This subset of metastatic colorectal cancer has historically been associated with a very poor prognosis with minimal response to cytotoxic chemotherapy. The BEACON CRC trial evaluated the doublet of encorafenib plus cetuximab, as well as a triplet of encorafenib plus cetuximab and MEK inhibitor binimetinib, as compared to standard chemotherapy for the treatment of BRAF V600E metastatic colorectal cancer. This was in the second or third-line setting.


The results presented at this ASCO are a post-hoc analysis of the previously published BEACON data, including an additional six months of follow-up. This data demonstrated a median overall survival of 9.3 months for both the encorafenib, cetuximab doublet, as well as the encorafenib, cetuximab, binimetinib triplet. And this was compared to only 5.9 months in the control arm with chemotherapy.


As expected, there was added toxicity in the triplet arm as compared to the doublet arm, consistent with the known toxicity of MEK inhibitor therapy. So as the FDA approval supports, this targeted regimen of encorafenib, cetuximab should be considered the standard of care for this population in the second-line setting and beyond, given improved survival outcomes as compared to standard chemotherapy and improved side effect profile as compared to the triplet combination.


ASCO Daily News:  Dr. Davis, are there any new agents that will potentially change standard of care moving forward?


Dr. Lindsey Davis: Some very promising data was presented on the compound trastuzumab deruxtecan, or T-DXd, an antibody drug conjugate composed of anti-HER2 antibody with a topoisomerase I inhibitor payload. Studies evaluating this compound were presented both for patients with HER2 expressing metastatic colorectal cancer, as well as HER2 expressing gastric cancer. We'll talk about each of these.


In the DESTINY-CRC01 study, T-DXd was evaluated in patients with HER2 expressing RAS wild-type metastatic colorectal cancer in the third line and beyond. 78 patients received T-DXd, of whom about 90% had left colon rectal cancer, which was heavily pre-treated with a median prior lines of therapy of 4, and it ranged from 2 to 11 prior lines.


The primary endpoint in this open label phase II study was objective response rate in patients with HER2 IHC 3+ or HER2 IHC 2+ with a positive ISH test. Confirmed overall response rate in this population was 45% with one complete response, which was quite impressive, given these patients are heavily pretreated with the median of four prior regiments.


Also of note is the overall response rate in patients with prior HER2 treatment, which actually represented 30% of the population. The overall response rate in this group was 44%. In terms of toxicity, grade 3 and greater treatment emergent adverse events were documented in 62% of patients, with the most common being cytopenias, neutropenia, and anemia mostly.


However, in addition, five patients developed interstitial lung disease related to treatment. This is a toxicity that has been seen in other trials of this compound. But in this study, it included two fatal grade 5 events of interstitial lung disease. So in terms of HER2 positive RAS wild-type metastatic colorectal cancer, I think T-DXd represents an encouraging option for treatment of this molecular subgroup, with notable effects in patients pretreated with HER2 targeted agents.


However, given the notable risk of treatment-related interstitial lung disease, this will need to be further vetted in a phase III trial. I think the study further highlights the importance of broad molecular testing in colorectal cancer, as though HER2 positivity is only identified in 2% to 3% of patients with this disease. Effective targets for this and other uncommon molecular alterations are being developed.


Similarly, promising results were presented in the DESTINY-Gastric01 study. This is abstract 4513, an open label, randomized, phase II trial evaluating T-DXd and HER2 expressing advanced gastric or GE junction adenocarcinoma. Patients had centrally confirmed HER2 positive disease, according to the same definition as the CRC01 study with progression on at least two prior lines of therapy.


Patients were randomized 2 to 1 to T-DXd or physician's choice of chemotherapy, which included irinotecan or paclitaxel. All patients in the trial had received prior HER2 therapy, of course, as this is standard of care for HER2 positive gastric and esophageal cancers. The primary endpoint on the study was overall response rate. And in the 187 patients treated, the overall response was 51% in patients treated with T-DXd, as compared to only 14% in those treated with chemotherapy.


With central confirmation of response, this overall response rate was a bit lower at 43% in the T-DXd arm, versus 13% in the control group. In addition, overall survival was prolonged in the T-DXd arm at 12.5 months versus 8.4 months in the chemotherapy group with a hazard ratio of 0.59.


Grade 3 and greater adverse events occurred in 86% of patients treated with T-DXd, as compared to 57% treated with standard chemotherapy, and were similar to those documented in the CRC01 study, including treatment-related interstitial lung disease documented in 12 patients.


Though there were no grade 5 events of ILD documented in this Gastric01 study, one grade 5 occurrence of pneumonia was noted in the treatment arm. These results are important, as they suggest a potential effect of a HER2 targeting therapy beyond trastuzumab, the only HER2 targeted therapy shown to be effective for the treatment of HER2-positive gastroesophageal cancers to date.


However, similar to the CRC01 study, the pulmonary toxicity documented in this trial remains a concern. We will look forward to a phase III study to further expand upon these findings.


ASCO Daily News: Are there any additional biomarker-focused studies of interest presented for GI malignancies outside of metastatic colon cancer?


Dr. Lindsey Davis: Yes, there are two additional studies focused on HER2-positive gastroesophageal cancers that were presented at this meeting. Here, they're evaluating the addition of HER2 targeted agents in the curative setting. The PETRARCA study, which is abstract 4502, evaluated perioperative FLOT, or FLOT with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab plus pertuzumab in patients with resectable HER2-positive gastric or GE junction adenocarcinoma.


The primary endpoint for this study was pathologic complete response rate, which was significantly improved in the trastuzumab pertuzumab arm at 35% versus only 12% in the FLOT alone arm. There's also suggestion of benefit on PFS and OS in this study, though it was not powered for formal analysis.


Important to note is the added toxicity of trastuzumab pertuzumab to the FLOT regimen, which is already associated with a significant burden of adverse effects. Grade 3 or greater adverse events were documented in 85% of patients in the trastuzumab pertuzumab arm versus 75% of patients in the FLOT alone arm. And diarrhea and leukopenia were the most notable in the arm that added trastuzumab and pertuzumab therapy.


It should be noted that this trial was originally designed as a phase II/III study, but it was halted at phase II due to the emerging results from the JACOB trial. The JACOB trial was a phase III study which failed to meet its primary endpoint of improved overall survival for the addition of pertuzumab to trastuzumab and chemotherapy in the metastatic setting.


Despite this, I believe these phase II results from the PETRARCA study suggest there is rationale for proceeding with further assessment of this combination in the phase III setting. In contrast to these promising results for the addition of HER2 targeted therapy to standard chemotherapy and HER2-positive gastric and GE junction adenocarcinoma, the RTOG 1010 study, abstract 4500, did not meet its primary endpoint.


This study evaluated the addition of trastuzumab to tri-modality therapy with carboplatin, paclitaxel chemoradiation, followed by surgery in 571 patients with HER2 overexpressing esophageal or GE junction adenocarcinoma. Patients receiving carboplatin paclitaxel chemoradiation followed by surgery had a median disease free survival of 14.2 months as compared to 19.6 months in the trastuzumab arm.


However, this did not meet the prespecified primary endpoint of increasing disease free survival from 15 to 25 months. These results further confirm that defining the role of anti-HER2 therapies for the treatment of HER2-positive gastroesophageal cancers in the curative setting is complex, though deserving of continued attention and investigation.


ASCO Daily News: Dr. Davis, are there any updates on immuno-oncology therapies for the treatment of GI malignancies beyond colorectal cancer?


Dr. Lindsey Davis: Yes, updated results from the randomized phase III KEYNOTE-061 study were presented at this virtual meeting in abstract 4503. The KEYNOTE-061 study is a randomized phase III trial evaluating pembrolizumab versus paclitaxel as a second-line therapy for advanced gastric or GE junction adenocarcinoma in patients with PDL1 combined positive scores greater than or equal to 1.


In the previously presented primary analysis of this study, the primary overall survival endpoint was not met. However, duration of response was significantly longer at 18 months in the pembrolizumab arm versus 5 months in the paclitaxel arm. Presented in this abstract is data from an additional two years of follow-up, as well as further assessment according to additional combined positive scores of greater than or equal to 5 and greater than or equal to 10.


The survival benefit of pembrolizumab over paclitaxel seemed to increase with increasing combined positive score. In the general cohort of CPS greater than or equal to 1, patients treated with pembrolizumab had an overall survival of 9.1 months versus 8.3 months with paclitaxel. This is a hazard ratio of 0.81.


This is compared to an overall survival of 10.4 months with pembrolizumab versus 8.3 months with paclitaxel, a hazard ratio of 0.72 in the CPS 5 or greater population. And finally, in patients with CPS 10 or greater, the overall survival in the pembrolizumab versus paclitaxel arms was 10.4 versus 8.0 months, with the hazard ratio of 0.69.


In addition, the duration of response numerically increased with increasing CPS score, from 19 months in the CPS 1 group to 33 months in the CPS 5 group. And the duration of response has actually not been reached in the CPS 10 group.


I think the conclusion from these updated results is that a proportion of patients have long-term survival benefit from second-line pembrolizumab, which might be somewhat improved with higher CPS. This calls into question a need to adjust our selection criteria for pembrolizumab in patients with gastroesophageal cancers.


In summary, I think the underlying theme of this group of abstracts focused on GI malignancies is that we are continuing to move toward personalized cancer care for the treatment of gastrointestinal tract cancers. These studies also highlight the importance of broad molecular testing for GI cancers, as well as the importance of involvement of our patients with targetable alterations in clinical trials in order to help us continue to improve the individualized care we provide our patients.


ASCO Daily News: Well, thank you, Dr. Davis, for sharing your valuable insights with us today on these promising developments in the GI field.


Dr. Lindsey Davis: Thank you, Geraldine. It was my pleasure.


ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please rate and review us on Apple Podcasts.


Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.


COI Disclosure: 

Dr. Lindsay Davis  - No Relationships to Disclose