Conor Killmurray

Utilizing a network meta-analysis to compare multiple studies looking at atezolizumab (Tecentriq) and bevacizumab (Avastin) compared to Lenvatinib (Lenvima) researchers did not find direct evidence, but their exploratory analysis suggests that the benefit of the combination therapy is not statistically significant for patients with unresectable hepatocellular carcinoma (HCC), according to results presented at the 2021 American Society of Clinical Oncology (ASCO) annual meeting.

Looking at the phase 3 IMbrave 150 trial (NCT03434379), phase 3 REFLECT trial (NCT01761266), phase 3 SHARP trial (NCT00105443), and the Asia-Pacific arm of the SHARP trial, researchers found that the estimated median hazard ratio (HR) for the combination of atezolizumab and bevacizumab compared to lenvatinib was .81 (95% CrI: 0.61, 1.08; posterior 

 = .078) for overall survival (OS). When looking at progression-free survival (PFS), the median HR was 0.99 (95%CrI: 0.76, 1.28; posterior 

 = .454) between atezolizumab and bevacizumab compared to lenvatinib.

According to the researchers, this was similar to results observed in another analysis that showed an OS HR of .63 (95% CI: 0.32-1.25) and PFS HR of .91 (95% CI: 0.23-3.65) when comparing atezolizumab and bevacizumab and lenvatinib in this patient population.

The results from the network meta-analysis presented at ASCO fell within the Bayesian range of equivalence, according to researchers. This range was defined as the upper limits of credible intervals greater than or equal to 1 for both OS and PFS results. Moreover, the results among all observed studies were subject to a high degree of uncertainty when compared in the network meta-analysis.

The network meta-analysis was based on a de novo systematic literature review that identified evidence for licensed therapies in the first-line setting of treatment for patients with unresectable HCC. Data from the IMbrave 150 trial was supplemented from clinical cut-off data from August 31st, 2020, while HRs for OS and PFS was taken from a multivariable analysis that adjusted imbalances in baseline prognostic covariates from the REFLECT trial. Model selection was based on deviance information criterion and all analyses were conducted in the Bayesian generalized linear model framework.

The IMbrave150 trial ultimately resulted in improved OS and PFS for patients with unresectable HCC on atezolizumab and bevacizumab compared to those patients on sorafenib (Nexavar).

 Researchers saw an OS of 12 months in 67.2% (95% CI: 61.3-73.1) of patients on the combination arm compared to 54.6% (95% CI: 45.2-64.0) on sorafenib. Median PFS was also higher in the combination arm at 6.8 months (95% CI: 5.7-8.3) compared to 4.3 months (95% CI: 4.0-5.6) in the monotherapy arm. The HR for disease progression or death in both groups was .59 (95% CI: 0.47-0.76; 

In the REFLECT trial, researchers looked at lenvatinib compared to sorafenib in patients with unresectable HCC and found a median OS of 17.6 months for lenvatinib versus 17.8 months for sorafenib (HR .90; 95% CI: 0.62-1.29) among 954 patients in a global trial. Moreover, Lenvatinib showed a statistically significant improvement over sorafenib with 7.2 months vs. 4.6 months PFS, respectively.

Previously, sorafenib was the first-line treatment for patients with unresectable HCC but these recent results have shown meaningful results for lenvtainib and the combination of atezolizumab and bevacizumab as a first-line option. However, these data presented at ASCO did not indicate which treatment had a statistically significant advantage over the other, thus, researchers consider this an exploratory analysis. This analysis was done in the absence of a head-to-head analysis of the combination and monotherapy and wanted to compare the efficacy of first line treatments for patients with unresectable HCC.

1. Trueman D, Liu Y, Lucero M, et al. The comparative efficacy of atezolizumab and bevacizumab versus lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC). Abstract presented at: 2021 American Society of Clinical Oncology Annual Meeting.; June 8-11, 2021; virtual. e16151. doi: 10.1200/JCO.2021.39.15_suppl.e16151

2. Vogel A, Saborowski A. Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. 

. 2020 Jan;82:101946. doi: 10.1016/j.ctrv.2019.101946

3. Finn RS, Qin S, Ikeda M, et al. IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. 

. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745

4. Yamashita T, Kudo M, Ikeda K, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. 

. 2020 Jan;55(1):113-122. doi: 10.1007/s00535-019-01642-1

Articles

A network meta-analysis looking at 4 studies that assessed atezolizumab/bevacizumab compared to lenvatinib showed there was not a statistically significant improvement for patients with unresectable hepatocellular carcinoma. 

Clear Efficacy Benefit Not Shown With Atezolizumab/Bevacizumab Versus Lenvatinib in Unresectable HCC 

The exploratory analysis of trastuzumab emtansine (T-DM1) in the KAMILLA trial (NCT01702571) showed that patients with HER2-positive (HER2+) locally or advanced metastatic breast cancer who have brain metastases had promising activity and tolerability on the therapy. Moreover, this study confirmed the safety and efficacy of T-DM1 and demonstrated no new safety signals, according to Rachel Wuerstein, MD.

Wuerstein, of the Universität München and lead investigator of the trial, discussed in an interview with 

the implications of the KAMILLA trial and the benefit of T-DM1. Wuerstein also discussed the data that show TDM1’s potential use for patients with HER2+ metastatic breast cancer beyond the standard-of-care second-line setting.

TM: Please describe the background of the study and its rationale.

KAMILLA was the safety and efficacy trial for a global and Asian cohort. It was of high importance because there was actually a need to get more safety data for T-DM1 (for patients with) metastatic breast cancer at the time. KAMILLA focused on a global cohort with large patient numbers, but also—and that’s of special interest—on an Asian cohort. Included in the KAMILLA trial is the highest number of patients entering a trial for T-DM1…more than 2000 patients in the global cohort and 182 patients in the Asian cohort. Ultimately, the reason for this trial at the time was need for more safety data of this new track, which, in the meantime, got standard of care for second-line treatment and second- or first-line treatment in HER2+ metastatic breast cancer.

Were there any key differences between the global cohort and Asian cohort?

Interestingly, what we did know from the previous trials, there are some differences in safety of some of the tracks so far in T-DM1 between the global cohort and Asian cohort. What we did find in KAMILLA, and therefore we also entered in the Asian cohort, is a higher rate of thrombocytopenia. Thrombocytopenia was 1 chosen end point in the KAMILLA trial. So what we did see in numbers is a difference in thrombocytopenia general adverse events of 8.7% in the global cohort, 27% in the Asian cohort, and for grade 3 thrombocytopenia, it was 3.7% in the global cohort and 36% in the Asian cohort again. Importantly, all these cases could be resolved by dose reduction and patients could remain on the track.

We had a low rate of trial (discontinuation) for those patients or dropouts, but equivalently, a difference in dose reductions of global 22% and in the Asian cohort 60%. What we did not see, fortunately, was a higher rate of bleeding complications due to thrombocytopenia. So yes, there is an effect and relevant difference in the adverse effect event of thrombocytopenia, and we think the rationale for this might be different genetic polymorphisms between global populations and Asian populations by itself. As I already said, there was no relevant new safety signal, just the difference in the population [sizes], but no difference in maintenance of the trial. And that’s also seen in the efficacy results of KAMILLA, and we do show results for progression-free survival as well as overall survival.

Overall survival even was a little higher for the aging population after our follow-up time. So I think that’s important information, and KAMILLA in both cohorts did also, again, prove the earlier line we use T-DM1 in HER2+ metastatic breast cancer, the more effective it is…. There is also important data coming from KAMILLA (with a) tweaked patient number with regard to brain metastases, and it’s also been shown that T-DM1 is highly effective and safe to use for brain metastases. Therefore, it also broadens our range of treatment options in not only metastatic, but also brain metastases in metastatic to positive breast cancer. We concluded for our poster that we added relevant information, but no new signals with regard to safety in comparison to previous publications of T-DM1, which is important, as I already told them now and is the worldwide standard of care from the second line and further in HER2+ metastatic breast cancer. And there is coming more and more interesting data with regard to these differences, not only in efficacy, but also safety. Now I also already pointed out those genetic reasons for that, and I think that’s something which is becoming very interesting for our worldwide oncology, in treating our patients, but also in our supportive treatments and modes of action.

What are the implications of this research?

As for implications of KAMILLA at ASCO this year, it’s major information, these data we got from previous trials and small numbers, and use of T-DM1 in metastatic breast cancer has been confirmed. One main result is that we didn’t find any new safety signals because if you look for secondary end points of KAMILLA, there has been a variety of adverse event events of special interest. Let’s say pneumonitis, for example, and we didn’t find any new signal. So just confirmation of what we didn’t know before, but this also plays an important role because in the meantime, T-DM1 is not only used in metastatic breast cancer, but it’s been moving to the post-neoadjuvant treatment in early breast cancer as well. We think for this situation, the large population of KAMILLA is relevant information. The confirmation of the efficacy data is important because it fits into the puzzle of new information we get about treatment options, but also sequencing of treatment in metastatic HER2+ breast cancer.

After this study, what is next for the use of T-DM1?

It’s an interesting question to think about what’s going to happen now with T-DM1. There is a well-described track in metastatic breast cancer in second line or further. But as we already know, also in the past-neoadjuvant treatment. We have been working on this question [and I believe] it’s time to move it to the neoadjuvant setting. We have to define the patient population. There have been some interesting presentations at this year’s ASCO, and I think safety populations like this are the backbone to start use of these tracks in the earliest setting. And I think it’s now been moving from metastatic to first line and we’ll have it also in the neoadjuvant setting.

What are your thoughts on the future landscape of treatment for patients with metastatic breast cancer?

As we all have seen in the last month, there is a variety of new tracks coming in trials, but also in an off-label setting in HER2+ metastatic breast cancer. We think T-DM1 plays a major role in this setting and is one of the main factors to prolong survival of our patients with metastatic disease. What’s going to be interesting in the near future is to see how will track combinations be working, and I already pointed out this fact: How are we going to sequence our therapies in this continuously changing field of treatment of early but also metastatic breast cancer? I’m looking forward to seeing these data in individualized sequencing of the new tracks in the field of HER2+ metastatic breast cancer. But again, (until that time), globallyT-DM1 is the second-line standard of care in HER2-positive metastatic breast cancer.

Montemurro F, Delaloge S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. 

. 2020;31(10):1350-1358. doi:10.1016/j.annonc.2020.06.020

In an interview with Targeted Oncology, Rachel Wuerstein, MD, discussed the implications of the KAMILLA trial and the benefit of T-DM1. Wuerstein also discussed the data that show TDM1’s potential use for patients with HER2-positive metastatic breast cancer beyond the standard-of-care second-line setting.

Wuerstein Discusses the Implications of the KAMILLA Trial and T-DM1 in HER2+ Metastatic Breast Cancer

-mutated metastatic castrate resistant prostate cancer (mCRPC) to evaluate all classes of genomic alterations showed how the complex structure of 

 can help determine the potential utility of multiple biomarkers to see which patients benefit from immunotherapy, according to research presented at the 2021 virtual American Society of Clinical Oncology.

5,617 cases of mCRPC were sequenced to evaluate all classes of genomic alterations within this patient population. Seventy-eight of these cases were 

-mutated compared to 5,539 patients with 

 wild type mCRPC with 11.3 genomic alterations in cases of 

-mutated cases were considered microsatellite instability (MSI) high, researchers concluded that this still exhibited how varied the phenotype is that can help clinicians make treatment decisions. Moreover, MSI-high status in patients with 

-mutated tumors was significantly greater than the 2% seen in MSH6 wild type cases (

-mutated cases had 73.1% short variant mutations, 23.1% had biallelic deletions, and 2.6% had genomic rearrangements. In comparison, in cases that were not MSI high, nor had an mismatch repair (MMR) mutational signature, 87% did not have biallelic loss of 

 or any other MMR gene. According to researchers, this confirmed that the monoallelic pathogenic mutations are insufficient to cause the MMR-D phenotype in this patient population. MMR signature was seen in 65% of the 

wild type cases in comparison to 3% in the 

 < 0.0001). Forty-five percent of pathogenic 

 alleles were germline and 58% of these did not have single MSI high or MMR nucleotide structure.

The loss of function in genomic alterations in 

 has been linked to a unique subtype of hypermutated mCRPC, according to researchers, that is microsatellite stable that can occur in sporadic or familial Lynch Syndrome, the most common cause of hereditary colon cancer and linked to a higher likelihood of prostate cancer. Researchers utilized a comprehensive genomic profiling assay to look at these cases, along with their tumor mutational burden (TMB). TMB was calculated from 0.80 mB of sequenced DNA and a median TMB of 21.3 mt/Mb was found in cases of 

 mutation compared to 2.5 mt/Mb in MSH6 wild type cases (

 < 0.0001). TMB greater than 10 mt/MB or more was found in 67% of 

-mutated cases, whereas only 4% was seen in 

 =.01), but had significantly higher frequencies of genomic alterations 

 =.046). Researchers believe that this is likely associated with the higher TMB in MSH6-mutated cases, compared to the low TMB in 

 wild type cases. Other biomarkers observed in these cases showed that most had a higher presence in 

“This complex phenotype highlights the potential utility of multiple rather than single biomarkers to understand tumor biology and determine patients who may benefit from immunotherapy,” researchers concluded. Sequencing was performed on 324 cancer-related genes and introns from 28 genes that are commonly rearranged in cancer.

Gennady B, Decker B, Jacob J, et al. Genomic landscape of MSH6-mutated clinically advanced castrate-resistant prostate cancer (mCRPC). 

. 2021;39 suppl 15; abstr 5062). doi: 10.1200/JCO.2021.39.15_suppl.5062

Sequencing of over 5,000 cases of patients with metastatic castration resistant prostate cancer showed potential for identifying multiple biomarkers in MSH6-mutated cases.

Sequencing Shows Potential for Identifying Multiple Biomarkers in mCRPC with MSH6 Mutation

The combination of paclitaxel (Abraxane) and GSK2636771 showed encouraging antitumor activity and a manageable toxicity profile and in patients with 

deficient advanced gastric cancer who progressed after first line chemotherapy, according to data presented at the 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

In a multi-center phase 1b/2 study (NCT02615730) of 42 patients, investigators found that the combination of paclitaxel chemotherapy and the novel PI3K

 inhibitor GSK2636771 had a median progression-free survival (PFS) of 12.1 weeks (95% CI, 11.1-13.2) and overall survival (OS) of 33.4 weeks (95% CI, 26.2-40.7) after a median follow up duration of 29.9 months (95% CI, 21.5-38.3). An objective response rate of 17.9% was observed among 28 patients with measurable disease who had the recommended phase 2 dose of 200 mg once daily combined with 80 mg/m2 of paclitaxel on days 1, 8, and 15 of the treatment. Nineteen patients (67.9%) exhibited disease control on the combination therapy. The median age of all enrolled patients was 59 years old (range, 32-88 years).

Patients with gastric cancer often have a loss of 

expression along with activation of their PI3K/AKT pathways. GSK2636771 is an inhibitor of these pathways and can be given orally in conjunction with chemotherapy. Patients included on the study failed to respond to first-line fluoropyrimidine and platinum chemotherapy, with 2 of 10 patients in the phase 1b part of the trial failing screening. Five patients were given 300 mg of GSK2636771 and 3 were given the second dose level of 200 mg GSK2636771.

Dose limiting toxicities were observed in a third of patients in the 300 mg arm and, after enrolling 2 more patients, grade 3 hypocalcemia was observed. In the 200-mg arm, no dose limiting toxicities were observed. The most common adverse events (AEs) of any grade were neutropenia (38.1%), peripheral neuropathy (28.8%), anorexia (21.4%), diarrhea (16.7%), and myalgia (14.3%).

PTEN expression was evaluated in patients via immunohistochemistry and the PTEN deficient patients were defined by having less than 100 of PTEN histoscore. The primary objective of the study was defining the recommended phase 2 dose and assessment of PFS. The secondary objectives focused on OS, ORR, disease control rate, and safety. Biomarker analysis of PTEN was also determined via somatic alteration of cancer by next-generation sequencing.

Patients considered to have PTEN-null tumors, those with a histoscore of 0, showed a favorable PFS of 18.9 weeks compared with a PFS of 11.6 weeks in other patients with PTEN-partial loss tumors with an histoscore of 1 to 99 (

 = 0.026). Tumor shrinkage was seen in 50% of patients in the efficacy evaluating cohort who were envaulted for PTEN. Patients considered PTEN-null also had a more favorable OS of 36.1 weeks in comparison with the PTEN-loss group at 27.4 weeks.

The investigators concluded that complete loss of PTEN expression may be associated with the clinical benefit observed in patient on GSK2636771 and paclitaxel. The trial was conducted across 7 centers in South Korea, and further analysis of the association between the biomarkers and clinical outcomes is underway.

Jung M, Kim C, Kim H, et al. An open-label, multi-centre, phase Ib/II study of PI3Kb selective inhibitor GSK2636771 administered in combination with paclitaxel in patients with advanced gastric cancer having alterations in PI3K/Akt pathway. Abstract presented at: 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; virtual. SO-10. doi: 10.1016/j.annonc.2021.05.034

The combination of paclitaxel and GSK2636771 showed encouraging antitumor activity and a manageable toxicity profile and in patients with PTEN-deficient advanced gastric cancer who progressed after first line chemotherapy.

Conor Killmurray | Authors

Articles

Clear Efficacy Benefit Not Shown With Atezolizumab/Bevacizumab Versus Lenvatinib in Unresectable HCC

Wuerstein Discusses the Implications of the KAMILLA Trial and T-DM1 in HER2+ Metastatic Breast Cancer

Sequencing Shows Potential for Identifying Multiple Biomarkers in mCRPC with MSH6 Mutation

Paclitaxel and GSK2636771 Combo Shows Benefit in Certain Patients with Gastric Cancer