October 07, 2019 - 10:10 am 0 Comments
Targeted oral tyrosine kinase inhibitors (TKIs) have an established role in third-line treatment of metastatic colorectal cancer (mCRC), but an expert outlined an entirely new direction of investigation with these drugs at the 2019 European Society of Medical Oncology (ESMO) Congress. The underlying theory that agents within this class might make mCRC susceptible to checkpoint inhibition has finally been given some credibility with positive results in a clinical study.
“This is an incredibly exciting time,” said Heinz Josef Lenz, MD, associate director of clinical research, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles. “There is a feeling that maybe we are unraveling a new option in metastatic CRC with response rates we have not seen in any third line scenarios.”
The story that led to the as-yet unpublished clinical study involves converging progress in understanding how macrophages mediate checkpoint inhibitor resistance and how multikinase inhibitors alter macrophage activity, particularly through effects on colony stimulating factor 1 (CSF-1) receptors. The clinical trial was initiated when regorafenib, which has an established role in mCRC, downregulated tumor-associated macrophages (TAM) in the experimental setting.
“This is looking like a very good strategy to make cold tumors hot,” Dr. Lenz explained.
The principles involved in this approach for converting tumors resistant to immunotherapy to those susceptible might apply across multiple tumor types, but the initial study was conducted in cancers of the gastrointestinal tract. The clinical study that Dr. Lenz found so impressive was recently presented as a poster at the 2019 meeting of the American Society of Clinical Oncology (Fukuoaka S et al. abstract 2522).
In this study, regorafenib and the checkpoint inhibitor nivolumab were evaluated in 25 patients with mCRC and 25 patients with advanced gastric cancer. Patients had a median of three prior lines of treatment. The objective response rate was 38%, a rate in this setting that “has never been seen before,” according to Dr. Lenz.
“Even more impressive, and potentially proving the point that regorafenib is overcoming immunotherapy resistance, three of the responses were observed in patients who had previously failed a checkpoint inhibitor,” Dr. Lenz said.
The potential for targeted therapies to alter the tumor microenvironment in order to enhance T cell infiltration and the anti-tumor efficacy of checkpoint inhibitors has long been appreciated. However, clinical studies until now have been disappointing. Dr. Lenz cited several, including the phase 2 MODUL trial, which found no significant benefit with a combination of atezolizumab and the anti-VEGF drug bevacizumab in mCRC.
Like bevacizumab, regorafenib also inhibits angiogenic activity by targeting VEGF, but a broader range of effects includes inhibition of other growth factors, such as PDGFR and FGFR, as well as oncogenic kinases, such as KIT, RET, and B-RAF. While all of these targets are implicated in an anti-tumor effect, it is the inhibition of the CSF-1 receptor that has become a major focus in the effort to understand its role in immune regulation.
“The CSF-1 axis appears to be important to immune regulation and inhibition, and we are now seeing evidence that activity on this target might be important through its inhibition of tumor associated macrophages,” Dr. Lenz said.
This all adds up to a rationale for the multiple ongoing trials now combining multikinase inhibitors with immune checkpoint inhibitors, including a mCRC study of regorafenib with pembrolizumab that is enrolling patients at Dr. Lenz’s center.
This new direction of study with regorafenib is being initiated just as a dosing optimization scheme has improved its clinical utility. In the pivotal CORRECT trial (Grothey A et al Lancet 2013; 2013:303-312), the overall survival benefit associated with regorafenib in mCRC was accompanied by a challenging rate of initial toxicities. However, a study called ReDOS that was published just weeks prior to the 2019 ESMO Congress has altered its benefit-to-risk ratio.
On the basis of the ReDOS study (Bekaii-Saab et al. Lancet Oncol 2019;20:1070-1082), “we now know how to dose this drug and not compromise quality of life,” said Alex Grothey, MD, Research Institute, Germantown, Tennessee. The principal investigator of CORRECT, Dr. Grothey emphasized that if clinicians have been slow to move to this therapy due to concern about adverse events, the ReDOS study has given regorafenib “a new life.”
In the multicenter ReDOS, 123 mCRC patients were randomized to the standard schedule of 160 mg regorafenib daily for 21 days of a 28-day cycle or to a starting dose of 80 mg/day with weekly 40 mg dose escalations as tolerated to a maximum of 160 mg day. The experimental arm also included one week off therapy in each 28-day cycle. When compared, about twice as many patients in the experimental arm (43% vs. 26%; P=0.04) met the primary endpoint, which was to start a third cycle of therapy.
“On standard dosing, the first cycle was always the most difficult,” said Dr. Grothey, explaining why evaluating a graduated dose made sense. These data are important, because “for a cytotstatic drug like regorafenib, it is the duration of therapy that matters.”
On another front regarding mCRC at the 2019 ESMO Congress, phase 1 results with AMG 510, a TKI targeting the KRAS G12C mutation, proved disappointing despite the promise in tumor models. In 29 patients with mCRC, there was only one partial response. In advanced non-small cell lung cancer (NSCLC) with the KRAS G12C mutation, 11 of 23 patients achieved an objective response, according to data reported from the same study a month ago.
The study did not associate AMB 510 with any dose-limiting toxicities, which was the primary focus of the study. Moreover, the principal investigator, Ramaswamy Govindan, MD, Siteman Cancer Center, Washington University, St. Louis, reported that the data are too limited to rule out clinical activity in mCRC. However, higher rates of response had been expected on the basis of the NSCLC activity, leading several experts to question the viability of the KRAS G12C to be a viable isolated target in mCRC.
by Ted Bosworth
September 30, 2019 - 11:09 am 0 Comments
The 2019 European Society of Medical Oncology (ESMO) opened with a series of trials with positive overall survival (OS) data. Generally considered the gold standard for practice change, survival benefits were associated with osimertinib in the FLAURA lung cancer trial and two different CDK 4/6 inhibitors in the MONARCH 2 and MONALEESA-3 breast cancer trials. New five-year data from the CHECKMATE 067 trial did not just reaffirm a survival advantage for combination checkpoint inhibitors in metastatic melanoma but a potential advantage for disease cure.
FLAURA: EGFR-Mutation NSCLC
In EGFR-mutation positive non-small cell lung cancer (NSCLC), new data from the FLAURA trial have confirmed that starting with the third-generation tyrosine kinase inhibitor (TKI) osimertinib is a better strategy than starting with a second-generation TKI. Osimertinib produced a survival benefit even though those initiated on the second-line TKIs were permitted to crossover at the time of progression.
“This is the first time that a survival benefit has been shown for one TKI over another in NSCLC,” said Suresh S. Ramalingam, MD, Winship Cancer Institute, Emory University, Atlanta, Georgia.
Patients randomized to second-line TKIs were permitted to take either gefitinib or erlotinib. Osimertinib was superior to these drugs for the primary endpoint of progression-free survival (PFS) in FLAURA data published last year (Soria et al. N Engl J Med 2018;378:113-125). On the secondary OS outcome, osimertinib provided a more than six-month relative advantage (38.6 vs. 31.8 months; P=0.0462) and a greater than 20% risk reduction (HR 0.799; P=0.0462).
The fact that patients in the comparator arm were allowed to switch at progression is critical for interpreting the results, according to the Pasi A. Jänne, MD, PhD, Dana-Farber Cancer institute, Boston. It shows that sequencing of TKIs is suboptimal. Rather, Dr. Jänne said, “you should use the best drug first.”
These data will change practice where drug sequencing is still being performed, but Dr. Jänne said that the PFS advantage had already convinced most physicians in the U.S. to use osimertinib first. One reason, as demonstrated in the FLAURA control arm, is that about one third of patients with EGFR mutation-positive advanced NSCLC never receive a second drug.
MONARCH 2 and MONALEESA-3
In hormone receptor positive/HER2-negative advanced breast cancer, two trials have shown an OS advantage for a CDK 4/6 inhibitor plus the estrogen-receptor antagonist fulvestrant relative to fulvestrant plus placebo.
The data from the two trials, MONARCH 2 and MONALEESA-3, are complementary, according to Nadia Harbeck, MD, University of Munich, Germany. Based on these data, she concluded this combination should now be considered “a standard of care” in this setting.
In the similarly designed MONARCH 2 and MONALEESA-3 studies, patients were randomized in a 2:1 ratio to a CDK 4/6 inhibitor plus fulvestrant or to the control arm. The CDK 4/6 inhibitor was abemaciclib in MONARCH 2 and ribociclib in MONALEESA-3, which, unlike MONARCH 2, limited enrollment to postmenopausal patients.
The OS advantage from adding a CDK 4/6 inhibitor to fulvestrant in the MONARCH 2 and MONALEESA-3 trials joins a previously reported OS advantage from ribociclib plus fulvestrant relative to fulvestrant alone in the MONALEESA-7 trial. Enrollment in the MONALEESA-7 trial was limited to premenopausal women and published earlier this year (Im SH et al. N Engl J Med 2019;381:307-316).
In MONARCH 2, which randomized 669 patients with HR+/HER2-breast cancer, the median OS was increased 9.4 months (46.7 vs. 37.3 months) after a median followup of 47.7 months, translating into a 22% relative advantage for abemaciclib over placebo (HR 0.78; P<0.0001).
“This was not only statistically significant but I would argue clinically relevant and important to patients,” reported George W. Sledge, MD, Stanford University, Stanford, California.
In addition, being randomized to the CDK 4/6 inhibitor more than doubled the time to subsequent chemotherapy (50.2 vs. 22.1 months; P<0.0001).
In MONALEESA-3, 726 patients were randomized. About half were being treated for the first time. After a median followup of 39.4 months, the median OS has not been reached in the experimental arm versus 40.3 months in the control arm, producing a roughly 28% relative advantage for ribociclib over placebo (HR 0.724; P=0.0046).
Also citing the MONALEESA-7 trial, Dennis J. Slamon, MD, University of California, Los Angeles concluded that CDK 4/6 inhibitor plus endocrine therapy “provides a meaningful prolongation of survival regardless of menopausal status.”
CheckMate 067—50% Cure Rate of Metastatic Melanoma
In patients with metastatic melanoma, five-year outcome data from the CheckMate 067 study has confirmed greater survival and possibly greater rates of cure in those patients treated with the combination of ipilimumab plus nivolumab when compared with either checkpoint inhibitor alone.
At five years, the rates of OS for ipilimumab plus nivolumab, nivolumab alone, and ipilimumab alone were 52%, 42%, and 26%, respectively. Those alive and free from subsequent therapy, suggesting possible cure, were 35.7%, 23.7%, and 14.3%, respectively.
The OS rates at five years were similar on the combination of checkpoint inhibitors regardless of whether patients had BRAF mutant or wild-type tumors, whether or not PD-L1 expression was above or below 5%, and whether or not they discontinued therapy early due to adverse events.
Juxtaposed to the estimated 5% five-year survival for metastatic melanoma prior to the introduction of checkpoint inhibitors, the data from CheckMate 067 suggest that about one in two patients treated with a combination of these agents can expect to be alive at five years, according to the principal investigator, James Larkin, MD, Royal Marsden NHS Foundation Trust, London, UK.
However, the combination of checkpoint inhibitors is associated with significant toxicity. In the previously reported OS data at three years (Wolchok JD et al. N Engl J Med 2017;377:1345-1356), grade 3 or higher adverse events occurred in nearly 60% of patients. Dr. Larkin also cautioned that there are no current methods for predicting which of the sizeable proportion of patients will be exposed to these side effects but achieve no clinical benefit.
by Ted Bosworth
July 15, 2019 - 08:07 pm 0 Comments
OBR and MDoutlook are pleased to share excerpts from the most recent MDoutlook OncoPolls™ following this year’s ASCO annual meeting in Chicago. This final report (from series of three releases with MDoutlook over the past week) highlights the three (3) oral presentations from Tuesday morning ASCO presentations concerning chronic lymphocytic leukemia (CLL). These presentations discussed the first-line use of Venetoclax + Obinutuzumab, the use of Acalabrutinib + Obinutuzumab in both the first-line and relapsed/refractory settings, and the CAR-T product Lisocabtagene maraleucel.
This research is based on separate, identical surveys conducted with US and EU5-based oncologists who treat CLL. The full complimentary report is available through MDoutlook.
Abstract #7502: Venetoclax plus Obinutuzumab as a 1st line treatment for CLL
Key Conclusions about Abstract #7502 (Venetoclax + Obinutuzumab in first-line CLL)
Abstract #7500: Acalabrutinib plus Obinutuzumab for 1st line CLL and r/r CLL
Key Conclusions about Abstract #7500 (Acalabrutinib + Obinutuzumab in untreated and r/r CLL)
Abstract #7501: Lisocabtagene Maraleucel (Liso-Cel) in r/r CLL
Key Conclusions about Abstract #7501 (Liso Cel in r/r CLL)
Expected Integration of New ASCO Data into Clinical Practices
Key Conclusions about Integration of New ASCO Data into Clinical Practice
Overall Conclusions: Immediate Impact of 2019 ASCO Presentations on the Clinical Practice for CLL
Submitted by Robert Stephan, SVP, Research & Operations and Jan Heybroek, President, MDoutlook.
July 11, 2019 - 02:07 pm 0 Comments
OBR and MDoutlook are pleased to share more excerpts from the most recent MDoutlook OncoPolls™ following this year’s ASCO annual meeting in Chicago. This report highlights four (4) oral presentations concerning new targeted agents being developed against recognized driver mutations in metastatic non-small cell lung cancer (mNSCLC). These agents are: Capmatinib and Tepotinib (both targeting MET with exon 14 mutations), TAK-788 (targets specific EGFR mutations with exon 20 insertions), and BLU-667 (RET inhibitor).
This research is based on separate, identical surveys conducted with US and EU5-based treaters of mNSCLC. The full complimentary report is available through MDoutlook per details below.
Current Awareness and Evaluation of New Targeted Agents in mNSCLC
Key Conclusions around New Targeted Agents for mNSCLC
Comparison of New Targeted Agents for mNSCLC
Key Conclusions about Comparison of New Targeted Agents for mNSCLC
Overall Conclusions: Impact of 2019 ASCO Annual Meeting on Clinical Practice for mNSCLC with Driver Mutations
Submitted by: Robert Stephan, SVP, Research & Operations and Jan Heybroek, President MDoutlook.