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Frontline RCC Treatment From ASCO GU 2019: Practice Implications | PracticeUpdate
Yeah. So, I mean, obviously, we had the press release just before ESMO that said that the combination of pembrolizumab axitinib offered an improvement in overall survival across subgroups, that patients who have metastatic clear cell renal cell carcinoma, as we had that press release, we were sort of waiting to see what the results show, and now we have the results, and it is a very impressive regimen. So the combination of pembrolizumab with axitinib, as opposed to sunitinib, offers a superior response rate, close to 60 percent, and more importantly, there is actually an improvement in overall survival, with a hazard ratio of just over 0.5, so this is certainly a very intriguing option, and it’s the first VEGF TKI/I-O combo to have an improvement in overall survival versus sunitinib at this point in time.

 

Dr. Sumanta Pal:

Very interesting. So, you know, with that in mind, I guess my mind shifts now to the existing regimens that we’ve got in our back pocket. The big topic of conversation over this past year has been NIVO, and it be for intermediate and _____ 01:49 disease. Can you give me a sense, is NIVO and ipi still going to be on your radar for patients? Are you going to use axitinib plus I-O more exclusively? What are your thoughts there?

 

Dr. Bradley McGregor:

So I think nivolumab ipilimumab is definitely a very active regimen, and I don’t think it’s going to be completely replaced by these new approaches. When we look at the data, although it is early, for the TKI/I-O combos, there’s clearly a great response rate, you know, approaching 50 to 60 percent, with axitinib avelumab, or pembrolizumab axitinib, but the CR rates, those complete response rates, they are about half of what we see with nivolumab and ipilimumab. Anywhere from four to six percent.
RCC  immunotherapy  sunitinib  nivolumab  TKInhibitors 
10 days ago by cnk
Cost-Effectiveness of First-Line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma | PracticeUpdate
IMPORTANCE

Recently, new drugs have been approved for the first-line treatment of metastatic renal cell carcinoma (mRCC). Nivolumab plus ipilimumab significantly increases overall survival for intermediate- and poor-risk patients with mRCC. However, considering the high cost of nivolumab plus ipilimumab, there is a need to assess its value by considering both efficacy and cost.

OBJECTIVE

To evaluate the cost-effectiveness of nivolumab plus ipilimumab vs sunitinib in the first-line setting for intermediate- and poor-risk patients with mRCC from the US payer perspective.

DESIGN, SETTING, AND PARTICIPANTS

A Markov model was developed to compare the lifetime cost and effectiveness of nivolumab plus ipilimumab vs sunitinib in the first-line treatment of mRCC using outcomes data from the CheckMate 214 phase 3 randomized clinical trial, which included 1096 patients with mRCC (median age, 62 years) and compared nivolumab plus ipilimumab vs sunitinib as first-line treatment of mRCC. In the analysis, patients were modeled to receive sunitinib or nivolumab plus ipilimumab for 4 doses followed by nivolumab monotherapy.

MAIN OUTCOMES AND MEASURES

Life-years, quality-adjusted life-years (QALYs), and lifetime costs were estimated, at a willingness-to-pay threshold of $100 000 to $150 000 per QALY. Univariable, 2-way, and probabilistic sensitivity analyses were performed to evaluate the model uncertainty. Additional subgroup analyses were performed.

RESULTS

Nivolumab plus ipilimumab provided an additional 0.96 QALYs, at a cost of $108 363 per QALY. Sensitivity analyses found the results to be most sensitive to overall survival hazard ratio (0.63; 95% CI, 0.44-0.89) and mean patient weight (70 kg, range, 40-200 kg). Other variables, such as the cost of nivolumab plus ipilimumab (mean, $32 213.44; range, $25 770.75-$38 656.13), utility values for nivolumab plus ipilimumab (mean, 0.82; range, 0.65-0.98), and proportion receiving nivolumab in sunitinib arm (mean, 0.27; range, 0.22-0.32), had a moderate or minor influence on model results. Subgroup analyses demonstrated that nivolumab plus ipilimumab was most cost-effective for patients with programmed cell death 1 ligand 1 expression of at least 1% ($86 390 per QALY).

CONCLUSIONS AND RELEVANCE

In this model, nivolumab plus ipilimumab was estimated to be cost-effective compared with sunitinib for intermediate- and poor-risk patients with mRCC at a willingness-to-pay threshold from $100 000 to $150 000 per QALY.
RCC  immunotherapy  sunitinib  HealthCare  Economics  statistics 
18 days ago by cnk
Pembrolizumab Plus Axitinib a New Standard in Metastatic RCC
NEW YORK (Reuters Health) - First-line treatment with the anti-PD-1 immunotherapy pembrolizumab plus the VEGF-targeted tyrosine-kinase inhibitor axitinib extended overall survival and progression-free survival in patients with clear-cell metastatic renal cell carcinoma (mRCC), compared with the current standard of care, sunitinib, in the phase 3 KEYNOTE-426 trial.
"These results are exciting," co-lead investigator Dr. Thomas Powles of Barts Cancer Institute in London, England, said in a news release. "By adding pembrolizumab to a VEGF-targeted therapy, we are seeing powerful anticancer responses, including improved survival - and importantly, the results are seen across broad subgroups of patients."
Based on the results, "pembrolizumab and axitinib should be a standard of care in this setting, in my opinion," Dr. Powles said during a press briefing February 11 ahead of presentation February 16 at the 2019 Genitourinary Cancers Symposium, co-sponsored by the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology and the Society of Urologic Oncology.
In the KEYNOTE-426 trial, 861 patients (mean age, 62; 73% men) with untreated clear-cell mRCC were randomly allocated to oral sunitinib once daily or to the combination of pembrolizumab given intravenously every three weeks plus oral axitinib twice daily. Treatment continued until the disease progressed, patients developed high toxicity, or they dropped out of the study.

At a median follow-up of 12.8 months, combination therapy was associated with a 47% reduction in the risk of death compared with sunitinib (hazard ratio, 0.53; P<0.0001).
Overall survival at 12 months was 89.9% in the combination group versus 78.3% in the sunitinib group, and at 18 months, it was 82.3% versus 72.1%. The benefits were seen irrespective of risk group or PD -L1 status, Dr. Powles noted.
Progression-free survival time was also longer with the pembrolizumab/axitinib combination than with sunitinib (15.1 months vs. 11.1 months).
More patients responded to the combination than to sunitinib (59.3% vs. 35.7%; P<0.0001) and the duration of response also favored combination therapy (median not yet reached vs. 15.2 months with sunitinib).

More than half of patients in the combination arm (59.0%) are still being treated versus 43.1% with sunitinib.
"Overall, we have not previously seen a renal cancer study which has improved response, progression-free survival, and overall survival. This is therefore a major step forward in renal cancer," Dr. Powles said in a statement.
Treatment-related side effects of grade 3 to 5 occurred in 62.9% of patients on the combination therapy compared to 58.1% on sunitinib, and there were more treatment-related discontinuations in the combination arm (25.9% vs. 10.1%).
"This is a very significant trial and it's going to have an impact on patient management going forward, as it works through the regulatory process," commented ASCO expert and briefing moderator Dr. Robert Dreicer.
immunotherapy  RCC  TKInhibitors 
4 weeks ago by cnk
'Exciting Times' With Immunotherapy for Kidney Cancer
San Francisco — Two new combination regimens are set to become new standards of care for the treatment of metastatic renal cell carcinoma (mRCC).
The new combinations contain an immunotherapy and a targeted agent.
New results with these combinations were presented here at the Genitourinary Cancers Symposium (GUCS) 2019 and were simultaneously published in the New England Journal of Medicine.
One combination is the immunotherapy pembrolizumab (Keytruda, Merck) and the vascular endothelial growth factor (VEGF)–targeted tyrosine-kinase inhibitor (TKI) axitinib (Inlyta, Pfizer). In the KEYNOTE-426 trial, the combination therapy yielded superior outcomes to the current standard of care, sunitinib (Sutent, Pfizer). As reported by Medscape Medical News, these results showed a significantly extended overall and progression-free survival for patients with previously untreated mRCC.

The other combination is the immunotherapy avelumab (Bavencio, Merck KGaA and Pfizer) and axitinib. Previously reported results from the JAVELIN Renal 101 trial showed that the combination significantly extended progression-free survival in the first-line setting in patients with advanced RCC, as compared to sunitinib. Updated results now show superior overall survival, with a 12-month rate of 89.9% vs 78.3% with sunitinib.
immunotherapy  RCC  nivolumab  TKInhibitors 
4 weeks ago by cnk
Cannabis Decreases Tumor Response Rate to Nivolumab | PracticeUpdate
In this retrospective study, data from patients treated with nivolumab and cannabis were evaluated to determine the effects of cannabis on immunotherapy response and survival. Cannabis significantly reduced the response rate to immunotherapy, but was not a significant factor in terms of progression-free or overall survival. The percentage of tetrahydrocannabinol or cannabidiol did not affect response rates.
These data suggest that caution should be taken when starting immunotherapy in cannabis users.
nivolumab  immunotherapy  cannabis 
5 weeks ago by cnk
Concerns Raised About Patient-Reported Outcomes in CheckMate 214 Trial | Cancer Network
PROs were assessed as an exploratory endpoint and gathered using three instruments: the Functional Assessment of Cancer Therapy–Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five-dimensional, three-level (EQ-5D-3L) tools.

At a median follow-up of 25.2 months, for two of the three assessment tools, patients in the combination arm reported better PROs than patients in the sunitinib arm from the start of treatment through 103 weeks, or about 2 years. For the FKSI-19 tool, which is validated for kidney cancer, the average change in the overall score between baseline and 103 weeks was 4.00 (95% CI, 1.91 to 6.09) for the combination arm compared with −3.14 (95% CI, –6.03 to –0.25) for the sunitinib arm (P < .0001). For the FACT-G tool, which is validated for cancer in general, the average change in overall score was 4.77 (95% CI, 1.73 to 7.82) for the combination arm vs −4.32 (95% CI, −8.54 to −0.11) for the sunitinib arm (P = .0005). For the EQ-5D-3L tool, however, PROs were not significantly different between treatment groups; EQ-5D-3L is validated for measuring general health status.

In addition to the potential bias of the open-label design, Mayer pointed out another concern. Despite showing better PROs, the combination arm had a higher discontinuation rate due to treatment-related adverse events vs the sunitinib arm (22% vs 12%).

“It’s hard to reconcile,” Mayer said. “[That] makes it difficult for me to go running to Ipi Nivo [ipilimumab plus nivolumab] as a drug regimen that’s going to give my patients better quality of life on the therapy,” he said.

A possible explanation for the higher discontinuation rate could be the inability to dose reduce the ipilimumab plus nivolumab combination. “If a patient can’t tolerance sunitinib, you might have some adjustments you can make to their therapy and they may still be able to stay on protocol, whereas in this particular trial, that might not have been true for Ipi Nivo,” Mayer explained.

Despite these study limitations, Mayer said that because the field is moving so quickly, he is not focused specifically on whether this one particular combination regimen is superior to sunitinib in terms of PROs. “We’ll probably find out in 6 months from now that it’s one big regimen—it’s all three of these [drugs]—so I try not to get too lost in those weeds,” he said.
RCC  nivolumab  immunotherapy  sunitinib 
5 weeks ago by cnk
AbbVie Biotherapeutics director leads team against cancer - San Francisco Business Times
Diane Hollenbaugh

Senior director, discovery

Company: AbbVie Biotherapeutics

HQ: Redwood City

Years at company: 5

Raised by a physician and a chemist in Chicago and the Pacific Northwest, Hollenbaugh always followed the science that she found the most interesting. As an undergrad at University of Washington, it was chemistry. And after receiving her Ph.D. in chemistry from the California Institute of Technology and completing her post-doc training at the Bristol-Myers Squibb Pharmaceutical Research Institute in Seattle, it became immunology, the study of immune systems. That spawned an interest in immuno-oncology, an area of research that aims to activate the body’s own immune system to fight cancer.

Hollenbaugh has been deep in immunology since 1991 and in immuno-oncology for the past 15 years at companies like Medarex, FivePrime Therapeutics and Schering-Plough/Merck. In 2013, she joined AbbVie Biotherapeutics in Redwood City, where she leads a team of scientists focused on developing new medicines.
immunotherapy  Caltech  Business 
5 weeks ago by cnk
New Standard of Care for Metastatic Renal Cell Carcinoma
First-line therapy with a combination of an immune checkpoint inhibitor and a tyrosine kinase inhibitor (TKI) improved outcomes in patients with clear-cell metastatic renal cell carcinoma (mRCC), as compared with the current standard of care, according to new findings.
Pembrolizumab (Keytruda, Merck) and the VEGF-targeted TKI axitinib (Inlyta, Pfizer) significantly extended both overall and progression-free survival, and elicited a higher objective response rate than sunitinib (Sutent, Pfizer) in patients with previously untreated mRCC.
"The risk of death was reduced by almost 50% with pembrolizumab plus axitinib," said study author Thomas Powles, MD, professor of urology oncology at Barts Cancer Institute in London, England. "The benefit of pembrolizumab plus axitinib was seen irrespective of risk group or PD-L1 status."
Based on these results, "pembrolizumab and axitinib should be a standard of care in this setting, in my opinion." Powles added.

The KEYNOTE-426 clinical trial was conducted in 861 patients, who were randomized to receive either pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles plus axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for the first 4 weeks of each 6-week cycle.
Treatment was given until disease progression, intolerable toxicity, or patient/investigator decision to discontinue therapy.
Superior at All Endpoints

At a median follow-up of 12.8 months, overall survival was higher among patients receiving pembrolizumab and axitinib and was associated with a 47% reduction in the risk of death compared with sunitinib (hazard ratio [HR] 0.53; P < .0001).

The 12-month overall survival rate was 89.9% in the combination group vs 78.3% in the sunitinib group, and at 18 months, it was 82.3% vs 72.1%. These benefits were seen across all risk groups and PD-L1 status.
Median progression-free survival was 15.1 vs 11.1 months favoring combination therapy (HR 0.69; P = .0001), with a 12 month rate of 59.6% vs 42.6%. At 18 months it was 41.1% vs 32.9%.
For secondary endpoints, the overall response rate was 59.3% vs 35.7%, favoring combination therapy (P < .0001), and duration of response was also prolonged with pembrolizumab plus axitinib (median not reached vs 15.2 months).
Powles noted that 59% of the patients in the combination group are still being treated, as compared to 43.1% with sunitinib.
Grade 3-5 adverse events were slightly higher in the combination group (62.9% vs 58.1%), and more treatment discontinuations were observed in that group as well (25.9% vs 10.1%).
The study was funded by Merck Sharp & Dohme. Powles reports consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; other relationship with Ipsen and Bristol-Myers Squibb; honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; research funding from AstraZeneca/MedImmune and Roche/Genentech. Other coauthors also report relationships with industry as noted in the abstract.
Genitourinary Cancers Symposium (GUCS) 2019: Abstract 543. To be presented February 16, 2019.
immunotherapy  TKInhibitors  RCC 
5 weeks ago by cnk
Immune Response Markers in Matched RCC Tissue Specimens
Results: A large minority of patients had discordant expression of PD-1 (31.2%), PD-L1 (22.5%), or PD-L2 (21.5%) between primary and metastatic sites. The expression of the novel marker PD-L2 correlated with both PD-1 (r = 0.47, P = .02) and PD-L1 (r = 0.67, P < .001) in metastatic deposits.
Conclusions: This study demonstrates that renal clear cell carcinoma primary tumors and metastatic deposits have some discordance in the expression of PD-L1, PD-1, and PD-L2.
Introduction
Metastatic renal cell carcinoma (RCC) has been a difficult disease to treat historically with minimal response to cytotoxic chemotherapy and high mortality rates. Immunotherapy had been used in RCC with only limited success such as with high-dose interleukin 2 (IL-2), which induces approximately 5% to 10% of patients into a durable remission.[1] Treatment outcomes have improved with the introduction of vascular endothelial growth factor (VEGF)–targeted therapies in the past decade, although durable responses are still uncommon. The understanding of the interplay between the tumor and the immune system has led to the development of immune checkpoint inhibitors that are active in many solid tumors, including RCC. Nivolumab, an anti–PD-1 antibody, was recently approved as a treatment for VEGF-refractory metastatic RCC. A phase III trial compared nivolumab with everolimus and showed a significant overall survival benefit.[2] Similarly, pembrolizumab, another PD-1 inhibitor, and atezolizumab, a PD-L1 antibody, are being investigated in combination with VEGF inhibitors with encouraging initial activity and ongoing phase 3 trials.[3] As immune checkpoint inhibitors and other targeted therapies continue development in RCC, there will be an increasing need to identify patients who are more likely to benefit to inform clinical decisions.

The expression of the PD-L1 ligand on the tumor cell surface is a logical choice as a marker of response to PD-1 inhibitors. In the abovementioned phase III trial of nivolumab, the hazard ratio for overall survival benefit of nivolumab over everolimus was nearly identical regardless of PD-L1 expression.[2] The anti–PD-L1 antibody atezolizumab also failed to show an association between response and PD-L1 expression in early phase studies.[4] Several hypotheses have been forwarded to explain this lack of association. One hypothesis is that there are considerable differences in expression of PD-L1 in metastatic lesions compared with primary tumors since metastatic deposits adapt under immune selection pressures. Some studies have demonstrated this to be the case in RCC. Discordant tumor cell PD-L1 staining between primary tumors and matched metastases was observed in 20% of clear cell kidney tumors in one analysis.[5] Similarly, PD-L1 expression has been found to be weakly correlated between metastasis and primary kidney tumors in another series.[6] Another hypothesis involves the presence of other clinically significant ligands apart from PD-L1. An example of such an alternative ligand is PD-L2.[7] The role of PD-L2 and its differential expression in metastatic sites and kidney cancer primaries has not been examined previously.
Macrophage and T-cell infiltration of tumors may also be important determinants of treatment response. Macrophage polarization into tolerance-promoting (M2) and antitumor phenotypes (M1) has been described.[8] M1 and M2 macrophages are identifiable by HLA-DR and CD163 staining, respectively.[9,10] T-cell subtypes involved in the tumor–immune system interaction include the regulatory and cytotoxic T cells. Regulatory T cells express FOXP3 and are active in increasing immune tolerance, resulting in muting of the immune-mediated anticancer response.[11] Regulatory T cells have been shown to influence outcome to IL-2 and sunitinib therapy in metastatic RCC.[12,13]
To gain further insight into expression of markers potentially relevant to checkpoint inhibition in RCC, matched primary and metastatic RCC tumors were characterized. The availability of matched samples could provide insight into intrapatient heterogeneity regarding biomarker expression. Such heterogeneity may have several implications, including which tissue is characterized prior to treatment selection and organ-specific clinical responses.
RCC  immunotherapy  nivolumab 
5 weeks ago by cnk
Nivolumab/Ipilimumab Improves HRQoL in Intermediate- and Poor-Risk RCC | PracticeUpdate
In early 2018, investigators of CheckMate 214 reported efficacy results of the randomized phase III trial comparing nivolumab plus ipilimumab with sunitinib in previously untreated patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC). Improved progression-free survival, overall survival, and objective response rate with the immunotherapy combination led to FDA approval of nivolumab plus ipilimumab as first-line therapy, establishing a new standard of care for intermediate- or poor-risk advanced RCC; however, a higher proportion of patients discontinued treatment in the nivolumab plus ipilimumab group than in the sunitinib group, leading to questions concerning health-related quality of life (HRQoL) with the combination.

Cella and colleagues further assess patient-reported outcomes (PROs) of the CheckMate 214 trial in a recent issue of The Lancet Oncology in order to characterize the benefit–risk profile of the nivolumab plus ipilimumab versus sunitinib. While on treatment, patients were asked to complete the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five-dimensional three-level (EQ-5D-3L) questionnaires. Investigators found that, over the first 103 weeks on study treatment, patients experienced improved HRQoL with nivolumab plus ipilimumab compared with sunitinib, with total scores from FKSI-19 and FACT-G instruments reaching statistical significance at times. Additionally, those with high baseline HRQol as well as improved HRQol from baseline were seen to have the longest overall survival in both treatment groups, suggesting that these points may be prognostic of survival. The data presented show that the combination of nivolumab plus ipilimumab has a superior benefit–risk profile as compared with sunitinib and support the combination as the new standard of care.

BACKGROUND

In the ongoing phase 3, CheckMate 214 trial, nivolumab plus ipilimumab improved overall survival compared with sunitinib in patients with intermediate or poor risk, previously untreated, advanced renal cell carcinoma. We aimed to assess whether health-related quality of life (HRQoL) could be used to further describe the benefit-risk profile of nivolumab plus ipilimumab versus sunitinib.

METHODS

In the phase 3, randomised, controlled, CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg/day for 4 weeks of each 6-week cycle. Randomisation was done with a block size of four and stratified by risk status and geographical region. Patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) instruments. The coprimary endpoints of the trial, reported previously, were overall survival, progression-free survival, and the proportion of patients who had an objective response in those categorised as at intermediate or poor risk. PROs in all randomised participants were assessed as an exploratory endpoint; here we report this exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment.

FINDINGS

Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) were randomly assigned to treatment, of whom 847 (77%) were at intermediate or poor risk and randomly assigned to nivolumab plus ipilimumab (n=425) or sunitinib (n=422). Median follow-up was 25·2 months (IQR 23·0-27·4). PROs were more favourable with nivolumab plus ipilimumab than sunitinib throughout the first 103 weeks after baseline, with mean change from baseline at week 103 for FKSI-19 total score being 4·00 (95% CI 1·91 to 6·09) for nivolumab plus ipilimumab versus -3·14 (-6·03 to -0·25) for sunitinib (p<0·0001), and for FACT-G total score being 4·77 (1·73 to 7·82) for nivolumab plus ipilimumab versus -4·32 (-8·54 to -0·11) for sunitinib (p=0·0005). Significant differences were also seen for four of five FKSI-19 domains (disease-related symptoms, physical disease-related symptoms, treatment side-effects, and functional wellbeing) and FACT-G physical and functional wellbeing domains. However, there was no significant difference between the treatment groups at week 103 in EQ-5D-3L visual analogue rating scale (VAS) scores, with mean change from baseline to week 103 of 10·07 (95% CI 4·35 to 15·80) for nivolumab plus ipilimumab and 6·40 (-1·36 to 14·16) for sunitinib (p=0·45). Compared with sunitinib, nivolumab plus ipilimumab reduced risk of deterioration in FKSI-19 total score (hazard ratio [HR] 0·54; 95% CI 0·46-0·63), FACT-G total score (0·63, 0·52-0·75), and EQ-5D-3L VAS score (HR 0·75, 95% CI 0·63-0·89) and UK utility scores (0·67, 0·57-0·80).

INTERPRETATION

Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.
RCC  nivolumab  immunotherapy  sunitinib 
6 weeks ago by cnk
Management of Brain Metastases in the Era of Checkpoint Inhibitors | PracticeUpdate
That’s why in the past, traditionally, brain metastases were handled by neurosurgeons or radiation oncologists. So, we used to take the brain mets out and then we used to give some focused forms of radiation. Either whole brain radiation or a focused form of radiation called stereotactic radiosurgery. However, this paradigm has changed significantly and there are two approaches to go on. One is a targeted therapy approach where you actually have drugs that will target particular molecule pathways that are actually driving the cancer cell. So, you typically target those mutations using targeted drugs and we use these tyrosine kinase inhibitors, which tend to be small drugs that easily traverse across the blood-brain barrier. The other approach is an immunotherapy-based approach where you actually boost someone’s immune system to go and kill the cancer cell. In the past, a brain was felt to be an immunoprivileged site. What that means is people thought that the immunotherapies would not work in the brain.

Now, we have several nature papers showing that’s not true. There is a trafficking of T cells going into the brain, there’s constant interaction with the cervical lymph nodes, so there is this crosstalk going on. And then there have been a number of clinical trials actually, which have clearly demonstrated that the immunotherapy works in the brain. And there are several trials that I would like to talk about today, which have shown the importance of immunotherapy in brain metastases. The first trial was a trial led by Kim Margolin, which was 72 patients. They gave the patients ipilimumab, which is a drug that targets the anti-CTLA-4, which is basically a negative immune checkpoint. This drug targets this checkpoint and activates the immune system. There were two cohorts. Cohort A was those patients who were not on steroids. Cohort B was 21 patients who were on steroids.

We’ve had three teaching points that we learned from that trial. The first one was that the drugs worked equally well in the brain as well as extracranially. The second was that the patients who were on steroids had less robust responses as compared to someone who was not on steroids. So, that means steroids impact response rate. You’ll have a higher response rate if you’re not on steroids. You’ll have a low response rate if you're on steroids. Albeit, we know generally large lesions tend to grow more rapidly and those are the patients, which need to be on steroids. The third teaching point from that trial that we learned was that the responses with immune checkpoint were durable. Most of the targeted therapies, when they work in brain metastases, typically have a response rate that lasts from 6 months to even 15 months with some of the new inhibitors, which are very exciting. But if you get a response rate with immune checkpoint, at least from the ipilimumab trial led by Kim Margolin, we have seen some of those patients to have responses 2, 3, even 5 years out, which is very exciting. Now, we have had several new immune checkpoint inhibitors that have come on since the ipilimumab.

Dr. Shah: Yes. So, I was going to ask you about that. So, if you do a dual checkpoint blockade would that help or is there one checkpoint blockade that seems to be better than the other?

Dr. Ahluwalia: So, great question. So, what we found with ipilimumab was the clinical benefit as they define in that trial was around 20 to 25%, at least in patients who are not on steroids. Patients who are on steroids, that benefit rate was around 10%. Then the new drugs came, which was the immune checkpoint blockade, which is the anti-PD-1 effort. There, we found single agent anti-PD-1 blockade produce response rates in the ballpark of 20 to 30% response rates with less toxicity than a drug like ipilimumab. Then the group of us got together and redesigned the next cadre of trials, which was one of the examples of checkpoint 204, in which we participated. Here, we combined both ipilimumab with nivolumab.

So, we’re now combining an anti-CTLA-4-based effort with an anti-PD-1 effort. And what we found was when we combine them in melanoma, our response rates were now 55%. So, we got 20 to 30% with one, got 20% or 25% clinical benefit rate over the one, and when we combined them we had much higher response rates. Albeit, there is slightly higher toxicity also, which is observed with the combination, because the ipilimumab or anti-CTLA-4 drugs tend to be more toxic than the anti-PD-1 drugs like pembrolizumab or nivolumab.

Dr. Shah: Now, would you expect there to be a difference in this therapy for, say, melanoma versus an NSCLC metastases or is there data showing a differential response?

Dr. Ahluwalia: So, great question. So, we do actually. There was a trial, which looked at pembrolizumab, which is one of the anti-PD-1 inhibitors, and they had two cohorts of it. This was a study led by Yale; Harriet Kluger and Sarah Goldberg led the effort. In melanoma, what the initial results that were published in The Lancet Oncology showed that 4 out of 18 melanoma patients had a response with single agent pembrolizumab, that is 22% response rate. Non-small cell lung cancer, on the other hand, 6 out of 18 patients had response rates, which amounted to 33% responses. Now, in melanoma, we have data with dual checkpoint blockade, as we discussed, which is 55% with both. In lung cancer, we still don’t have that data and there are ongoing trials looking at what will be the outcomes of these patients with the combination approach, which I believe is going to be higher based on our experience with melanoma.

Dr. Shah: And do you see any further combinations as being effective? So, that is, you take the single or dual checkpoint blockade inhibition and you combine that with, say, stereotactic radiation or some other existing therapy for brain mets. Do we have data on this and where do you see that field going?

Dr. Ahluwalia: So, great question. I think the field is going to go into combinatorial approaches now because traditionally, as we discussed, radiosurgery has been an important part of management of patients with brain metastases. Now, some of these immune checkpoint inhibitor studies that we discussed actually, typically, in well patients who are asymptomatic or who are low doses of steroids. Because immunotherapy doesn’t work very well if patients are on steroids. So, although there is no perspective data so far in combination, we have retrospective data.

In fact, we ourselves presented this data at ASTRO and several others have done it. And what we have found in at least retrospective experiences when we are combining stereotactic radiosurgery with immunotherapy, we are getting response rates, which are higher than at least with stereotactic radiosurgery alone in such patients. So, I think in the future trials will test this combination-based approach. One of the other challenges that we will want to address is what’s the right sequencing? Do you give the anti-PD-1 before you do radiosurgery or do you do radiosurgery first where the radiation can act as a new antigen expression-based approach and then you mount an anti-PD-1 approach on that? So, we and several others are working on this effort where we’re looking at scheduling and sequencing as well.
cancer  brainmets  immunotherapy  nivolumab  TKInhibitors 
6 weeks ago by cnk
My Two-Decade Journey with Cancer Immunotherapy
Different, specific, and long: very informed Lymphoma survivor champions immunotherapy, including CAR-T, reviews its progress
sh1  bullsi  cartcell  advocate  18sbx  immunotherapy  history  treatment  ws3  bullsi2 
6 weeks ago by csrollyson
Immunotherapy: A Glimmer of Hope for Prostate Cancer
Abstract
Prostate cancer was the first cancer in which immunotherapy vaccine was approved by FDA in 2010 named Sipuleucel-T. No new immunotherapies have been approved since, as phase 3 trials didn't show any improvement in overall survival (OS) especially with immune checkpoint inhibitors. Currently tremendous amount of research is going on, in studying microenvironment of prostate cancer, finding new targets and biomarkers, and trying different combination therapies. Some of the new targets explored are VISTA and PARP inhibitors. Combination therapies have shown promising results in early phase trials and likely in near future we will have an effective immunotherapy for advanced prostate cancer. In this article we will review the current data and future of immunotherapy in prostate cancer.
Introduction
Metastatic prostate cancer is the second leading cause of cancer deaths worldwide. It was the first cancer in which vaccine immunotherapy was approved by FDA thus an immune responsive disease. However, the immunotherapeutic advances in prostate cancers are quite restricted, as no other drugs have shown clinical results in phase 3 trials. Still there is glimmer of hope, as active research is ongoing on combination of different forms of immunotherapy for prostate cancer. Recently new targets have been identified for prostate cancer like VISTA and PARP inhibition. So there are chances that immunotherapy will evolve as effective therapy in advanced prostate cancer.
cancer  immunotherapy  prostatecancer 
7 weeks ago by cnk
Second-Line Targeted Therapies After Nivolumab–Ipilimumab Failure in mRCC | PracticeUpdate
Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naïve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear.

METHODS

Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected.

RESULTS

Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (≥6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade ≥3.

CONCLUSION

This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.
RCC  immunotherapy  nivolumab  sunitinib  TKInhibitors 
7 weeks ago by cnk
Immune Escape to PD-L1/PD-1 Blockade: Seven Steps
The emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)–targeted therapy has demonstrated the importance of the PD-L1 : PD-1 interaction in inhibiting anticancer T-cell immunity in multiple human cancers, generating durable responses and extended overall survival. However, not all patients treated with PD-L1/PD-1–targeted therapy experience tumor shrinkage, durable responses, or prolonged survival. To extend such benefits to more cancer patients, it is necessary to understand why some patients experience primary or secondary immune escape, in which the immune response is incapable of eradicating all cancer cells. Understanding immune escape from PD-L1/PD-1–targeted therapy will be important to the development of rational immune-combination therapy and predictive diagnostics and to the identification of novel immune targets. Factors that likely relate to immune escape include the lack of strong cancer antigens or epitopes recognized by T cells, minimal activation of cancer-specific T cells, poor infiltration of T cells into tumors, downregulation of the major histocompatibility complex on cancer cells, and immunosuppressive factors and cells in the tumor microenvironment. Precisely identifying and understanding these mechanisms of immune escape in individual cancer patients will allow for personalized cancer immunotherapy, in which monotherapy and combination immunotherapy are chosen based on the presence of specific immune biology. This approach may enable treatment with immunotherapy without inducing immune escape, resulting in a larger proportion of patients obtaining clinical benefit.
immunotherapy  RCC 
8 weeks ago by cnk
Axitinib plus Pembrolizumab Is Well Tolerated and Exhibits Antitumor Activity in Treatment-Na&iuml;ve Patients with Advanced Renal Cell Carcinoma | PracticeUpdate
Subjects have not received systemic treatment for their metastatic renal cell carcinoma. They receive axitinib orally 5 mg twice daily, and pembrolizumab 2 mg/kg intravenously on day 1 of each 3-week cycle. Response Evaluation Criteria in Solid Tumors v1.1 is used to assess tumors at baseline, week 12, and every 6 weeks thereafter.

Study endpoints include:

Adverse events
Other safety measures
Tumor response
An immunohistochemistry-based assay is used to stain tumor cells for programmed death – ligand 1 expression.

In March 2016, 52 patients were enrolled (79% male; 87% white; mean age 61 years). Eleven (21.2%) patients discontinued both axitinib and pembrolizumab due to:

Disease progression (n=4)
Treatment-emergent adverse events (n=6). These included diarrhea, headache/joint pain, fatigue/joint pain, colitis/hepatitis, aggravated rheumatoid arthritis/psoriasis, and drug-induced liver injury
Another cause (n=1)
Thirty-five (67.3%) patients exhibited an objective response:

Two experienced a complete response
33 experienced a partial response
Eleven patients achieved stable disease. After 11 months, of the 11 patients enrolled in the dose-finding phase, seven remained free of progression.
immunotherapy  RCC 
8 weeks ago by cnk
Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases. - PubMed - NCBI
Abstract
Cancer immunotherapy can confer durable benefit, but the percentage of patients who respond to this approach remains modest. The ability to concentrate immunostimulatory compounds at the site of disease can overcome local immune tolerance and reduce systemic toxicity. Surgical resection of tumors may improve the efficacy of immunotherapy by removing the concentrated immunosuppressive microenvironment; however, it also removes tumor-specific leukocytes as well as tumor antigens that may be important to establishing antitumor immunity. Moreover, surgery produces a transient immunosuppressive state associated with wound healing that has been correlated with increased metastasis. Using multiple models of spontaneous metastasis, we show that extended release of agonists of innate immunity-including agonists of Toll-like receptor 7/8 (TLR7/8) or stimulator of interferon genes (STING)-from a biodegradable hydrogel placed in the tumor resection site cured a much higher percentage of animals than systemic or local administration of the same therapy in solution. Depletion and neutralization experiments confirmed that the observed prevention of local tumor recurrence and eradication of existing metastases require both the innate and adaptive arms of the immune system. The localized therapy increased the numbers of activated natural killer (NK) cells, dendritic cells, and T cells and induced production of large amounts of type I interferons, thereby converting an immunosuppressive post-resection microenvironment into an immunostimulatory one. The results suggest that the perioperative setting may prove to be a useful context for immunotherapy, particularly when the release of the therapy is extended locally.
cancer  immunology  immunotherapy 
8 weeks ago by cnk

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