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- Margaret Thatcher in The Spectator 1975-1990.
Blog Donate. Special Report. Hot Off The Press. Main Street U. Of Impeachers and Extra Drumsticks. He had it made in the shade, said my complacent conservative friends. The result was brutal. But we do not have to look back 32 years to see how unruly the leftwing mob can be.
What Comes After (The Walking Dead) - Wikipedia
Recall the recent fate of Judge Brett Kavanaugh. Only his courage and unscotchable determinate saved him. The simple fact is that the conservatives are often slow on the draw against the American left.
It is time for the conservatives to rally around him. He can probably win with the President on his side. He apparently has the votes.
The Right Prescription. Be a Free Market Loving Patriot. History faces a new and existential threat: climate change. Liberals must adapt to the idea that unlimited economic progress may be destroying civilisation. Conservatives will struggle to find a place for an unprecedented event such as a global climate crisis in a cyclical view of history. And is it really possible to dream of a socialist utopia on the other side of a climate apocalypse? For the Indian writer Amitav Ghosh, climate change represents the end of history in a more fundamental way than Fukuyama could have dreamed of.
For if the entirety of our past is contained within the present, then temporality is drained of significance. Sign up. You are browsing in private mode. Related articles. First Thoughts: Flooding in Venice, royal term limits and why professional sportsmen are like robots. Although these agents have significantly improved outcomes, they rarely result in complete responses, and resistance to these agents is inevitable, leading to progressive disease PD in virtually all patients [ 7, 8 ].
Renal cell carcinoma is an immune-responsive tumor and high dose IL-2 has been used in select patients leading to complete and durable responses in a subset of them [ 9 ]. Improved understanding of T cell function and associated immunosuppressive molecules such as cytotoxic T-lymphocyte-associated protein 4 CTLA-4 , program death 1 PD-1 and PD-1 ligand 1 PD-L1 , called immune checkpoints, have led to the development of novel immunotherapies [ 10 ].
Nivolumab, an immune checkpoint inhibitor ICI in the form of a monoclonal antibody directed at PD-1, has been investigated for the treatment of refractory metastatic RCC. The treatment was well tolerated. Here we discuss data regarding these agents. As compared to sunitinib, the nivolumab and ipilimumab combination led to improved OS HR, 0. The median progression-free survival PFS was The situation is more complex in good-risk patients where response and PFS favor sunitinib over nivolumab and ipilimumab, but long term follow-up for overall survival data is required.
A randomized phase III trial evaluated the combination of axitinib and pembrolizumab in untreated advanced or metastatic RCC compared to sunitinib. The trial met both of its primary endpoints and showed that treatment with the combination of axitinib and pembrolizumab, lowers the risk of death HR for death, 0. The ORR was These favorable outcomes with combination treatment were observed across all risk groups and regardless of PD-L1 expression [ 15 ].
The trial met one of its co-primary endpoints with an improvement in PFS. Median PFS was OS data was immature at the time of presentation.
The median PFS in the overall population, a key secondary endpoint, was Similarly, a randomized phase III trial met one of its co-primary endpoint demonstrating superiority of combination of atezolizumab, an anti-PD-L1 antibody, with bevacizumab, as compared to sunitinib monotherapy [ 17 ]. The median PFS was 8. The PFS with cabozantinib was 8. However, several limitations of the trial have been highlighted [ 21 ] including an underperformance of sunitinib arm 5.
Based on a composite assessment of these datasets, an ICI based therapy has been adopted as a standard of care SOC for untreated RCC patients with the option of cabozantinib usually reserved for patients who are not candidates for an immune based therapy. As discussed above, the first line treatment landscape of RCC is rapidly evolving. These changes in the treatment paradigm have raised several important clinical questions regarding the sequencing of treatment after patients progress on these immune based therapies.
Although these patients will likely go on to receive TKIs or other targeted treatments like mTOR inhibitors , the data regarding their efficacy and safety in this setting is needed. The main objective of this review is to summarize and discuss available data regarding various treatment options in these patients, our opinion regarding treatment sequence and selection, and future directions in this space. Few retrospective analyses have evaluated the efficacy of targeted treatment in patients who have disease progression on ICI-based therapy [ 23—25 ].
These studies represent a heterogeneous patient population with several limitations but generally suggest feasibility and at least reasonable efficacy of targeted agents in this setting. Another retrospective study evaluated the clinical outcomes of patients receiving second-line TKIs after progression on nivolumab and ipilimumab treatment as part of the Checkmate study, thereby providing data in a more homogenous patient population [ 26 ]. This study demonstrates clinical efficacy of TKIs after progression on front-line nivolumab and ipilimumab treatment.
Here we describe available data regarding the available agents in the treatment of refractory disease and specifically after PD on ICI-based therapy.
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Axitinib showed an improved PFS of 6. In patients who received cytokine-based immunotherapy as first line therapy, patient given axitinib on this study had a median PFS of Based on these data, axitinib was approved for patients with relapsed disease or refractory to cytokine and TKI therapy [ 13 ]. The activity of axitinib after progression on an ICI was evaluated in a prospective phase II trial where axitinib was given on an individualized dosing algorithm.
The primary endpoint of the trial was PFS. The estimated median PFS in the evaluable patients was 9. There were no unexpected toxicities related to axitinib observed on the study [ 28 ]. The retrospective studies discussed above have also reported data on axitinib use in patients with progression on an ICI.
In the updated results, cabozantinib was found to have improved overall survival with median overall survival of In a subgroup analysis of patients with bone metastases, cabozantinib showed an improved PFS as compared to everolimus 7.
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These data may suggest benefit of cabozantinib in patients with bone metastases. However, the PFS with cabozantinib in patients with bone metastases 7. Median age on this study was 62 years range 37—78 and median number of prior therapies was 2 range 1— The median TTF was 6. Tivozanib showed an improvement in PFS as compared to sorafenib The ORR for tivozanib, based on blinded independent radiology review, was No improvement in OS was observed with tivozanib treatment.
Tivozanib compared to sorafenib was then investigated in refractory failed at least two prior regimens advanced or metastatic RCC. The median PFS was 5. Patients who received pazopanib had improved PFS of 9. It has been a commonly used initial agent in untreated metastatic RCC based on these data and favorable tolerability [ 13, 14 ].
No prospective data exists regarding the use of pazopanib in post ICI space, however an ongoing trial is accruing patients as discussed later in this article. In the retrospective review from Albiges et al. Best response was SD in 9 patients whereas PD occurred in the remaining 5 patients.
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