Sorafenib trial results

In a discontinuation phase II study, previously treated NSCLC patients who had SD after 8 weeks of treatment with sorafenib were randomized to further treatment with sorafenib or placebo. Before randomization, patients received sorafenib for 8 weeks—patients who responded continued sorafenib; patients that progressed went off study.

In total, 81 patients with SD were randomized to receive sorafenib or placebo. The PFS was 3. Although a trend in improvement in OS was observed As sorafenib was found to have some efficacy in these two studies the compound was further investigated in a phase III trial.

The overall response rate ORR p 10 It failed to meet prespecified criteria in at least two responses in the first 20 patients after 8 weeks of treatment. In conclusion, sorafenib monotherapy failed to demonstrate benefit in unselected NSCLC patients, both in the first-line setting as well as in pretreated patients; however, in these trials some achieved long-term disease control, and, equally importantly, it was shown that long-term treatment with sorafenib was tolerable and no safety problems were encountered.

Sorafenib and Chemotherapy Combinations Sorafenib was also studied in combination with several cytotoxic agents. The study was preliminary terminated after a prespecified interim analysis that showed a median OS of The RR was also similar in both arms. The ORR was Again, this study failed to show survival benefit in patients treated in the sorafenib arm compared with patients in the placebo arm median OS The median PFS in the sorafenib and placebo groups was 6.

Median PFS was 5. The toxicity level was acceptable. In a second phase II study of sorafenib and erlotinib, pretreated advanced NSCLC patients were randomized to sorafenib and erlotinib or erlotinib and placebo. In 72 patients EGFR mutational analysis was performed. In the 67 patients with EGFR wild type wt , the median PFS was significantly better in the group treated with sorafenib and erlotinib 3. Median OS was 8. A slight increase in toxicities in sorafenib-treated patients was observed.

Both studies encourage further evaluation of the combination of sorafenib and erlotinib in EGFR wt patients. In elderly patients with advanced NSCLC the combination of sorafenib and erlotinib was found to be more feasible as first-line treatment than sorafenib and gemcitabine. Sixty patients were included in this phase II study. The primary objective was 1-year survival rate. The ORR was 6. The combination of sorafenib and erlotinib had a numerically higher 1-year survival rate than patients receiving sorafenib and gemcitabine.

This study suggests that patients with a KRAS mutation may benefit from treatment with sorafenib, although the trial result was not significant. However, a small single-centre study aimed at biomarkers that could predict response to sorafenib did not find benefit in patients with either a KRAS or EGFR mutation compared with patients without these mutations.

Primary endpoint was DCR at 6 weeks of treatment. PubMed Article Google Scholar. Download references. Hospital del Mar. You can also search for this author in PubMed Google Scholar. Correspondence to J. Reprints and Permissions. Bellmunt, J. Clin Transl Oncol 9, — Download citation. Received : 01 June Accepted : 27 July Published : 18 November Issue Date : October Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Patients on therapeutic-dose anticoagulation were also excluded. Sorafenib was administered at the dose of mg orally twice daily on a continuous basis. Blood pressure was monitored and recorded by the patient at least weekly until stable or at least for the first 4 weeks.

Physical examination, CBC count, and serum chemistries were performed at baseline and every 4 weeks for the first 24 weeks and then every 8 weeks. At each visit, patients were assessed for adverse events AEs , concomitant medications, and compliance using patient diaries and pill count. Patients with evidence of clinical benefit defined as symptomatic or tumor marker improvement, decreased tumor burden compared with baseline, or limited progression in nontarget lesion treated with radiation or surgery despite PD per RECIST were allowed to continue sorafenib.

Serum calcitonin and CEA levels were obtained at baseline, every 8 weeks during treatment, and within 2 to 4 weeks after completion of treatment. All SUVs were normalized to body weight, and response to therapy was determined by the change in SUV for scans acquired before and during therapy.

In all patients, RET genotyping from peripheral blood was performed as a part of the standard of care evaluation. Paired tumor fine-needle aspiration biopsy samples before treatment and at 8 weeks after treatment if patients had disease that could be biopsied and were willing to undergo biopsies for research purposes were obtained to evaluate the degree of Ret-Ras-MAPK signaling inhibition by sorafenib Appendix.

The secondary end points were to assess the toxicity of sorafenib and to correlate tumor response with serum tumor marker changes, functional imaging, and the presence and type of RET mutations. Arm A was terminated on September 10, , because of poor accrual for this rare cancer and availability of several competing trials in the United States.

We report the data on all patients collected through April 15, At the time of data analysis, seven patients remained on study, whereas 14 patients came off therapy for the following reasons: arm B, six patients with PD, one clinical progression, and three AEs including one grade 5 event; and arm A, one AE, one patient withdrawal, one discontinuation of sorafenib for more than 21 days, and one loss of insurance coverage. Progression was noted in various metastatic sites including lymph nodes, bone, and liver, with no specific site of metastasis accounting for PD.

The median duration of sorafenib therapy was 15 months range, 1 to Among 15 evaluable arm B patients, all patients experienced some measurable degree of tumor shrinkage. For arm B, the median PFS time was SD, stable disease; PR, partial response. B Progression-free survival for arm B patients.

The median progression-free survival time is C Overall survival for arm B patients. The median overall survival was not estimable at the data analysis cutoff point. Of 15 patients with grade 1 to 2 diarrhea, 11 had new onset of diarrhea, two had worsening of baseline diarrhea, and two had no change in the baseline diarrhea. Grade 3 AEs occurred in eight patients and included hypertension, HFSR, diarrhea, joint pain, infections, thrombocytopenia, and hyponatremia. Of the two patients with grade 3 diarrhea, one had worsening of baseline grade 1 diarrhea, whereas the other patient developed new-onset diarrhea.

Grade 4 AEs included pulmonary embolus and hypokalemia. There was one grade 5 event of death in a patient in arm B with an adrenocorticotropic hormone—producing metastatic MTC who had a sepsis-like clinical picture including renal failure, hyperkalemia, and disseminated intravascular coagulation.

On autopsy, no obvious bowel perforation was found, although there was a segment of hemorrhagic and necrotic small bowel and widespread Clostridium infection detected. Twenty patients had calcitonin and CEA tumor marker measurements at both baseline and at least one other time point 8 weeks after study initiation. As shown in Table 3 and Figure 3 , 17 patients had a decrease in either the calcitonin or CEA level, and 11 patients had a decrease in both tumor markers.

However, neither the timing nor the degree of tumor marker response significantly correlated with the degree or duration of RECIST response. RECIST response refers to the change from baseline in the sum of the diameter of all indexed lesions. RET mutational analysis of all patients is reported in Table 3. However, because of low tumor cellularity in the samples obtained, such evaluation was not possible. At baseline, the median number of index lesions per patient identified was eight lesions range, three to 17 lesions , and the median SUV max was 3.

At the 8-week follow-up, the median SUV max was 2. The correlation between changes in SUV max and objective tumor response was not statistically significant. There was no decrease in K ep in one patient. Nine patients had SD, and one patient had PR. For all patients evaluated, there was no correlation between the magnitude of decrease for both K ep and Amp and objective tumor response.

Accrual to the hereditary MTC arm was prematurely terminated, and conclusions about efficacy of sorafenib in patients with hereditary MTC cannot be drawn.

In the sporadic MTC arm, the target of two objective responses out of 16 patients treated in the first stage was not reached. Although this suggestion of prolonged SD is encouraging, it is based on post hoc analysis of a small subset of patients in this trial. Attempts have been made to identify high-risk patients with sporadic MTC. This tendency toward tumors with an aggressive course is reflected in our study population in that all of the patients with sporadic MTC with the RET mutation had had PD within 12 months of study entry or were newly diagnosed with advanced disease at study entry.

A decrease of either calcitonin or CEA, or both, was observed in the majority of patients on this study. However, neither baseline tumor marker level nor the degree of tumor marker response significantly correlated with the degree or duration of RECIST response.

Whether calcitonin decreases are related to transcription inhibition of calcitonin or tumor shrinkage remains unclear. The Ret kinase inhibitor NVP-AST was shown to inhibit calcitonin gene expression and transcription in TT cell xenografts, leading to lowered plasma calcitonin levels shortly after treatment. Sorafenib was reasonably well tolerated in this study. In general, the AEs observed were mostly low grade and were similar to toxicities previously reported.

These rare but fatal AEs must be taken into account for assessing risk versus benefit when offering sorafenib to patients with metastatic MTC. Most of the observed AEs were managed effectively with dose reduction and symptomatic therapy. Although we do not know the true targets of sorafenib or the degree of contribution from Ret inhibition, VEGFR inhibition seems to play an important role.

In summary, sorafenib is a reasonably well-tolerated oral therapy that offers clinical benefit and may be an option for patients with sporadic metastatic MTC who are not able to participate in clinical trials. Early recognition and prompt management of the expected AEs of sorafenib will allow more patients to continue on therapy as long as they are achieving clinical benefit.

Future studies should evaluate the predictors of response to sorafenib and combination therapies to enhance the degree and duration of response. Ten-micrometer slices were cut from the tumor paraffin tissue block, hematoxylin and eosin slides were prepared to verify pathologic diagnosis, and tumor margins were marked by the pathologist.

RET mutation studies were performed for common hotspots in exons 10, 11, and For exons 10 and 11, the entire exonic sequence was amplified from the isolated genomic DNA by polymerase chain reaction using m13 tailed primers and then bidirectionally sequenced on an ABI automated sequencer using the Big-Dye terminator cycle sequencing kit Applied Biosystems, Foster City, CA. Hum Mol Genet , Fine-needle aspiration FNA biopsies using to gauge needles of the tumor ie, either cervical lymph nodes or bulky bony or lung or liver metastasis were to be performed under imaging guidance or blindly depending on the location and size of the tumor.

Eight slides were prepared, of which two slides were stained with Pap Stain for cytologic diagnosis to verify that tumor was indeed present in the FNA specimen. Supported by Grant No. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Although all authors completed the disclosure declaration, the following author s indicated a financial or other interest that is relevant to the subject matter under consideration in this article.

For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Ringel, Veracyte C ; Richard T.

Conception and design: Matthew D. Ringel, Richard T. Kloos, Michael V. Knopp, John J. Wright, Manisha H. Financial support: Michael V. Knopp, Miguel A. Villalona-Calero, Manisha H.