Introduction
The FDA approved the combination therapy avelumab and axitinib for first-line treatment of metastatic kidney cancer patients on May 14, 2019 based on the results of a Phase III trial, Javelin 101 Renal, led by Toni Choueiri of Dana Farber Institute, comparing the combination of avelumab (Bavencio) and axitinib (Inlyta) versus sunitinib (Sutent) for first-line treatment of patients with metastatic, clear cell kidney cancer. The trial results showed a 31% reduction in disease progression or death for the avelumab + axitinib patient arm as compared with the sunitinib arm. The results were reported on at the ESMO Conference in Munich, Germany in October 2018, the ASCO GU Symposium in February 2019 in San Francisco, the ASCO General Meeting in June 2019, and in a New England Journal of Medicine article by Robert Motzer et al, on March 21, 2019. The following is a summary of the trial results using the above as references.
Dosage
In this 886-patient trial, avelumab, the anti-PD-L1 immunotherapy was administered by infusion every two weeks, while axitinib, the oral VEGFR TKI (tyrosine kinase inhibitor) was prescribed at 5 mg and taken orally twice daily. Sutent was delivered orally in its standard dose of 50 mg, four weeks on and two weeks off. The dosages of axitinib and sunitinib could be varied depending on reaction to toxicities, however, the dosage for avelumab remained constant, although they could be skipped. If the regimen became intolerable, the patient was dropped from the trial.
Performance
The primary objective of the trial was to determine if the combination therapy of avelumab + axitinib is superior to sunitinib in metastatic, clear cell, kidney cancer patients who tested positive for the biomarker PD-L1. Superiority was defined as either higher progression-free survival or longer overall survival. Data were collected and reported on for the overall population as well.
In the PD-L1 positive trial population, the median PFS (progression-free survival) was 13.8 months for the avelumab/axitinib combination versus 7.2 months for sunitinib. In the overall population, i.e., patients with and without the marker, the PFS was also 13.8 months in the avelumab + axitinib arm, but it was 8.4 months in the sunitinib arm, suggesting that patients with a negative PD-L1 biomarker do slightly better on sunitinib than do patients with a positive biomarker. Based on the hazard ratio of 0.61, the avelumab + axitinib patients had a 39% reduction in disease progression or death as compared with the sunitinib population. This was higher than the 31% reduction for the general trial population, the difference being the lower PFS response of the sunitinib patients who were PD-L1 positive.
The PFS for sunitinib for this trial was notably lower than for use of sunitinib in other Phase III trials, which averaged 10.3 mos. There was no explanation by the investigators as to why there was a difference.
The overall response rate (the sum of complete and partial responses) for the PD-L1 positive population for the combination therapy was 55.2% versus 25.5% for the sunitinib patients. The total trial patients had similar results with 51.4% and 25.7% for ORR for avelumab/axitinib versus sunitinib.
This is the second combination therapy using a PD-1 checkpoint inhibitor immunotherapy with an anti-VEGF therapy that the FDA has approved for renal cell carcinoma in the last three months, the first being pembrolizumab and axitinib versus sunitinib.
The median overall survival (OS) had not yet been reached for either group at a 19-month follow-up. Grade 3 or higher Adverse Events occurred in 71.2% of the avelumab/axitinib group and 71.5% of the sunitinib patients.
Summary of the Trial
Rationale
There are several reasons why the combination of axitinib with avelumab was chosen to test their efficacy in clear cell patients. The two drugs have different targets with axitinib inhibiting the vascular endothelial growth factor (VEGF), which promotes angiogenesis, or the tumor’s ability to promote the growth of blood vessels that nurture the tumor’s growth, while avelumab is an anti-PD-1 checkpoint inhibitor. In a breast cancer study, anti-VEGF therapy was shown to promote immune cell infiltration into the tumor as well as inhibiting myeloid-derived suppressor cells (MDSCs) infiltration. MDSCs have been shown to suppress immune responses to tumor growth. Axitinib has also been shown to have lower hepatotoxic (liver toxicity) effects than other anti-VEGFs such as sunitinib or pazopanib. Finally, this trial was sponsored by Pfizer, which produces both axitinib and sunitinib and has entered into a joint agreement with Merck, the producer of avelumab, to develop and market the avelumab/axitinib combination.
There were 144 sites that treated trial patients in North America, Europe and in parts of Asia. Patients were recruited from the end of March 2016 through mid-December 2017. The first interim analysis was reviewed on August 20, 2018. Overall survival continues to be monitored.
Results
As can be seen from the following graphs, there was no difference in PFS for avelumab/axitinib patients who were PD-L1 positive versus those who were a mixture of positive and negative, both being at 13.8 months. Interestingly, there was a minor difference in PFS for the overall sunitinib patient population, which was 8.4 months, versus those who have PD-L1 positive tumors, which was 7.2 months. In any case, a positive PD-L1 marker has again shown itself to be deficient in predicting response to an anti-PD-1 checkpoint inhibitor. This is good for the drug company but not for the patient, since, without other limiting factors such as specific toxicities, any metastatic kidney cancer patient can be encouraged to take any anti-PD-1 checkpoint inhibitor since there is nothing yet to predict the success of one over another.
According to the NEJM article authors, the final primary objective of the study was “to show the superiority of avelumab plus axitinib over sunitinib with respect to either progression-free or overall survival among patients with PD-L1–positive tumors.”
Patient Characteristics
For this trial, patients were randomized between the two groups with the approximate breakdown by IMDC risk status as follows: favorable – 21%, intermediate – 61%, and poor – 16%; 80% had a previous nephrectomy; and most had either one or two sites of metastasis. The patient breakdown was: 75% male and 25% female; 29% from the U.S., 29% from Canada and Europe, and 42% from the rest of the world; previous nephrectomy 83.
A total of 1,155 patients were evaluated for inclusion in the trial. Of these, 873 were included and were randomized to either arm, with 434 receiving avelumab/axitinib and 439 receiving sunitinib.
Of the 434 patients assigned to avelumab/axitinib, 187 discontinued the trial (some patients discontinued one or the other drug in the combination, but remained on the trial), and of the 439 patients assigned to sunitinib, 277 discontinued, see below.
Patient Endpoints
*Other reasons include deterioration of health, withdrawal of consent, and death
The following table shows the patient response to each therapy categorized by those patients who were positive for the biomarker PD-L1 versus the response of the overall patient population, i.e., those who were positive to PD-L1 and those who were negative to PD-L1.
Response to Therapy in Both PD-L1 Positive Tumors and in the Overall Population
*The odds ratio for patients with PD-L1 positive tumors was 3.7. The odds ratio for the overall population was 3.1. This means, for example, that patients with PD-L1 positive tumors who were taking avelumab plus axitinib were 3.7 times more likely to have an objective response than those on sunitinib with PD-L1+ tumors.
Patients in the overall population who received avelumab + axitinib had superior performance in all three risk categories than those receiving sunitinib.
Patient Objective Response per Risk Category
After Disease Progression and PFS2
After patients progress, many go on to take other therapies, 22.6% of the avelumab + axitinib group and 40.5% in the sunitinib group. The most common post- progression therapy for the sunitinib patients was nivolumab (24.1%), while for the avelumab + axitinib patients it was cabozantinib (9.5%). No matter the subsequent therapy, the avelumab + axitinib group still had a longer PFS, defined as PFS2 or the time from original randomization to tumor progression or death while on the second-line therapy. The PFS2 for the sunitinib patients was 18.4 months, while the PFS2 for the avelumab + axitinib patients had not yet been reached at time of analysis, although it was greater than 19.9 months. The Hazard Ratio was 0.56 meaning that the avelumab + axitinib patients were 44% less likely to progress or die than the sunitinib patients while on the secondary therapy. These data are for the overall population.
Toni Choueiri, who made the presentation on the avelumab trial at this year’s GU Symposium, hypothesized that the initial therapy could change the biology of the tumor, which might affect the patient’s response to the follow-up therapy. In the era of targeted, anti-VEGF therapies, the second-line therapy invariably had a lower PFS than the first-line therapy, so it’s interesting that the sunitinib group had a longer median PFS on the second-line therapy than on sunitinib itself. We don’t know the PFS2 for the avelumab + axitinib group as it hasn’t been reached yet, nor do we know the median overall survival of the two groups, although, so far, avelumab + axitinib, unlike pembrolizumab + axitinib, has not demonstrated a longer survival time over sunitinib. This may change when the data are mature.
Biomarkers
As heretofore said, PD-L1 has not been shown to be a reliable biomarker of response to anti-PD-1 checkpoint inhibitors, although PD-L1 positive patients fared worse on sunitinib than those with PD-L1 negative tumors. In this trial, the investigators started looking for other genetic indicators of response.
By examining tumor tissue, would they find a relation between PFS and mutated genes? Indeed there was a difference in PFS between the treatment arms when there were mutations in genes such as CD1631L, PTEN, and DNMT1. This is an attempt to develop a gene expression signature (GES) to predict clinical outcomes. They also found that a high-angiogenesis GES indicated a higher PFS in the sunitinib arm but not in the avelumab-axitinib arm, while a low-angiogenesis GES resulted in a PFS benefit in the combination arm versus sunitinib, further validating that the combination of an anti-PD-1 checkpoint inhibitor with an antiangiogenic agent is apprpriate. Patients with a high concentration of effector T cells (Teffector) and inflamed T cells (Tinflamed) in the avelumab + axitinib arm had a longer PFS than the sunitinib patients. Finally, tumor mutational burden did not have an effect on PFS, unlike with melanoma and other cancers for which there is a direct relation between response to checkpoint inhibitors and tumor mutational burden. So far, no one has been able to explain this enigma. i.e., why kidney cancer patients respond to checkpoint inhibitors despite having a low tumor mutational burden.
Adverse Events
Just about everyone in the trial, both avelumab + axitinib and sunitinib patients, had some sort of adverse event. Similarly, 71% of patients on both arms experienced at least one Grade 3 or higher event. The following lists Grade 3 or higher events affecting at least 5% of the avelumab + axitinib arm.
The trial investigators linked hypertension and hand-foot syndrome to the use of axitinib.
166 patients (38.2%) of the 434 patients taking avelumab + axitinib had immune-related adverse events with 39 of those patients, or 9.0%, having Grade 3 or greater AEs. The most frequent immune-related AEs were thyroid disorders with 48 patients being administered steroids to control the event. Hypothyroidism is a known side effect of both avelumab and axitinib.
Finally, death due to toxicity of the trial treatment occurred in three patients on avelumab + axitinib and one patient on sunitinib.
Comments
The combination of avelumab and axitinib outperformed sunitinib both in progression-free survival and in objective response with the combination having doubled the ORR of sunitinib both among PD-L1 positive patients and in the overall population. Patients on avelumab + axitinib were over three times more likely to have an objective response than those on sunitinib. So far, there is no advantage in overall survival for avelumab + axitinib, but the median OS has not yet been reached on either arm so that might change. There was little difference in the performance of the combination whether or not the patients were PD-L1 positive or negative, with both groups showing positive performances.
The authors referenced a Phase 3, first-line trial of axitinib versus sorafenib (Nexavar) that
was reported on in 2012 (axitinib and sunitinib never went head-to-head as they are both made by Pfizer). In that trial, the axitinib patients had a median progressive-free survival of 10.1 months and an objective response rate of 32%. They go on to say that the magnitude of the efficacy of the combination of avelumab and axitinib in this trial “supports at least additive if not synergistic effects of the VEGF tyrosine kinase inhibitor–immune checkpoint inhibitor combination”.
The combination arm also increased the toxicity especially among those patients who experienced Grade 3 or higher Adverse Events. A quarter of avelumab + axitinib patients had Grade 3 or higher hypertension. The investigators attributed the hypertension to axitinib, which is well known to cause hypertension (although there is a correlation between hypertension and positive response in axitinib patients). With respect to avelumab, the results of a Phase II trial in Merkel Cell showed 13% all-grade hypertension with 6% being Grade 3 or higher, which implies a contributory effect to increased hypertension with this combination.
In trials combining a TKI and a checkpoint inhibitor, toxicity will be an issue that will have to be addressed. In this trial, 33% discontinued avelumab, 22% discontinued axitinib, while only 18% discontinued sunitinib due to adverse events. So, it seems that while response is additive, so may be the toxicity.
The Future
Combinations of therapies that have different targets is obviously the way to go in order to develop durable responses in metastatic kidney cancer patients. PD-1 is not sufficient to get us there so other molecules have to be developed to inhibit drivers of metastatic kidney cancer.
For example, a molecule called PT2977 was developed by a small company called Peloton Therapeutics to inhibit HIF-2a, a driver of clear cell kidney cancer (ccRCC). Merck recently purchased Peloton for $1.05 billion in order to gain access to a promising molecule together with the rest of Peloton’s pipeline. Merck is the co-developer of avelumab, with Pfizer, and also developed pembrolizumab so it is rapidly becoming a big player in kidney cancer.
A second example is myeloid-derived suppressor cells (MDSCs), which suppress T-cells. There are efforts to develop a molecule inhibitor of these cells. But in order to include these and other tumor fighters in a cocktail of drugs to battle kidney cancer, something has to be done to reduce the toxicity of these agents.
It would also be helpful to test the new drugs head-to-head to see which ones are the most effective and to develop biomarkers to predict response to a drug or class of drugs, which was never done for the anti-angiogenic therapies.
Finally, ccRCC may be the most prevalent type of kidney cancer but it’s not the only one, and more of an effort must be made to develop agents to treat non-clear cell RCC.
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