Table 1-Checkmate 214 - updated data from 2017:
PDL1+ presence leads to higher efficacy of the immune checkpoint inhibitors, but also lower sunitinib efficacy. However, there are still plenty of responders and substantial complete response to immune checkpoint inhibitors in patients who are PDL-1<1%, as can be seen in table 2. When assessing progression free survival, a clear advantage can be seen in the nivolumab and ipilimumab combination in the intermediate and poor risk patients, but this advantage cannot be demonstrated in favorable risk patients (Figure 1). Health related quality of life is also better with nivolumab + ipilimumab compared to sunitinib, as shown in figure 2.
Table 2 – Antitumor activity by tumor PD-L1 expression level:
Figure 1 – Progression free survival according to disease risk:
Figure 2- Health related quality of life:
The next topic discussed was monotherapy with anti-PD1. The keynote 427 is a study assessing the effect of pembrolizumab as monotherapy in advanced/metastatic clear cell or non-clear cell renal cell carcinoma (RCC), as shown in Figure 3. This study demonstrated an objective response rate of 38.2%, with a complete response and partial response rate of 3% and 39%, respectively. When stratifying according to the IMDC categories, the objective response rate was 31.7% and 42% for favorable and intermediate/poor risk disease, respectively.
Figure 3 – Keynote 427 trial scheme:
Dr. Atkins also mentioned the nivolumab monotherapy trial for patients with metastatic kidney cancer as being assessed the HCRN GU 260 trial (Figure 4).
Figure 4 – Trial diagram – HCRN GU 260 BMS 209-669:
Summarizing the presented data thus far, Dr. Atkins reiterated that Nivolumab + ipilimumab represents the current standard of care for treatment naïve patients with intermediate and poor risk advanced RCC. The role of anti-PD1 monotherapy in comparison to the combination therapeutic options needs to be further explored. VEGFR tyrosine kinase inhibitors (TKIs) monotherapies are largely non-curative and associated with poor quality of life and lower complete response rates, and therefore should be reserved for patients who can’t receive immune checkpoint inhibitors. Lastly, PD-L1 status is sill too fluid to be used for clinical decision making.
After summarizing the different options of monotherapies, Dr. Atkins moved on to discuss the various treatment combination options (figure 5). In 2019, many new options of treatment will most likely be available and making data-based treatment decisions is going to get complicated.
Figure 5- Comparison of the various treatment combinations:
There are several issues with comparing different combination therapies across trials, even with a common control arm. The first problem is the different balance in IMDC risk groups between the studies. It is known that a higher proportion of good risk patients favors sunitinib, while a higher proportion of intermediate and poor risk patients favors pure immune checkpoint inhibitors. The 2nd problem is the PDL1 expression as a biomarker, and the definition of PDL1+ differs across the various studies (from 20%-60%). Additionally, the endpoints are different between the studies. The stopping/censoring rules are also different between the studies, and lastly the quality of life varies, depending on when the patient was asked.
There are two approaches to combination of immunotherapy:
1. Use of immunotherapy (PD1/PDL1 pathway blockers) to improve the effects of standard therapies
2. Use other agents/therapies to improve the effect of immunotherapy
The anti PD1/PDL1 + anti VEGF combinations are exciting, and several will likely be FDA approved. It is unclear if the activity is synergistic or merely additive. The expense and the toxicity will likely exceed sequential treatment approaches. The overall survival benefits may be less clear than those demonstrated in progression free survival.
It is unclear which patients should get the ipilimumab + nivolumab combination or the VEGF + PD1 blockade combination. There is a need for longer follow-up and appropriate phase 3 trials with immune checkpoint inhibitors endpoints, standardized biomarkers, and universally available crossover to be able to make rational treatment decisions. There is also a need for biomarker studies to help us sort out who should get which therapy, rather than focusing on clinical variables. The biomarkers should be tied to immune checkpoint inhibitor endpoints. Potential phase 3 assessments of anti-VEGF + immune checkpoint inhibitor combinations in RCC are shown in table 3.
Table 3 – Potential phase 3 assessments of Anti-VEGF + immune checkpoint inhibitor combinations in RCC:
Dr. Atkins concluded his interesting talk predicting that in five years from now, the first line therapy for advanced metastatic RCC will be either an immune checkpoint inhibitor alone vs. a combination of VEGF inhibitor + immune checkpoint inhibitor. Dr. Atkins hopes that by that time, results with the 1st line will be god enough, and 2nd line therapy will not be required.
References:
Presented by: Michael B. Atkins, MD, Georgetown University
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre (@GoldbergHanan) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA