Immunotherapy strategies for patients with kidney cancer, liver cancer, stomach cancer, esophageal cancer, and melanoma were highlighted during the fourth day of the 2019 annual meeting of the American Society of Clinical Oncology (ASCO19) in Chicago.
Jianjun Gao, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center, started the day with a discussion of a Phase 1 pilot trial (NCT02210117) involving two other MD Anderson scientists affiliated with CRI: James P. Allison, Ph.D., the director of the CRI Scientific Advisory Council, and Padmanee Sharma, M.D., Ph.D., a CRI Clinical Accelerator grantee who led the study.
In this trial, patients with metastatic kidney cancer (renal cell carcinoma) were treated with PD-1 checkpoint immunotherapy (nivolumab) either alone, in combination with CTLA-4 checkpoint immunotherapy (ipilimumab), or in combination with a VEGF-targeting antibody (bevacizumab).
Overall, the patients who received PD-1 immunotherapy alone appeared to have the best outcomes: 59% responded and 72% were alive at the two-year mark, compared to a 44% response rate and 60% two-year survival rate in patients who received PD-1 plus VEGF therapy, and a 43% response rate and 56% two-year survival rate in patients who received dual checkpoint immunotherapy. Patients who also underwent surgical resection did better than those who did not, with 84% of the surgery group surviving at least two years compared to only 46% of those who did not undergo surgery. Based on these results, Gao suggested that PD-1 immunotherapy and surgery should be explored further in a larger trial.
Also in the realm of kidney cancer, Neeraj Agarwal, M.D., of the University of Utah Huntsman Cancer Institute, discussed patient-reported outcomes in the Phase 2 IMmotion150 (NCT01984242) trial, which involved CRI Clinical Accelerator grantee Lawrence E. Fong, M.D., of the University of California, San Francisco, who also serves as a member of the CRI Clinical Accelerator Leadership.
Neeraj Agarwal, M.D., discusses patient-reported outcomes in the Phase 2 IMmotion150 trial at ASCO19.
This trial compared three different first-line therapies in patients with metastatic kidney cancer (renal cell carcinoma): PD-L1 immunotherapy (atezolizumab) alone, the combination of atezolizumab plus a VEGF-blocking antibody (bevacizumab), and the standard-of-care treatment (sunitinib).
Osama E. Rahma, M.D., of the Dana-Farber Cancer Institute, began with an update on the Phase 1/2 CheckMate-040 (NCT01658878) in which patients with advanced liver cancer (hepatocellular carcinoma) were treated with either PD-1 checkpoint immunotherapy (nivolumab) alone, or with dual PD-1 and CTLA-4 (ipilimumab) checkpoint immunotherapy.
Osama E. Rahma, M.D., provides an update on the Phase 1/2 CheckMate-040 trial at ASCO19.
In this study, which involved CRI CLIP Investigator Ignacio Melero, M.D., Ph.D., of Clínica Universidad de Navarra, 31% of the patients treated with the combination responded, compared to only 14% of those treated with PD-1 immunotherapy alone, and half of these responses lasted at least 17 months. In terms of overall survival, the combination-treated patients who received the higher dose of CTLA-4 immunotherapy fared best, with half surviving at least 23 months.
Rahma then turned to esophageal cancer, focusing on the Phase 3 KEYNOTE-181 (NCT02564263) in which PD-1 immunotherapy (pembrolizumab) was compared to chemotherapy as a second-line treatment. While the benefits weren’t seen in the overall patient population, PD-1 immunotherapy did lead to improved overall survival in patients with squamous cell carcinoma—where 39% of immunotherapy-treated patients were alive at the one-year mark compared to 25% of the chemotherapy-treated patients—as well as those whose tumors expressed high levels of PD-L1 (combined positive score ≥10%), where 42% of immunotherapy-treated patients were alive at the one-year mark compared to 20% of the chemotherapy-treated patients. As a result, Rahma claimed, these results are considered practice-changing for these two patient populations.
Next, Rahma discussed long-term follow up data from the Phase 2 KEYNOTE-059 (NCT02335411) in which patients with advanced stomach or gastroesophageal cancer were treated with PD-1 immunotherapy (pembrolizumab) with or without chemotherapy. Immunotherapy alone led to durable responses in heavily pre-treated patients, especially those whose tumors expressed PD-L1.
In previously untreated patients, the combination therapy led to responses 60% of all patients, including 73% of those with PD-L1-positive tumors and 37.5% of those with PD-L1-negative tumors. Of 29 patients with PD-L1-positive tumors who received PD-1 immunotherapy alone, 12 had responses and another 14 had their disease stabilize, and only 3 had their disease progress.
Lastly, in a Phase 2 trial (NCT02954536) in patients with HER2-positive metastatic gastroesophageal cancer, the first-line combination of PD-1 immunotherapy (pembrolizumab) plus an HER2-targeting antibody (pembrolizumab) and chemotherapy led to responses in nearly 90% of the patients treated. However, given the small sample size, this strategy must be investigated further.
Turning to melanoma, Douglas B. Johnson, M.D., of the Vanderbilt University Medical Center, discussed the long-term outcomes of patients treated with PD-1 immunotherapy. The analyzed work involved two CRI Clinical Accelerator grantees from Memorial Sloan Kettering Cancer Center: Margaret K. Callahan, M.D., Ph.D., and Jedd D. Wolchok, M.D., Ph.D., who also serves as an associate director of the CRI Scientific Advisory Council.
Douglas B. Johnson, M.D., discusses a study on the long-term outcomes of patients treated with PD-1 immunotherapy at ASCO19.
Among melanoma patients who had complete responses, roughly one-third had relapses, with most occurring within the first two years. After the first two years, survival remained relatively stable, with 80% ultimately surviving at least five years. Among the overall population of patients who relapsed and were re-treated with PD-1 immunotherapy, only five of the 34 patients in the study responded. While this response rate was not as promising as anticipated, one intriguing observation was that there were patients who had disease progression after prior treatment who responded after the subsequent re-treatment.
Next, Johnson discussed the Phase 1/2 KEYNOTE-029 (NCT02089685), which was led by CRI Clinical Team Leader Georgina V. Long, M.D., Ph.D., of the Melanoma Institute Australia. In this trial, patients with advanced melanoma were treated with PD-1 immunotherapy (pembrolizumab) in combination with two different doses of CTLA-4 immunotherapy (ipilimumab). The first group received a dose that was half as much as the second group, but received it twice as often. Overall, response and disease control rates were similar, with the first group experiencing a 55% response rate and 78% disease control rate, compared to the 61% response rate and 86% disease control rate seen in the second group.
Finally, Jason J. Luke, M.D., of the University of Pittsburgh Medical Center, highlighted a Phase 3 trial (NCT02967692)—led by Long and also involving Antoni Ribas, M.D., Ph.D., of the University of California, Los Angeles, who serves on the CRI Clinical Accelerator Leadership—in which patients with advanced melanoma that possesses mutated BRAF were treated with the first-line combination of PD-1 immunotherapy (spartalizumab) plus a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib).
Jason J. Luke, M.D., highlights a Phase 3 trial for melanoma at ASCO19.
More than 40% of patients had complete responses, and half the patients went at least 23 months without experiencing progression. In agreement with previous results, including some discussed yesterday at ASCO19, patients who did experience disease progression had tumors with lower mutational burdens, or tumor microenvironments characterized by immunosuppression and a lack of T cell inflammation, compared to patients who remained progression-free.
A poster analyzed how body composition related to responses in patients treated with PD-1 immunotherapy. Interestingly, patients with high amounts of both fat and muscle tissue had the best outcomes, whereas those with high amounts of fat but low amounts of muscle seemed to fare the worst.
Luke ended his discussion with a study that looked at how circulating exosomes—extracellular “capsules”—containing PD-L1 were associated with responses in melanoma patients. While baseline levels of PD-L1 exosomes were not predictive of response, how those levels changed during and after treatment did appear to correlate with tumor shrinkage and patient survival. This led to the suggestion that these PD-L1 exosomes might provide a more reliable—and more easily acquired—biomarker than tumor PD-L1 expression when it comes to predicting patient responses, and should certainly be examined further with respect to its clinical value.
That’s it for Day 4 of ASCO19. For our highlights of the final day of ASCO19, be sure to check on our blog in the coming days and remember to join our “Cancer Immunotherapy Insights from ASCO” Twitter chat (#CIMchat) on June 11, at 12pm ET, moderated by Sharon Begley, senior science writer at STAT.
Photos by Arthur Brodksy, Ph.D. for Cancer Research Institute