Experts Discuss Immunotherapy's Role in the Shifting Landscape in Solid Tumors

In recent years, immunotherapy offered hope for the treatment of many tumor types by showing efficacy, safety and durability. A recent panel of oncology professionals came together to discus the rapidly-evolving field that is shifting the treatment paradigm of cancer treatment.

“Everything we’ve done up until a few years ago has really been to fight the cancer, usually with chemotherapy, but now we have tools that help an individual fight his or her own tumor,” said Dean F. Bajorin, M.D.

During the Peer Exchange program, the panelists provided an overview on how immunotherapies are changing the treatment landscape for melanoma, lung, kidney, bladder, and head and neck cancers. Much of the discussion focused on immune checkpoint inhibitors, including PD-1, PD-L1 and CTLA-4 inhibitors, which have generated some of the greatest developments in this field to date.

As these new therapies are integrated into treatment paradigms, clinicians are raising many questions about managing associated toxicities that patients experience, said Mark A. Socinski, M.D., who served as moderator for the program. The new agents have “a different spectrum of toxicity,” he said.

“I field many phone calls on a weekly basis from our regional referring community oncologists about how to handle toxicities,” Socinski said. “There’s a huge learning curve in terms of recognition and treatment.”

Melanoma

Melanoma set the stage for immunotherapies, and several agents have been approved by the FDA for these patients, including the PD-1 inhibitors Opdivo (nivolumab) and Keytruda (pembrolizumab), the CTLA-4 inhibitor Yervoy (ipilimumab), and a combination of Yervoy and Opdivo. “These agents are increasingly be- coming the standard of care for melanoma,” said Howard L. Kaufman, M.D. Because these agents got their start in melanoma, the follow-up data are the longest for these patients and the results have been unprecedented.

In a recently presented long-term follow-up study of patients with metastatic melanoma treated with Opdivo for up to two years, 34 percent were alive five years after starting treatment, which is slightly more than double the historical five-year survival rate of 16.6 percent. “If you get a good response with these drugs, it translates to real durability and response,” said Kaufman.

Lung Cancer

In 2015, Opdivo and Keytruda were both approved for squamous and nonsquamous non—small cell lung cancer (NSCLC). For squamous histology, where advances have been slow to come, patients had an improvement in median overall survival (OS) from six months with docetaxel to 9.2 months for Opdivo. Additionally, 18-month survival was improved from 13 percent with docetaxel to 28 percent with Opdivo. “What patients want is a chance at being alive many months or years down the road...this was a very meaningful improvement,” said Jared M. Weiss, M.D.

In patients with nonsquamous histology, the median OS improved from 9.4 months with docetaxel to 12.2 months with Opdivo, and one-year survival increased from 39 percent to 51 percent. Keytruda showed similar results, but patients were selected based on their PD-L1 status and not on their histology, as in the Opdivo trials; however, when PD-L1 staining of Opdivo-treated patients was retrospectively examined, “there was no class of PD-L1 status that did not benefit,” said Weiss.

Initially, both drugs were approved for patients with progressive disease after the failure of other therapies but that picture changed dramatically in late October when the FDA granted Keytruda a frontline indication for patients with metastatic NSCLC whose tumors show 50 percent or more PD- L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations.

The agency’s ruling came just weeks after research presented at the 2016 ESMO Congress demonstrated that single-agent Keytruda reduced the risk of death by 40 percent compared with doublet chemotherapy for previously untreated patients with NSCLC with PD-L1 expression on less than 50 percent of cells, called a tumor proportion score.

In the progressive-disease setting, Keytruda has a companion diagnostic that requires at least 1 percent staining with the 22C3 antibody for the drug to be administered, whereas Opdivo has a complementary diagnostic but can be given without knowing PD-L1 status, noted Weiss.

Weiss said that the testing requirement might prompt clinicians to ask themselves why they should bother with Keytruda. “The practical answer is that pembrolizumab is a three-week drug, whereas nivolumab is an every two-week drug,” he explained, indicating this can be a significant advantage for patients who need to travel longer distances to receive treatment.

The panelists also discussed several PD-L1 inhibitors in later-stage clinical trials for lung cancer, including Tecentriq (atezolizumab) and durvalumab with or without tremelimumab. Of the ongoing trials discussed, PACIFIC generated excitement among the panelists because it is examining an area of lung cancer that has not seen much development and is seeking to answer what the interplay is between immunotherapy and chemoradiotherapy and whether maintenance should be given after chemoradiotherapy.

“Part of the reason I think immunotherapy is so promising here is you have patients’ tumor bulk down but it is coming back, so putting immunotherapy afterward might get it down to where the immune system may be better able to control it,” said John L. Heymach, M.D., Ph.D.

After the Peer Exchange discussion took place, Tecentriq went on to receive FDA approval for the treatment of metastatic NSCLC in patients who progress after a platinum-containing regimen and an FDA-approved targeted therapy in the setting of EGFR or ALK abnormalities. Approval was based on the OAK and POPLAR trials. In the OAK study, the median OS with Tecentriq was 13.8 months versus 9.6 months with docetaxel.

Kidney Cancer

Because renal cell carcinoma, like melanoma, is considered an immunogenic tumor, immunotherapies have been used in this setting for some time, but with considerable toxicity and few complete responses until Opdivo came into the picture.

“Survival was clearly superior in patients who got nivolumab...and the toxicity was substantially less” versus those who received Nexavar (sorafenib) with Afinitor (everolimus) as second-line therapy, said Bajorin. “In fact, in addition to a six-month improvement in survival, from 19 to 25 months, nivolumab also had half the toxicity observed with everolimus,” he said. Benefit was observed regardless of PD-L1 expression and the treatment is starting to move forward to first-line therapy, he noted, indicating he suspects these trials will be quick in reporting their results.

There are also several ongoing trials examining immunotherapy combinations, including a randomized trial assessing Tecentriq plus bevacizumab versus Sutent (sunitinib) in patients with untreated metastatic renal cell carcinoma (NCT02420821). Although Avastin (bevacizumab) is an antiangiogenic agent, research suggests it might help enhance the immune effect, such as by altering the immune environment and stimulating the immune system.

Heymach noted that “there’s enormous cross-talk” between signals that make blood vessels grow and factors that stimulate the immune system. “The notion of bringing together bevacizumab and Tecentriq or VEGF inhibitors and immunotherapy is a very appealing one,” he said.

Bladder Cancer

On May 18, 2016, the FDA approved Tecentriq for locally advanced or metastatic urothelial carcinoma based on the IMvigor 210 study, making it the first new drug approved for bladder cancer in decades. “We’ve been waiting 30 years and then some for a new drug,” said Bajorin, noting that cisplatin was the last drug approved in this setting.

The IMvigor 210 study reported an overall response rate (ORR) of 15 percent for those receiving atezolizumab. “Although that seems low, in this patient population of previously treated patients, we see about a 10 percent response rate with systemic chemotherapy,” said Bajorin. Additionally, ORR was improved for patients who showed PD-L1 positivity, with an ORR of 28 percent.

Based on these findings, the FDA also approved a complementary diagnostic, the Ventana PD-L1 (SP142) assay, to help clinicians determine which patients may benefit the most from Tecentriq, although a negative result is not a contraindication to treatment, as these patients still achieved an ORR of 8 percent to 10 percent.

Tecentriq and other immunotherapies are being assessed in numerous clinical trials, including for earlier stages of bladder cancer and in areas of unmet need. Patients with superficial disease who have recurrence within 12 months are classified as BCG unresponsive and are at high risk of developing muscle-invasive disease and subsequent nodal or metastatic disease, explained Bajorin, but there is no effective treatment for these patients.

To address this unmet need, the FDA accepted a non-comparator trial approval process in this setting, he said, enabling a variety of drugs to be studied in this space. Among these are Tecentriq (NCT02450331), and he is hopeful it may help fill that void. “We know that once patients are BCG unresponsive, there’s a pretty substantial upregulation of PD-L1 positivity...so we know that it’s certainly a good candidate for this therapy,” he explained.

Head & Neck Cancers

In August 2016, the FDA approved Keytruda for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed despite standard-of-care chemotherapy. Approval was based on the results of the nonrandomized KEYNOTE-012 trial, which showed an ORR of 16 percent, with 82 percent of these patients maintaining a response for six months or more, with some responses lasting more than two years. Additionally, response was seen in patients regardless of their human papillomavirus (HPV) status, unlike with chemotherapy, where response is improved in HPV-positive patients.

Opdivo also appears to be close to approval. Based on data from an interim analysis of the CheckMate-141 study, the FDA has granted Opdivo priority review for use in patients with recurrent or metastatic HNSCC.

In the study, the median OS was 7.5 months with Opdivo versus 5.1 months with investigator’s choice, and the ORR was 13.3 percent versus 5.8 percent, respectively. Additionally, survival was more than doubled, with 36 percent of Opdivo-treated patients alive at 12 months versus 17 percent of those receiving investigator’s choice.

Because CheckMate-141 is the first randomized clinical trial to show a clear improvement in OS for patients with platinum-refractory recurrent or metastatic HNSCC, it has the potential to establish Opdivo as a new standard of care option for these patients.

During the Peer Exchange, the panelists discussed several ongoing trials of durvalumab alone and in combination in patients with HNSCC, but no results were yet available for these studies.

In late October, AstraZeneca announced that the FDA had placed a partial hold on enrollment of new patients into clinical trials evaluating durvalumab as monotherapy and in combination with tremelimumab or other agents in HNSCC after incidents of bleeding were observed in participants.The company said a detailed analysis would be conducted among patients who experienced bleeding during the phase 3 KESTREL and EAGLE trials. In its statement, the company characterized bleeding as a “known complication” in HNSCC treatment due to the underlying disease, the proximity of tumors to blood vessels, and the impact of prior anticancer therapies.

Challenges and Opportunities

Throughout their discussion, the panelists touched upon several key challenges and opportunities in immunotherapy across solid tumor types. One major challenge is determining treatment duration. Many clinicians use RECIST criteria, which can be problematic, as it risks discontinuing treatment too early, especially when patients are not showing good early response.

“We’ve seen some late responses at eight and nine months, with patients achieving stable disease after having fluctuations that could be interpreted as progressive disease,” said Bajorin. “So it’s important not to withhold therapy too early and to keep in mind that using strict RECIST criteria may not be in the best interest of every patient.”

Another challenge has been determining how to proceed when there is relapse or when a patient desires or requires a break in treatment following a good response. Per recent data, the panelists agreed that patients can be put back on the same treatment and still show response.

“With immunotherapy, we’re inducing the adaptive immune system and those T cells don’t disappear,” said Heymach. “So it is quite possible that we’re going to be overtreating by treating for years or you may be able to give a break and then start treatment again if the cancer wakes up.”

Additionally, response might be independent of number of doses. “The concept with the immune system is that if you’re going to get a response, you may get it regardless of how many doses we give,” said Kaufman. “This is why finding biomarkers, particularly predictive biomarkers, is going to be important.”

The panelists also discussed the management of toxicities which, while they have generally been significantly less severe with immune checkpoint inhibitors than with standard cancer treatments, they remain a major concern and appear to be undertreated because they can be subtle and difficult to diagnose.

“Patients can develop any itis you can imagine — pericarditis, pneumonitis, colitis — and the average symptom that you’re going to see with one of these drugs is not going to be related to the drug, but is more likely going to be something else, making the diagnosis incredibly hard,” said Weiss.

Therefore, the panelists agreed that it is important for clinicians and their oncology nurses to stay on high alert for any unusual symptoms, no matter how trivial they may seem. “There’s much greater harm from not acting than from acting a little bit too often,” said Weiss.

Despite such challenges, the future in immunotherapy is incredibly bright and we have only started to scratch the surface. The panelists believe the future will likely involve more personalized immunotherapy combinations, where patients will receive 3 or more drugs based on their tumor type and characteristics.

They also believe treatments will move beyond T-cell anergy toward more complex components of immune suppression. “We’re going to be talking about suppressive B cells, suppressive monocytes, and all kinds of other suppressive components,” said Weiss. “I think we can look forward to this becoming a whole lot more complex, if it’s not complex enough already, and I think we can look forward to seeing real clinical victories,” he said.