Deborah Abrams Kaplan

Although there is resistance to use the word “cured” to describe patients with long-term progression-free survival (PFS) in renal cell carcinoma (RCC), “that word sometimes gets whispered around the meetings,” Christian Thomas, MD, director of clinical research at New England Cancer Specialists in Scarborough, Maine, said in an interview with 

. “Sometimes patients are on the drugs for 5 years with no evidence of disease. But we don’t think we can routinely cure kidney cancer yet.”

Although curing advanced RCC is an admirable goal, there are many treatment options available on the horizon that result in substantial improvements in long-term outcomes. A handful of novel combination therapies have been approved for the frontline setting in the past few years, with others now in trials. These regimens mark a shift away from monotherapy, as seen in data shared at the 2021 Genitourinary (GU) Cancers Symposium, which highlighted a move toward combinations of immuno-oncology (IO) agents or an IO agent combined with a tyrosine kinase inhibitor (TKI), including VEGF inhibitors.

“I never use monotherapy anymore, like sunitinib [Sutent] or pazopanib [Votrient],” said Michael Humeniuk, MD, a hematologist/oncologist at the SMC Center for Hematology/Oncology in Spartanburg, South Carolina. “There are a lot of new first-line therapies.” If the patient has no contraindications, Humeniuk said he uses double IO or IO/VEGF-TKI combination therapies.

Advanced RCC, although a fairly loose descriptor, is unlikely to be surgically curable, so patients with metastatic RCC in the favorable-risk category based on the International Metastatic RCC Database Consortium (IMDC) scale may be just observed initially, Thomas said. For those in the intermediate- or poor-risk categories, Thomas would consider debulking nephrectomy. But he would also consider frontline double-IO combinations or an IO/TKI combination, a big change from treatment a decade ago, he said.

The current standard of care for someone with intermediate- or poor-risk disease is a combination of IO agents, such as ipilimumab (Yervoy)/nivolumab (Opdivo), or an IO/TKI combination, such as pembrolizumab (Keytruda)/axitinib (Inlyta), said Pooja Ghatalia, MD, assistant professor, Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“[Although] a combination of dual checkpoint inhibitors, [like] ipilimumab/nivolumab, isn’t the wrong answer based on data seen more recently, there is a greater number of treating physicians who prefer an IO/TKI combination for these patients,” Ghatalia said.

Based on data presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and 2021 GU Cancers Symposium, a patient with intermediate or poor risk can also receive frontline cabozantinib (Cabometyx)/nivolumab.

The newer, orally administered TKI agents have now been successfully combined with IO agents. “The first wave of IO drugs including nivolumab, pembrolizumab, and avelumab [Bavencio] are being combined with an oral agent,” Thomas said.

The FDA approved the ipilimumab/nivolumab combination for frontline treatment of advanced, intermediate or poor risk RCC in 2018.1 Approval was based on superior efficacy in this patient population compared with sunitinib monotherapy in the CheckMate 214 trial (NCT02231749).

“Ipilimumab/nivolumab was the first [IO combination] to make a significant overall survival impact in this space, and it certainly changed our standards on treatment selection for patients with metastatic kidney cancer,” said Tian Zhang, MD, MHS, assistant professor of medicine at Duke Cancer Institute in Durham, North Carolina. “It is really improving outcomes in terms of targeting patients to get them to live longer and without progression for longer.”

For patients in the favorable-risk category, however, the advantages of ipilimumab/nivolumab over sunitinib are more questionable. In fact, exploratory analyses in CheckMate 214 revealed that sunitinib produced a significantly better objective response rate (ORR) and PFS for patients with favorable-risk disease, although the complete response (CR) rate was higher with ipilimumab/nivolumab.

The FDA approved the pembrolizumab/axitinib combination for frontline treatment of advanced RCC in 20193 based on data from the KEYNOTE-426 trial (NCT02853331). Updated data were presented at GU Cancers Symposium 2021.

 A poster showed that per the KEYNOTE-426 protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent because of toxicity. However, pembrolizumab was stopped for all patients at 2 years, whereas axitinib could be continued until the patient progressed or experienced toxicity.

Results in patients treated with pembrolizumab showed that extended follow-up of the combination of pembrolizumab/axitinib continued to demonstrate clinically significant improved efficacy when compared with sunitinib for previously untreated patients with advanced RCC.

The pembrolizumab/axitinib combination and the axitinib/avelumab regimen from the JAVELIN Renal 101 trial (NCT02684006) were the first IO/VEGF-TKI combinations for frontline treatment of advanced RCC, Zhang said. The axitinib/avelumab combination was approved in 2019.5 A poster presentation at the 2021 GU Cancers Symposium shared JAVELIN Renal 101 efficacy data from the second interim overall survival (OS) analysis of axitinib/ avelumab compared with sunitinib, based on various IMDC risk factors and target tumor sites at baseline.

Although OS data were still immature, the results showed that with extended follow-up, the combination generally showed efficacy benefits compared with sunitinib. Specifically, median follow-up for OS for the axitinib/ avelumab arm was 19.2 months versus 19.3 months for the sunitinib arm. Median PFS was 16.8 months for the axitinib/avelumab arm versus 15.2 months for the sunitinib arm.

Data from the CheckMate 9ER trial (NCT03141177) investigating the nivolumab/ cabozantinib combination in patients with previously untreated clear cell RCC were also presented at GU Cancers Symposium 2021 and ESMO 2020.7,8 Results published in the New England Journal of Medicine9 showed that the combination had a significant OS and PFS improvement compared with sunitinib. “I’ve switched everyone over to cabozantinib/ nivolumab [based on the study] if I have to use an IO/VEGF[-TKI] combination. Cabozantinib is just a better overall inhibitor of kidney cancer because there are more off-target hits. I think it’s a better drug,” Humeniuk said. The combination gained an FDA approval on January 22, 2021.

CheckMate 9ER also analyzed qualityof-life data, with patients reporting better health-related quality of life in the combination arm compared with sunitinib. “I haven’t seen quality-of-life data in the other studies yet,” Ghatalia said, adding that this study included a greater number of patients in the poor-risk category versus the KEYNOTE-426 or CLEAR study (NCT02811861), which evaluated lenvatinib (Lenvima)/pembrolizumab versus lenvatinib/everolimus (Afinitor) versus sunitinib.

The pembrolizumab/lenvatinib combination has not yet been approved by the FDA; however, “the data presented at [GU 2021 were] encouraging,” Ghatalia said, noting “It had a very good response rate and improvement in all efficacy end points.” Ghatalia said she would consider using this combination and anticipates it will receive FDA approval based on the CLEAR study results: 71% ORR compared with 53.5% for lenvatinib/everolimus and 36% for sunitinib; and 16.1% CR rate compared with 9.8% for lenvatinib/everolimus and 4.2% for sunitinib.10 Pembrolizumab/ lenvatinib “demonstrated significant progression-free survival benefit and overall survival benefit compared with sunitinib,” Zhang said.

However, the 18-mg lenvatinib dose can cause significant adverse effects for patients, Ghatalia said. She expressed surprise that patients in the CLEAR study were given lenvatinib in a 20-mg dose along with pembrolizumab. “Investigators reassured us that in the frontline setting, patients can tolerate higher treatment doses because they’re not receiving prior treatment or prior toxicity,” said Ghatalia.

Choosing a Frontline RCC Treatment It is challenging to decide what to use for a first-line treatment in RCC, Zhang said. “We now have multiple trials that are showing the benefits of immunotherapy-based treatments in all comers, in particular in patients with IMDC intermediate- and poor-risk disease.”

Zhang said she thinks about the full continuum of treatment when considering frontline options. “We think about potential resistance patterns,” she noted. In addition to considering which frontline treatments are available, she takes the patient’s treatment goals into account. “Some of the treatment combinations have yielded higher response rates,” she said. For example, the ipilimumab/nivolumab combination or the pembrolizumab/lenvatinib combination have CR rates of more than 10%. That is meaningful if patients can get to CR and potentially consider discontinuing treatment a year or 2 after sustained CR. “Those are the type of things I think about when starting on first-line treatment and selecting from these options,” Zhang said

Zhang is pleased about the handful of immunotherapy-based combinations with positive OS impacts, which are all considered superior to more traditional treatments for patients with intermediate-risk disease. “We are looking at this era of checkpoint inhibitor–based combination strategies as the main go-to for most patients,” she said, adding that these combinations were all benchmarked against sunitinib as a control. Patients whose disease is more driven by angiogenesis may benefit more from IO/ VEGF-TKI combinations.

Both IO and VEGF-TKI are important classes of RCC therapies, said Humeniuk, but patients with autoimmune disease should not use a double-IO combination. He recommends going with a single IO or a VEGF-TKI agent for patients with severe autoimmune disease.

Despite the many options, clinicians still need longer-term OS data, Ghatalia said. “These are all studies with a median follow-up of about 18 to 30 months. More mature data will inform our decisions going forward.”

Data are more limited for patients with metastatic non–clear cell RCC (nccRCC), who represent a fraction of patients with RCC. A poster presented at GU Cancers Symposium 2021 shared results of a retrospective analysis of IMDC data from 1181 patients with nccRCC. Patient outcomes were compared based on type of frontline therapy: IO-based monotherapy or combination therapy, VEGF-TKI monotherapy, or mTOR inhibitor monotherapy. Data showed that for advanced nccRCC, frontline IO-based treatment produced the best OS result.

Currently in Trials Other trials are underway and producing data. What follows are a few to watch.

The PDIGREE trial (NCT03793166) is evaluating ipilimumab/nivolumab and cabozantinib in patients with intermediate- or poor-risk clear cell RCC.

“This adaptive phase 3 trial is based on induction with ipilimumab/nivolumab, and at the 3-month cutoff, response is assessed,” Zhang said. Patients with a CR then receive nivolumab alone, and those with disease progression receive cabozantinib alone. All other patients are randomized to receive nivolumab alone or combined with cabozantinib, she said. Investigators will examine optimal sequencing of drugs in this trial. “We’ll have some understanding of [which patients will be] complete responders and [whose disease] might recur. It’s an important study in terms of trying to benchmark treatments against the standard of ipilimumab/nivolumab,” Zhang said.

In the COSMIC-313 study (NCT03937219), patients are randomized to receive 4 doses of triplet therapy comprising ipilimumab/ nivolumab/cabozantinib or ipilimumab/ nivolumab/placebo (the CheckMate 214 regimen; FIGURE13), followed by nivolumab/ cabozantinib or nivolumab/placebo.13 Zhang said this trial is almost finished with enrollment. 

“Ipilimumab/nivolumab is a strong competitor in the IO/TKI space. So it will be interesting to see what the addition of the TKI to the combination will do,” Ghatalia said.

The PROBE trial (NCT04510597) is exploring the effects of adding cytoreductive nephrectomy to standard-of-care immunotherapy. Patients with metastatic RCC are randomized to receive 4 cycles of an immunotherapy combination, either alone or followed by cytoreductive nephrectomy, Zhang said.

One criticism of current trials is that the studies have not been “totally clean in terms of using just patients with intermediate- or [poor-risk] disease,” Thomas said, noting that the trials often include patients with favorable-risk disease as well.

Another issue is that in studies such as CheckMate 9ER and CLEAR, the comparator arm used “a fairly ineffective old-style drug, [sunitinib],” Thomas said. He looks forward to seeing trials combining IO and new oral TKIs compared with new oral TKI agents as monotherapy. 

Fortunately, that process has already begun. “We’re phasing out sunitinib based on these phase 3 trials for metastatic kidney cancer,” Zhang said.

Treatment sequencing will be an even more important issue moving forward because of the lack of data on how to best sequence administration of these advanced agents. “That’s where the field is going now,” Thomas said. “What we clearly have now is a plethora of options relating to first-line treatment, especially for intermediate- and [poor]-risk disease.”

Future studies will include comparator arms using combination therapies, rather than single agents. “Randomizing patients to single-agent TKI as a comparator arm will probably be unethical” considering the robust data for combining 2 agents, Ghatalia said.

Research will also continue to search for treatments for RCC associated with specific genetic abnormalities, Thomas said. “We haven’t found a molecular Achilles’ heel for RCC yet.” Although the VHL tumor suppressor gene is lost or inactivated in most cases of clear cell RCC, it is not yet understood how to correct the resulting functional effects on the cell.

Although there is a lot of work to be done, Zhang said the kidney cancer field has blossomed recently with the addition of immunotherapy and novel targeted treatments. “It’s a really exciting time for GU oncology,” she said.

1. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. Updated April 16, 2018. Accessed March 18, 2021. 

2. Sheng IY, Ornstein MC. Ipilimumab and nivolumab as first-line treatment of patients with renal cell carcinoma: the evidence to date. 

. 2020;12:4871-4881. doi:10.2147/CMAR.S202017

3. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. Updated April 22, 2019. Accessed March 18, 2021. 

4. Plimack ER, Rini BI, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): updated analysis of KEYNOTE-426. 

. 2020;38(suppl 15):5001. doi:10.1200/JCO.2020.38.15_suppl.5001

5. FDA approves avelumab plus axitinib for renal cell carcinoma. FDA. Updated May 15, 2019. Accessed March 18, 2021. 

6. Tomita Y, Motzer RJ, Choueiri TK, et al. Efficacy of avelumab plus axitinib (A + Ax) versus sunitinib (S) by number of IMDC risk factors and tumor sites at baseline in advanced renal cell carcinoma (aRCC): extended follow-up results from JAVELIN Renal 101. 

. 2021;39(suppl 6):302. doi:10.1200/JCO.2021.39.6_suppl.302

7. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. 

. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308

8. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. 

. 2020;31(suppl 4):S1142-S1215. doi: 10.1016/j.annonc.2020.08.2257

9. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. 

. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

10. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

. Published online February 13, 2021. doi:10.1056/NEJMoa2035716

11. Graham J, Wells C, Dudani S, et al. Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma (ccRCC). 

. 2021;39(suppl 6):316. doi:10.1200/JCO.2021.39.6_suppl.316

12. Zhang T, Ballman KV, Choudhury AD, et al. PDIGREE: an adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). 

. 2019;37(suppl 15):TPS4596. doi:10.1200/JCO.2019.37.15_suppl.TPS4596

13. Choueiri TK, Albiges L, Powles T, et al. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. 

. 2020;38(suppl 6):TPS767. doi:10.1200/JCO.2020.38.6_suppl.TPS767

14. Dizman N, Philip EJ, Pal SK. Genomic profiling in renal cell carcinoma. 

. 2020;16(8):435-451. doi:10.1038/s41581-020-0301-x

Articles

Although curing advanced RCC is an admirable goal, there are many treatment options available on the horizon that result in substantial improvements in long-term outcomes.

Immuno-Oncology/TKI Combinations Take the Lead in Frontline RCC Therapy 

Oncologists deciding what to do about coronavirus disease 2019 (COVID-19)vaccines are not alone. Which patient should be prioritized over another? Brahm Segal, MD, was prompted by that concern to join the National Comprehensive Cancer Network (NCCN) COVID-19 vaccine panel for patients with cancer.

“You look at how many different centers were represented (on the panel), and we were all struggling with the same issues and coming up with the same gaps in knowledge. We’re trying to do what we can to come up with answers,” said Segal, chair of the Department of Internal Medicine and chief of the Division of Infectious Diseases at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

The first COVID-19 vaccine in the US outside a clinical trial was given on December 14, 2020. The NCCN guidelines for vaccinating patients with cancer were published on January 22, 2021, just more than a month after that newly emergency use authorized-vaccine was given.

Although this is the panel’s preliminary 1.0 version set of recommendations, “the principles of vaccines are already there. The principles of immunology are the same,” Segal said. “That’s where we based our decision-making.”

The NCCN guidance, which were issued before the Emergency Use Authorization for the Johnson & Johnson vaccine, notes that patients with cancer are an at-risk population with an obvious need for vaccination to prevent associated morbidity and mortality. Included are patients in active treatment, those who were treated fewer than 6 months before, and those planning for future treatment. Here are the NCCN key findings, which recommend that clinicians:

Prioritize the vaccine for patients with cancer, as CDC priority group 1b/c. Patients should receive a COVID-19 vaccination as soon as it’s available to them.

Immunize all patients in active therapy, even with limited safety and efficacy data available for this population.

Delay vaccination for 3 months or more after a patient receives hematopoietic cell transplantation or engineered cellular therapy such as chimeric antigen receptor (CAR) T cells. This is to maximize vaccine efficacy, not for safety reasons. Vaccination also should be delayed for 3 months for any reasons the general population would also delay receiving a COVID-19 vaccine, such as recent exposure to the disease.

Immunize caregivers and close contacts, such as household members, when possible to do so.

The guidance also noted that vaccines should be equitably distributed to racial and ethnic minorities, non–English-speaking individuals, those with disabilities, and other economic and socially vulnerable risk groups that have been shown to be more affected by the disease.

The guidelines do not rely on vaccine trial data for patients with cancer who are receiving active therapy, as there are no data at this time, Segal said. The panel consulted studies published in the Lancet and Nature Medicine that showed that patients with cancer who contracted COVID-19 had substantial rates of morbidity and mortality.

“We knew certain patients with cancer have a higher risk for hospitalization and death,” Segal said. That includes comorbidities that are also common in the general population, such as older age, with the 80 years and older population being particularly vulnerable, he said.

Other common comorbidities that affect COVID-19 morbidity and mortality include heart disease, chronic lung disease, diabetes, high blood pressure, and chronic obstructive pulmonary disease. “These tend to increase risk and tend to be common in patients with cancer because it’s an older population,” Segal said.

The panel also relied on studies showing the safety of the Pfizer and Moderna vaccines, and those showing the disproportionate impact on racial and ethnic minorities.

Efficacy and Safety Issues in the Cancer Population

The committee did not have concerns about safety issues in giving the COVID-19 vaccine to patients receiving treatment for cancer. The NCCN guidelines note that the available mRNA vaccines do not contain live virus and thus do not pose an immediate risk for safety issues in immunosuppressed patients. “We’re reasonably confident about safety, but we can’t be 100% sure that for every cancer therapy, there isn’t an interaction with the vaccine,” Segal said. Practitioners who immunize patients with cancer are carefully monitoring them for adverse effects, he said.

The main knowledge gap involves those patients who are immune compromised, he said. “We don’t know how effective the vaccine is in this population,” Segal said. These patients likely will have a decreased immune response compared with the general population, the guidelines note, and patients should be educated about following current prevention guidelines after they are vaccinated.

In addition, patients receiving checkpoint inhibitors and those receiving investigational agents may have an interaction with the vaccine that is currently unknown. “It was unanimous that this should not dissuade [individuals] from getting immunized,” Segal said. “The risk of COVID-19 complications is strong enough that we strongly encourage immunization, [even] knowing that there may be additional toxicities we still need to learn about.”

The committee also unanimously agreed that if a patient is receiving active cancer therapy, they should be prioritized over those whose cancer was cured, he said. The guidelines recommend prioritizing patients who plan to start treatment, as well (TABLE1). The panel acknowledged that prioritizing patients is both evidence- and values-based, and that clinicians may disagree about the prioritization rules. That debate could include patients with no current evidence of disease versus those with advanced cancer and a limited life expectancy.

However, the committee recommended prioritizing those with COVID-19-related mor-bidity and mortality factors, such as advanced age and specific disease processes, if there are vaccine shortages. Other risk factors for prioritization include those covered by social and demographic factors, such as limited access to health care or poverty.

The guidelines don’t address prioritization for patients receiving treatment in the cancer community. “We don’t specifically prioritize [individuals] with hematologic malignancies over solid tumors, even though [those with hematologic malignancies] are at greater risk for COVID-19 complications,” Segal said. “They also might be the ones who benefit the least.” The panel also did not recommend prioritizing based on treatment type, whether chemother-apy, radiation, surgery, targeted therapy, or immunotherapy. The panel did recommend that those receiving hormonal therapy, but with no active cancer, receive a lower prioritization.

Some oncology offices are determining their own prioritization list. “Logistically, we have to do it,” Segal said, as practitioners need to schedule appointments based on the number of vials they have. “By definition, that requires prioritization.” The guidelines note that multiple NCCN panel members’ facilities use scoring systems for prioritizing patients, based on age, comorbidities, metastatic or local disease, and hematologic or solid tumor malignancies.

Segal said his practice prioritizes those with hematologic malignancies because, in their experience, these patients have had more complications from the disease. But that is not prioritized in isolation. They also considered general comorbidities, and whether the patient is on active therapy. They also prioritize those with leukemia and receiving stem cell therapy over solid tumors. “We had to make that decision. We just don’t have enough vaccines to go around,” he said. They look at the patient’s risk factors and comorbidities and make a decision. “Across the board, cancer centers are grappling with this,” Segal noted.

The guidelines recommend giving the vaccine to patients with hematologic malignancies when the vaccine is available. The exception is for those receiving intensive cytotoxic chemotherapy(such as cytarabine/anthracycline-based induction regimens for acute myeloid leukemia), in which case they recommend delaying the vaccine until the patient’s absolute neutrophil count recovers.

For patients with solid tumor malignancies, the panel recommends giving the vaccine when available, even if the patients are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiation.

Patients who are stem cell transplant recipients need time for their immune system to reconstitute, especially after an allogenic transplant. “To give that patient a vaccine immediately would be a waste of vaccine,” Segal said. “It will be ineffective. You have to wait longer for the immune system to reconstitute, to maximize the chance the patient will respond.” The guidelines recommend waiting at least 3 months after allogenic or autologous transplantation, in addition to cellular therapy such as CAR T.

Patients who are undergoing surgery should separate the surgical and vaccine dates by a few days. Segal recommends not giving the vaccine before surgery. If there are any issues, it’s important to know whether they are surgical or vaccine-related.

The guidelines recommend national advocacy so patients participating in clinical trials can receive the COVID-19 vaccine. Patients shouldn’t have to choose between being in a trial and getting vaccinated, Segal said. “The general rule is, if they’re on a clinical trial, get the COVID-19 vaccine. I view vaccines as standard of care, not investigational,” he said. “I think it should be given [to patients] in clinical trials for cancer, even knowing that some drugs might be first-in-human use, and early-stage trials.”

That said, if patients are getting an anti-tumor vaccine in a clinical trial, the standard is to delay the COVID-19 vaccine. “The anti-tumor vaccine may be set on a schedule that you can’t delay. We agree with not delaying it,” Segal said. If a clinical trial sponsor says there is a contraindication in giving the patient a COVID-19 vaccine during a trial, Segal recommends telling them the vaccine is standard of care and endorsed by the CDC and the NCCN guidelines. “There’s not a good reason in the vast majority of [individuals] to delay the COVID-19 vaccination,” he said.

This NCCN guideline set is preliminary. “We’re planning to write a more substantial set, but we wanted to get something up with consensus from the group,” Segal said. The biggest knowledge gap is knowing how effective the vaccine will be in different patients who have cancer. “So many different therapies for cancer target different parts of the immune system,” he said. Investigators aren’t conducting large, randomized trials for the vaccine in patients with cancer. Segal said his practice plans to measure antibody responses to the vaccine for different therapies.

The panel, which has 36 members, will add updates when they are available. “With COVID-19, everything is record turnaround time,” Segal said. The next update won’t take a year. “We’re working more on a scale of weeks to months,” he said.

1. NCCN. NCCN: cancer and COVID-19 vaccination. Version 1.0. January 22, 2021. Accessed February 14, 2021. https://bit.ly/2ZhkBFa

2. Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. 

. 2020;395(10241):1907-1918. doi:10.1016/S0140-6736(20)31187-9

3. Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. 

. 2020;26:1218-1223. doi:10.1038/s41591-020-0979-0

4. Lee LY, Cazier JB, Angelis V, et al. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study. 

. 2020;395(10241):1919-1926. doi:10.1016/S0140-6736(20)31173-9

5. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. 

. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577

6. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. 

. 2021;384:403-416. doi:10.1056/NEJMoa2035389

Oncologists deciding what to do about coronavirus disease 2019 vaccines are not alone. 

NCCN Guidelines Prioritize COVID-19 Vaccinations for Patients With Cancer

Immune checkpoint inhibitors blocking CTLA-4 or PD-1/PD-L1 often provide durable antitumor benefits to certain patients who respond to them; however, the percentage of responders is low, around 15% to 25%.1 Investigators are hopeful that agents targeting other checkpoint molecules, along with combinations of immunotherapies, can fill that gap to provide broader therapeutic coverage. One of the more promising targets of checkpoint inhibitors currently in early trials is TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains). Agents targeting this coinhibitory receptor are the subject of early clinical and preclinical studies.

Research on TIGIT has explored its roles in cancer, autoimmunity, and viral immunity.3 It is part of the poliovirus receptor (PVR)/nectin family. The pathway formed by TIGIT, CD96 (TACTILE), and costimulatory receptor CD226 (DNAM-1) is analogous to the CD28/CTLA-4 pathway.4 TIGIT, along with LAG-3 and TIM-3, form a group of coinhibitory receptors considered to be the next generation of clinical cancer targets following the notable yet limited success of CTLA-4 and PD-1 inhibitors.5 Though TIGIT, LAG-3, and TIM-3 are members of the same receptor class as CTLA-4 and PD-1, they exert unique functions, making them nonredundant.

“TIGIT inhibits T-cell activation,” Vijay K. Kuchroo, DVM, PhD, the Samuel L. Wasserstrom Professor of Neurology at Harvard Medical School and a senior scientist in neurology at Brigham and Women’s Hospital in Boston, Massachusetts, who has studied TIGIT for the past 15 years, said in an interview with 

. “Our data suggest that [inhibiting] it cooperates well with PD-1 blockade.” Tumors use the inhibitory TIGIT pathway to avoid attack by the immune system. Thus, therapeutic agents that inhibit TIGIT signaling by, for example, disrupting ligand binding promote the ability of T cells to proliferate and attack tumor cells.

TIGIT is expressed on multiple immune cell types, with potentially different functions on each.3 Expression of TIGIT on regulatory T cells (Tregs), particularly tumor-infiltrating Tregs, enhances their immunosuppressive function, with indirect effects that include inhibition of proinflammatory cytokine production. TIGIT also directly suppresses the antitumor effector function of CD8 T cells. Immune activation of TIGIT-expressing cytotoxic T cells and natural killer (NK) cells is suppressed when TIGIT interacts with 1 of its ligands, CD155 (PVR) or CD112 (PVRL2; Nectin 2), which are widely expressed on tumor cells.

After making a knockout mouse model of TIGIT, Kuchroo found that the receptor also promotes the regulatory activity of B cells. “If you make a deletion of TIGIT only on B cells, these mice spontaneously develop multiorgan autoimmunity,” he said. Furthermore, eliminating TIGIT on Tregs severely compromises those cells’ function, he said.


Tiragolumab Data presented at the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting by Johanna Bendell, MD, director of the Gastrointestinal Cancer Research Program at Sarah Cannon in Nashville, Tennessee, from the phase 1a/1b GO30103 trial (NCT02794571) demonstrated efficacy of atezolizumab (Tecentriq) plus the anti-TIGIT antibody tiragolumab in patients with PD-L1–positive non–small cell lung cancer (NSCLC).

Patients treated as part of phase 1a were given single-agent tiragolumab; those treated in phase 1b received a combination of tiragolumab and atezolizumab. Patients with advanced solid tumors, including those in the colon, rectum, breast, lung, head and neck, and ovaries, were allowed onto the study.6 The CT302 investigators’ hypothesis was that blocking TIGIT along with PD-L1 would reinvigorate tumor- specific T effector cells, offering potentially better clinical responses (FIGURE).

“Given the safety profile and clinical activity of anti–PD-1 and anti–PD-L1 [agents, investigators] are now using them as a therapeutic backbone to combine with other approaches, though the caveat is that it should not adversely [affect] health-related quality of life,” said invited discussant Michele Teng, PhD, associate professor and head of the Cancer Immunoregulation and Immunotherapy Laboratory at the QIMR Berghofer Medical Research Institute in Brisbane, Australia, following Bendell’s presentation of the trial results. The study enrolled 73 patients for whom standard treatment was unavailable or ineffective. Phase 1a included 24 patients, of whom 67% experienced treatment-related adverse effects (TRAEs). The phase 1b cohort included 49 patients, with 59% experiencing TRAEs; anemia, the most common, was reported in 31% of these patients. Investigators noted that the safety profile was acceptable across all dose levels in phase 1b. There were no objective responses in patients treated in phase 1a, with half of patients crossing over to the phase 1b group upon progression.

Three tumor responses were observed in patients treated in phase 1b. The responders, all of whom had PD-L1–positive tumors, included 2 patients with NSCLC, including 1 complete response (CR), and 1 patient with head and neck squamous cell carcinoma who experienced a partial response (PR). 

Investigators created expansion cohorts of immunotherapy-naïve patients with PD-L1–positive tumors after noting that the combination of tiragolumab and atezolizumab produced preliminary antitumor 

activity in these patient subsets in phase 1b. The 14-patient metastatic NSCLC expansion cohort had a conf irmed objective response rate (ORR) of 46%, including 2 CRs and 4 PRs. The disease control rate (DCR) was 85%, and the safety profile was similar to that seen in the dose-escalation cohort. Patient enrollment in the expansion cohorts is ongoing.

Based on preliminary efficacy and safety observed in the phase 1a/1b trial described, the phase 2 CITYSCAPE (NCT03563716) trial was initiated to examine atezolizumab, alone or combined with tiragolumab, for firstline treatment of 135 patients with locally advanced or metastatic NSCLC with measurable disease. Participants in this randomized, double-blind trial had PD-L1–positive tumors with wild-type 

. Results were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.

Consistent with prior findings, CITYSCAPE results showed that tiragolumab plus atezolizumab was superior to atezolizumab monotherapy in terms of both ORR (31.3% vs 16.2%; odds ratio, 2.57; 95% CI, 1.076.14) and progression-free survival (PFS; 5.4 months vs 3.6 months; HR, 0.57; 95% CI, 0.37-0.90). The combination was well tolerated and associated with rates of grade 3 or higher all-cause AEs similar to those with atezolizumab alone (48% vs 44%).7 Investigators recently launched 2 phase 3 trials, SKYSCRAPER-01 (NCT04294810) in NSCLC and SKYSCRAPER-02 (NCT04256421) in extensive-stage small cell lung cancer, for further testing of the drug duo.

An upcoming phase 1/2 study will focus on a combination of BMS-986207, nivolumab (Opdivo), and COM701 to study the blockade of the TIGIT, PD-1, and PVR immunoglobulin domain (CD112 receptor; CD112R) immune checkpoint pathways, respectively, in patients with advanced solid tumors, including those that may be refractory or nonresponsive to standard-of-care immune checkpoint inhibitors.

 BMS-986207 is an anti-TIGIT monoclonal antibody that binds to TIGIT expressed on several types of immune cells, including tumor-infiltrating T lymphocytes. This prevents TIGIT from interacting with its ligands, CD112 and CD155.1 It also enhances interactions of CD112 and CD155 with the costimulatory receptor CD226 expressed on immune cells like NK cells and CD8+ T cells. The resulting CD226-mediated signaling activates the immune system to execute a T-cell–mediated immune response against the tumor cells.

COM701 is an investigational anti–poliovirus receptor–related immunoglobulin (PVRIG) antibody developed by Compugen. PVRIG and TIGIT are parallel inhibitory pathways counteracting stimulatory CD226 signaling. PRs have been achieved in previous trials of COM701, both as monotherapy and in combination with nivolumab, for patients with difficult-to-treat cancer types, including microsatellite-stable forms of platinum-resistant primary peritoneal cancer and colorectal cancer. These earlier clinical results support preclinical data showing that the PVRIG and PD-1 pathways are separate and that inhibiting both could clinically benefit patients. Compugen hypothesizes that the TIGIT pathway is also nonredundant with the PVRIG and PD-1 pathways; thus, inhibiting all 3 could expand the number of patients with tumors that respond to immunotherapy. The study’s investigational new drug application was approved by the FDA in June 2020. During a phase 1/2 trial dose-escalation trial of COM701 combined with fixed doses of BMS-986207 and nivolumab, investigators will aim to determine the agent’s safety, tolerability, and preliminary antitumor activity. Antitumor efficacy will be further assessed in expansion cohorts of patients with ovarian and endometrial cancer, and a biomarker-driven arm will assess tumor types with high CD112 expression.

The MyCheckpoint (MMRC-089) open-label phase 1/2 clinical trial (NCT04150965) is examining the anti-TIGIT agent BMS-986207 in patients with multiple myeloma and started recruiting patients in June 2020. The estimated 104 participants with heavily pretreated relapsed/refractory disease will be randomized to 1 of 3 treatment arms. Patients in arm C will receive BMS-986207 monotherapy for the first 28-day cycle, then in combination with pomalidomide (Pomalyst) and dexamethasone from cycle 2 onward. The comparator arm A consists of the combination of elotuzumab (Empliciti), pomalidomide, and dexamethasone, with the experimental arm B examining the anti–LAG-3 agent BMS-986016 given in the same schedule as treatment on arm C.

In another phase 1/2 trial of BMS-986207 alone or combination with nivolumab (NCT02913313), patients with advanced solid tumors will be assessed for safety of the combination. This firstin-human trial of BMS-986207 began in 2016 with an estimated enrollment of 170 patients. The study is active but not currently recruiting patients, and no results are available.

In preclinical data presented at AACR 2020, the fully human anti-TIGIT antibody EOS884448 (EOS-448), dependent on Fcγ receptor engagement, showed strong in vitro competition with TIGIT natural ligands and prevented CD155-mediated inhibition of T cells from both healthy volunteers and patients with cancer. It also induced cytotoxicity preferentially against Tregs compared with CD4 and CD8 effector cells. In a mouse tumor model, single-agent EOS-448 strongly delayed tumor growth; combining it with an anti–PD-1 antibody produced an additional increase in antitumor activity, with CRs in 7 of 8 mice. EOS-448 demonstrated a safe profile in a primate toxicology study, and robust expression of several TIGIT pathway members in multiple tumor types led investigators to hypothesize that the agent may benefit a broad range of cancer indications. These findings, combined with additional translational medicine data, supported the initiation of a first-in-human study of EOS-448. In February 2020, the first of an estimated 30 patients with advanced cancers was enrolled in the dose- escalation portion of the phase 1/2a IO-002 trial (NCT04335253).

Other trials are investigating the PD-1 inhibitor pembrolizumab (Keytruda) in combination with investigational anti-TIGIT agents. The phase 2 KEYNOTE-01A study (NCT04165070) is assessing the efficacy and safety of pembrolizumab in combination with the anti-TIGIT agent MK-7684, carboplatin, and either paclitaxel or pemetrexed in patients with treatment-naïve advanced squamous or nonsquamous NSCLC. The nonrandomized, open-label study, which began in December 2019, has an estimated recruitment of 

90 patients. Investigators are evaluating ORR as a primary outcome measure and PFS and safety as secondary outcome measures. Another study is the randomized, open-label phase 1b trial of anti-TIGIT antibody ASP837414 as a single agent or combined with pembrolizumab (NCT03260322). The trial began in 2017 and expects to ultimately enroll 300 patients with locally advanced (unresectable) or metastatic solid tumors. Investigators plan to determine the recommended phase 2 dose and examine the tolerability and safety of ASP8374 as a single agent and combined with pembrolizumab. Additional outcome measures include ORR, duration of response, persistence of response after discontinuation, and DCR.

Kuchroo noted that, outside of the approved agents with proven efficacy, choosing investigational immunotherapies for specific tumor types remains difficult. “There are a lot of clinical trials with anti-TIGIT [agents],” he said. “There is no immunological reason as to which tumors are going to be affected by which particular therapy. It’s all empirical right now.” Hierarchy will eventually emerge based on the 

results of clinical trials, Kuchroo said, adding that controversy persists regarding whether PD-L1 expression on tumors can be used as a biomarker of response to help select patients for treatment with anti-TIGIT agents.

“The time will come where we will have the agent, and it will match perfectly well with the tumor,” Kuchroo said. Until then, he added, there is no magic formula: “It’s a lot of guessing of who should get a combination and then which combination. These are all the questions that the scientific community has to grapple with.”

, part 3: challenges and future trends. P T. 2017;42(8):514-521. 

2. Plieth J. Roche’s next immuno-oncology combo is a big bet on Tigit. Evaluate Vantage. Jan 31, 2020. Accessed August 19, 2020. bit.ly/329tz8m 

3. Manieri NA, Chiang EY, Grogan JL. TIGIT: a key inhibitor of the cancer immunity cycle. 

. 2017;38(1):20-28. doi:10.1016/j.it.2016.10.002 

4. Dougall WC, Kurtulus S, Smyth MJ, Anderson AC. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. 

. 2017;276(1):112-120. doi:10.1111/imr.12518 

5. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. 

. 2016; 44(5):989-1004. doi:10.1016/j.immuni.2016.05.001 

6. Bendell JC, Bedard P, Bang YJ, et al. Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors. 

. 2020;80(suppl 16):CT302. doi: 10.1158/1538-7445.AM2020-CT302

7. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as f irst line (1L) treatment in patients with PD-L1-selected NCLC (CITYSCAPE). 

l. 38;2020(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503 

8. Roche to present first clinical data on novel anti-TIGIT cancer immunotherapy tiragolumab at ASCO. News release. Roche. May 14, 2020. Accessed August 19, 2020. bit.ly/2PBlN15 

9. Compugen announces FDA clearance of IND application for phase 1/2 triple combination study of COM701 with Bristol Myers Squibb’s Opdivo (nivolumab) and TIGIT inhibitor. News release. Compugen Ltd. June 1, 2020. Accessed August 19, 2020. prn.to/3h8gTVA 

10. Anti-TIGIT monoclonal antibody BMS-986207. National Cancer Institute Drug Dictionary. Accessed August 9, 2020. bit.ly/2DAXgXJ 

11. Compugen announces phase 1/2 triple combination study to evaluate COM701 in combination with Bristol-Myers Squibb’s Opdivo (nivolumab) and TIGIT inhibitor. News release. Compugen Ltd. February 20, 2020. Accessed August 19, 2020. bit.ly/2EkEUdo 

12. iTeos Therapeutics presents preclinical data for its anti-TIGIT antibody, EOS-448, at the AACR II Virtual Annual Meeting 2020. News release. iTeos Therapeutics. June 22, 2020. Accessed August 19, 2020. bit.ly/3iqovTD 

13. Nguyen, TLA Cuende J, Preillon J, et all. Preparation of a clinical trial with a-TIGIT antagonist antibody EOS884448, which demonstrates potent preclinical activity and safe toxicology profile. 

. 2020;80(suppl 16):3161. doi:10.1158/1538-7445.AM2020-3161 

14. Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. 

. 2020;200(2):108-119. doi:10.1111/cei.13407

Immune checkpoint inhibitors blocking CTLA-4 or PD-1/PD-L1 often provide durable antitumor benefits to certain patients who respond to them; however, the percentage of responders is low, around 15% to 25%.





TIGIT Emerging as Target in Clinical Research Across Cancer Settings

Despite efforts to produce chemotherapy agents that are more effective and less toxic, most of these agents are still difficult to tolerate, especially for patients with small cell lung cancer (SCLC) and breast cancer.

“You have this landscape where myelosuppression in general is hurting patients,” said Jared Weiss, MD, associate professor of medicine in the Division of Hematology/Oncology at the University of North Carolina at Chapel Hill School of Medicine and a thoracic oncologist at Lineberger Comprehensive Cancer Center, also in Chapel Hill. “The existing armamentarium to ameliorate this is not satisfactory.”

Two agents under investigation, trilaciclib and ALRN6924, are termed myelopreservation agents because of their ability to combat the hematologic events that are commonly observed with toxic chemotherapeutics.

“It’s important to understand that [these drugs are] different [from] most of the cancer drugs we talk about,” Weiss said, explaining that their primary purpose is to decrease toxicity, not increase antitumor efficacy. When a physician is deciding whether to add another drug to a patient’s regimen, the main concern is typically safety, he said: “How much did you hurt safety, and was it worth it for the benefit to the patient?”

Chemotherapy damages hematopoietic stem and progenitor cells (HSPCs), leading to multilineage myelosuppression. Myelosuppression affects quality of life—with symptoms such as fatigue or shortness of breath caused by anemia—which can lead to critical setbacks in treatment plans, including dose reductions and skipped chemotherapy cycles. When white blood cells cannot regenerate, the patient is less equipped to fight infections, resulting in possible hospitalization and death. Fighting the adverse effects (AEs) of myelosuppression can create new difficulties, such as diarrhea caused by antibiotics. Likewise, therapy-induced thrombocytopenia can cause delays in treatment and decreased efficacy, leading to patient anxiety.

“While I do believe we’re relieving more suffering than we’re causing, we cannot ignore that we’re causing suffering with chemotherapy,” Weiss said. The desire to help his patients experience fewer AEs during oncology treatment caused him to look outside his normal research interests for an opportunity to become involved in a myelosuppression study.

Existing agents to treat myelosuppression are reactive instead of protective and proactive. Granulocyte colony- stimulating factor (G-CSF) can be given to prevent febrile neutropenia resulting from chemotherapy, but G-CSF treatment can cause thrombocytopenia, nausea, fever, and bone pain.

 “It’s a reactive treatment given after the damage is done,” Weiss said. “You stimulate whatever progenitors are left to make more cells.” Erythropoiesis-stimulating agents (ESAs) for managing anemia have encountered substantial obstacles, leading to black box warnings for patients with cancer and those with kidney disease.

 As a result, Weiss said, ESAs are not commonly used in the United States.

There is also emerging evidence of problems with blood transfusions. “Volume [over] load can hurt patients,” Weiss said. Allogeneic blood transfusions are potentially immunosuppressive and can increase treatment time. Moreover, he noted, blood transfusions are reactive; treatment involves giving blood after the patient receives chemotherapy. As a result, progenitor cells are not protected from this toxic treatment.

Chemoprotective agents, such as amifostine used in patients with ovarian or head and neck cancer to protect healthy tissues from some treatment-related AEs

 or mesna for preventing hemorrhagic cystitis caused by ifosfamide,

 were developed to prevent toxicities rather than treat symptoms. Targeted agents for multilineage myelopreservation are the latest chemoprotectants to gain attention in the cancer care space.

Four phase 2 trials demonstrated that intravenous trilaciclib (G1T28), a CDK4/6 inhibitor that can induce transient G1 arrest in HSPCs,

 preserved immune system function during chemotherapy treatment. “Individually, each of the studies did demonstrate myelopreservation,” Weiss said.

The G1T28-02 trial (NCT02499770) examined trilaciclib in combination with etoposide and carboplatin in patients with newly diagnosed extensive-stage SCLC (ES-SCLC). The study comprised 2 parts: a dose-finding phase 1b (n = 19) and a randomized, placebo- controlled phase 2 (n = 75).

 Prespecified primary outcome measures were dose-limiting toxicities and treatment-related AEs; secondary outcome measures included safety, efficacy, and pharmacokinetic parameters. The phase 2 dose of trilaciclib was 240 mg/m

 given once daily before chemotherapy administration. All patients received etoposide at 100 mg/m

 on days 1 through 3 and carboplatin at a target area under the plasma drug concentration-time curve of 5 on day 1 of each cycle.

Patients receiving trilaciclib showed improvements in neutrophil, red blood cell (RBC), and lymphocyte measures. Safety was improved with trilaciclib, with fewer grade 3 or greater AEs in the experimental arm (50%) compared with placebo (83.8%), mostly due to less hematologic toxicity. Additionally, no trilaciclib- related AEs of grade 3 or greater occurred.

In terms of antitumor efficacy, a numerically improved overall response rate (ORR) of 66.7% with trilaciclib was achieved versus 56.8% with placebo, but this result failed to reach statistical significance (

 = .3831). Median progression-free survival (PFS) also showed numerical improvement at 6.2 months for trilaciclib versus 5.0 months for placebo (HR, 0.70; 

 = .1695), with longer PFS sustained across most patient subgroups. Overall survival (OS) was comparable between the 2 groups.

The results indicated that patients in the trilaciclib group had increased tolerance of chemotherapy, including improved myelopreservation across multiple hematopoietic lineages, and therefore needed fewer supportive care interventions and dose reductions. The addition of trilaciclib mitigated myelosuppression without reducing the antitumor efficacy of etoposide and carboplatin.

Another phase 2 trial in ES-SCLC, G1T28-03 (NCT02514447) included 61 previously treated patients in 2 arms receiving either topotecan alone or in combination with trilaciclib. Primary end points were the occurrence and duration of severe neutropenia, and key secondary end points were all-cause dose reductions and the rates of RBC transfusion, G-CSF administration, and platelet transfusion. Other prespecified end points included measures of antitumor efficacy, patient-reported outcomes, and AEs.

Study results presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated that patients receiving trilaciclib completed more cycles and had fewer dose reductions compared with the placebo arm. Data showed that trilaciclib did not impair chemotherapy efficacy, with comparable ORR, PFS, and OS in the placebo and trilaciclib arms.

In the critical area of myelosuppression, G1T28-03 revealed a clear benefit of trilaciclib. Trial results showed that 75.9% of patients in the placebo group experienced severe neutropenia compared with 40.6% in the treatment arm. Also, 65.5% of the placebo group received G-CSF versus 50% of the treatment arm. In terms of grade 3/4 anemia, 63% of the placebo group versus 38.7% of the treatment group experienced this toxicity. RBC transfusions were given to 41.4% of the placebo group versus 31.3% of the treatment group, and 31% of the former received platelet transfusions as opposed to 25% of the treatment group.

At the European Society for Medical Oncology (ESMO) Congress 2019, results from a cohort of patients with ES-SCLC treated with firstline etoposide/carboplatin plus atezolizumab (Tecentriq) with or without trilaciclib in the phase 2 G1T28-05 trial (NCT03041311) were reported.

 The main objective of the study (n = 107) was to evaluate the potential of trilaciclib to reduce chemotherapy-induced myelosuppression. The primary end points were 2 aspects of grade 4 neutropenia: its overall occurrence and its duration in cycle 1. Key secondary end points were rates of RBC transfusion beginning in study week 5, G-CSF use, and all-cause dose reductions, as well as OS.

Just below half (49.1%) of patients in the placebo group experienced grade 4 severe neutropenia compared with just 1.9% in the trilaciclib arm. Also, 47.2% of the placebo group received G-CSF versus 29.6% of the treatment arm. In terms of grade 3/4 anemia, 28.3% of the placebo group experienced this AE versus 18.5% of the treatment group. RBC transfusions were given to 20.8% of the placebo group versus 13.0% of the treatment group, and 3.8% of the former received platelet transfusions as opposed to 1.9% of the treatment group.

Study results showed that patients receiving trilaciclib had a higher relative chemotherapy dose intensity compared with the placebo group, which was due to fewer patients on trilaciclib undergoing etoposide or carboplatin dose reductions and/or cycle delays compared with placebo. Investigators also found lower frequencies of etoposide and carboplatin dose reductions over time among patients receiving trilaciclib versus placebo. The placebo group had a rate of all-cause dose reductions (per 100 cycles) of 8.5 compared with 2.1 in the treatment arm.

Based on the myelopreservation data generated in these clinical trials, trilaciclib received breakthrough therapy designation for use in patients with SCLC, and G1 Therapeutics is expected to file a new drug application in 2020.

Pooled data from the G1T28-02, -03, and -05 trials were examined to address concerns about missing safety signals in individual studies with small sizes, Weiss said. Data presented as part of the 2020 ASCO Virtual Scientific Program showed that adding trilaciclib before chemotherapy significantly and meaningfully reduced chemotherapy-induced myelosuppression and its consequences, including a substantial reduction in high-grade hematologic AEs (FIGURE).

 Moreover, trilaciclib did not negatively affect PFS or OS. Because trilaciclib reduces the toxicity of chemotherapy in SCLC treatment, Weiss and colleagues suggested its potential to become a new standard of care.

Weiss said one of the most common questions he gets about trilaciclib involves survival advantage: “I would love it if it [induced] a survival advantage [in SCLC], except that misses the point that the goal of the drug is to improve quality of life.” He said his patients’ top concern is typically improving their quality of life, but clinicians are still looking for a survival advantage. “Quality of life is extremely important,” he said. “You don’t have to go further than that to show benefit."

Results from the phase 2 G1T28-04 trial (NCT02978716) of patients with metastatic triple-negative breast cancer (mTNBC) treated with gemcitabine and carboplatin with or without trilaciclib were presented at the ESMO Congress 2019 and simultaneously published in The Lancet Oncology.

 The randomized trial assigned 102 patients with mTNBC to 1 of 3 treatment arms: Patients in 2 groups received trilaciclib and chemotherapy (gemcitabine and carboplatin), with the other group receiving only chemotherapy. The primary end points were duration of severe neutropenia during cycle 1 and occurrence of severe neutropenia during the treatment period. Secondary end points included antitumor efficacy measures, such as PFS and OS; pharmacokinetics; and safety.

Investigators found no significant differences in primary myelosuppression end points with trilaciclib plus chemotherapy versus chemotherapy alone. In particular, there were no significant differences (

 = .70) in severe neutropenia, which occurred in 26% of patients in group 1 (chemotherapy only on days 1 and 8), in 36% of group 2 (chemotherapy and trilaciclib on days 1 and 8), and in 23% of group 3 (chemotherapy on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9). Median OS was 12.6 months, 20.1 months, and 17.8 months, respectively.

Agents developed to prevent myelosuppression are the latest chemoprotectants under investigation in the treatment of various solid tumor malignancies. 

Deborah Abrams Kaplan | Authors

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