Debbie Abrams Kaplan

Investigators treating patients with gynecologic malignancies are optimistic that multiple clinical trials exploring new second-line cervical cancer treatments will result in a much-anticipated breakthrough for the field, with improved response rates from these new strategies already generating excitement.

In an interview with Targeted Therapies in Oncology(TTO), R. Wendel Naumann, MD, discussed the phase 1/2 CheckMate 358 trial (NCT02488759) in which patients received the PD-1 inhibitor nivolumab (Opdivo) for up to 2 years. Naumann, a gynecologic oncologist and associate medical director of clinical trials at Levine Cancer Institute, Atrium Health in Charlotte, North Carolina, reported that 1 patient in this trial who received this therapy still has no evidence of disease a full year after treatment completion. “You don’t see that often,” he said. Overall, the 19 patients with metastatic cervical cancer who were treated with nivolumab monotherapy in that trial had a 26.3% objective response rate (ORR; 95% CI, 9.1%-51.2%).

 When immunotherapy works, it works very well, he said.

Though the incidence of new cervical cancer cases has decreased incrementally over the past decade, mortality rates have not changed much. This is partly due to a lack of rapid development in cervical cancer therapies, which have lagged behind treatments for other cancer types, such as lung and breast.

Combination therapy with the VEGF inhibitor bevacizumab (Avastin) and the chemotherapy doublet of paclitaxel and either cisplatin or topotecan, the current frontline standard for patients diagnosed with recurrent or metastatic (R/M) cervical cancer, was approved in 2014 based on efficacy data from the GOG-0240 trial (NCT00803062).

“The response rate [was] about 50%,” Naumann said. “For somebody who has recurrent cervical cancer, the prognosis is poor.” With no established standard of care for second-line treatment of recurrent or metastatic cervical cancer, patients may be given chemotherapy and/or radiation, immunotherapy, or targeted therapy to slow tumor growth and treat symptoms.

 Current second-line treatments typically have poor response rates and minimal effect on overall survival (OS).

Recently, research has demonstrated that novel agents and combination therapies can improve response rates and survival in this patient population with traditionally few viable options following frontline treatment failure.

One of the most promising new agents in this space is balstilimab (AGEN2034), a PD-1 inhibitor being explored in trials either as monotherapy or in combination with the CTLA-4 inhibitor zalifrelimab (AGEN1884).

Preliminary phase 2 results from 2 international, parallel, single-arm trials, which included 161 patients receiving balstilimab monotherapy (NCT03104699) and 155 patients receiving the combination of balstilimab and zalifrelimab (NCT03495882) for recurrent or metastatic cervical cancer, were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 in September. All patients had previously received platinum-based first-line treatment. In both trials, patients received balstilimab 3 mg/kg every 2 weeks; those in the combination trial also received zalifrelimab 1 mg/kg every 6 weeks. Patients in both trials were treated for up to 2 years. The primary end point was ORR per RECIST 1.1.

The investigators found that both monotherapy and the combination were effective and well tolerated, with ORRs of 14% (95% CI, 10%-21%) and 22% (95% CI, 16%-29%) and any-grade immune-related adverse effect (AE) rates of 30% and 35%, respectively. Responses to both regimens were observed regardless of whether patients were positive for tumor PD-L1 expression (defined as a combined positive score [CPS]≥1) or negative (CPS<1); however, the former group had higher ORRs. Similarly, there were treatment responses in both trials irrespective of tumor histology, but higher ORRs were reported for patients with squamous cell carcinoma compared with adenocarcinoma. At a median follow-up of approximately 12 months, the median duration of response (DOR) was 15.4 months (range, 1.1+ to 15.4) in the balstilimab group versus not reached (NR; range, 1.3+ to 16.6+ months) in the combination group. These data led the investigators to conclude that adding zalifrelimab to balstilimab therapy resulted in increased ORR and DOR with only a marginal increase in AEs.

As a result of promising trial data, the FDA granted fast track designation to balstilimab both as monotherapy and in combination with zalifrelimab.

Tisotumab VedotinTisotumab vedotin (HuMax-TF-ADC)—an antibody-drug conjugate (ADC) comprising a tissue factor (TF)–specific, fully human monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E connected by a protease-cleavable linker—is being studied alone and in combination therapies for several tumor types in trials.

“In ADCs, the antibody recognizes a particular protein expressed in cancer cells. With tisotumab vedotin, it’s tissue factor,” said Ursula A. Matulonis, MD, chief of the Division of Gynecologic Oncology and Brock-Wilson Family Chair at Dana-Farber Cancer Institute as well as professor of medicine at Harvard Medical School in Boston, Massachusetts, in an interview with TTO. 

The antibody is linked to a drug, and internalization of the ADC by the cancer cell initiates a chain of events that culminates in cell cycle arrest and apoptosis, Matulonis said. TF is highly expressed in cervical cancer, as well as many other solid tumors, and can promote tumor growth, metastasis, and angiogenesis.

 High TF expression is seen in many tumor types and is correlated with poor prognosis. Further, TF is not associated with response to tisotumab vedotin, thus making it a poor choice as a bio-marker, and there is no prescreening required for these trials, Matulonis said.

The single-arm phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 trial (NCT03438396) included102 previously treated patients diagnosed with recurrent or metastatic cervical cancer. Single-agent tisotumab vedotin at 2.0 mg/kg was administered once every 3 weeks until dis-ease progression or unacceptable toxicity, and patients received a median of 6 doses.

Confirmed ORR, the primary end point, was 24% (95% CI, 15.9%-33.3%), including 7 complete responses (CRs) and 17 partial responses (PRs). Investigators found a median DOR of 8.3 months (95% CI, 4.2-NR) (TABLE8).

The median progression-free survival (PFS) was 4.2 months (95% CI, 3.0-4.4), and the 6-month PFS rate was 30% (95% CI, 20.8%-40.1%). Median OS was 12.1 months (95% CI, 9.6-13.9), with a 6-month OS rate of 79% (95% CI, 69.3%-85.6%). 

These results led the investigators to conclude that tisotumab vedotin, which had shown a manageable safety profile, also demonstrated durable and clinically meaningful activity. Based on the trial results, the agent’s manufacturers announced a plan to submit a biologics license application to the FDA under the Accelerated Approval Program.

In the earlier phase 1b/2 innovaTV 201 trial (NCT02001623), tisotumab vedotin monotherapy at the same dosage was administered to 55 pretreated patients with recurrent or metastatic cervical cancer, half of whom had received 2 or more lines of prior therapy. In that trial, the median DOR was 4.2 months (range, 1.0+ to 9.7 months), and the 6-month PFS rate was 29% (95% CI, 17%-43%).

Tisotumab vedotin is also being tested in the phase 1b/2 innovaTV 205/ENGOT-cx8/GOG-3024 trial (NCT03786081) as monotherapy or in combination with pembrolizumab (Keytruda), bevacizumab (Avastin), or carboplatin. This global, open-label trial in patients with previously treated or untreated recurrent or metastatic cervical cancer has enrolled 175 patients. The phase 1, dose-escalation portion will identify the recommended phase 2 dose. In phase 1, patients will be assigned to 1 of 3 arms for treatment every 3 weeks; all will receive escalating doses of tisotumab vedotin plus either escalating doses of bevacizumab, a fixed dose of pembrolizumab, or a fixed dose of carboplatin. In phase 2 dose expansion group, treatment-naïve patients will receive the recommended dose of tisotumab vedotin plus pembrolizumab or carboplatin every 3 weeks. Those with prior systemic therapy will receive tisotumab vedotin monotherapy weekly or tisotumab vedotin and pembrolizumab every 3 weeks. The primary end point for the phase 2portion is ORR per RECIST 1.1 criteria.

Recently, the phase 3 innovaTV 301 trial was launched to evaluate the agent compared with single-agent chemotherapy in patients with recurrent or metastatic cervical cancer.

Another approach to treating recurrent or metastatic cervical cancer involves using a VEGFR2-targeting tyrosine kinase inhibitor, apatinib (rivoceranib), to enhance the effects of an anti–PD-1 immunotherapy agent, camrelizumab.

A multicenter, open-label, single-arm phase 2 trial (NCT03816553) of the combination was conducted in China in 45 patients, more than half (57.8%) of whom had previously received2 or more lines of chemotherapy for recurrent or metastatic cervical cancer. Patients received camrelizumab every 2 weeks and apatinib once per day, with a primary end point of ORR assessed by RECIST 1.1. At a median follow-up of 11.3 months (range, 1.0-15.5), the ORR was 55.6% (95% CI, 40.0%-70.4%), including 2 CRs and 23 PRs. The median PFS was 8.8 months (95% CI, 5.6-not estimable). Neither the median DOR nor median OS was reached.

Investigators noted that this trial was likely the first to combine an anti–PD-1 antibody with a VEGFR inhibitor in this setting. Comparing their results to those of previous trials, the authors stated that the combination was superior to individual PD-1/L1 or VEGF pathway inhibitors used as monotherapy.

“The combination of camrelizumab and apatinib is basically the combination approved in endometrial cancer,” said Naumann, referring to the anti–VEGFR/PD-1 combination of lenvatinib (Lenvima) and pembrolizumab that received accelerated approval in 2019 for the treatment of advanced endometrial cancer with disease progression following prior systemic therapy.

Patients with endometrial cancer can have responses in many lesions even as a single lesion progresses. Naumann believes this phenomenon may be attributable to an alteration in the tumor microenvironment. “Either the T cells are exhausted or the tumor environment has upregulated the Tregs [regulatory T cells] and cut the immune response,” he said.

Established Immunotherapy Agents Move Into Cervical Cancer Settings

In 2018, the FDA approved pembrolizumab for patients with recurrent or metastatic cervical cancer, disease progression on or after chemotherapy, and tumors that express PD-L1 with a CPS of 1 or greater.14 The approval was based on an ORR of 14.3% found in this population in the KEYNOTE-158 trial. “You can see the bar [for demonstrating efficacy] is pretty low, and there have not been many cervical cancer–specific treatments,” said Matulonis.

The phase 2 KEYNOTE-158 basket study (NCT02628067) evaluated predictive biomarkers in patients with advanced solid tumors, specifically 98 patients with previously treated recurrent or metastatic cervical cancer.

In the cervical cancer cohort, 83.7% of patients had PD-L1–positive tumors (defined as CPS≥1). The ORR was 12.2% (95% CI, 6.5%-20.4%) in the entire cohort, with 3 CRs and 9 PRs. All responses were in the PD-L1–positive group. In the subset of previously treated patients with PD-L1–positive tumors, the ORR was 14.3%. Overall, the median PFS was 2.1 months (95% CI, 2.0-2.2), and the estimated 6-month PFS rate was 25%. Median OS was 9.4 months (95% CI, 7.7-13.1) in the total population and 11 months (95% CI, 9.1-14.1) in the group with PD-L1–positive tumors. The median DOR was not reached (range, 3.7+ to 18.6+ months).15 “The response rates are not the whole story,” Naumann said. “Those who responded, responded very well.”

With these data in mind, other trials are attempting to replicate the successes, albeit limited, of KEYNOTE-158 by repurposing immunotherapeutic agents that have had documented success treating other solid tumors.

The phase 3, randomized, placebo-controlled ENGOT-cx11/KEYNOTE-A18 study (NCT04221945) is testing pembrolizumab with chemoradiotherapy in the frontline setting in patients with high-risk, locally advanced cervical cancer (FIGURE

). The standard of care in this setting is external beam radiotherapy with concurrent che-motherapy, followed by brachytherapy. The investigators plan to recruit 980 patients who have not received systemic therapy, immunotherapy, TABLE.ANTITUMOR ACTIVITY OF TISOTUMAB VEDOTIN IN PATIENTS WITH METASTATIC CERVICAL CANCER8Confirmed ORR, n (%; 95% CI)24 (24; 15.9-33.3)Complete response, n (%)7 (7)Partial response, n (%)17 (17)Stable disease, n (%)49 (49)Progressive disease, n (%)24 (24)Not evaluable, n (%)4 (4)definitive surgery, or radiation. The primary end points are PFS per RECIST 1.1 and OS.

Combination therapy with nivolumab and ipilimumab (Yervoy), another CTLA-4 inhibitor, is also being tested in an arm of CheckMate 358. Interim results were shared at the ESMO Congress 2019. Patients in the Combo A group received nivolumab at 3 mg/kg every 2 weeks and ipilimumab at 1 mg/kg every 6 weeks; the Combo B group received nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab alone at 240 mg every 2 weeks. Both groups received this treatment for up to 2 years. The primary end point was ORR by RECIST 1.1. Interim results showed that at a median follow-up of 10.7 months (combo A) and 13.9 months (combo B), the ORR was higher with combo B than with combo A for patients both with (36% vs 23%) and without (46% vs 32%) prior systemic therapy. Median OS in combo B was not reached (95% CI, 13.9-NR) for treat-ment-naïve patients and was 25.4 months (95% CI, 17.5-NR) for previously treated patients.

“The patients who received [this regimen in] the first line had as good a response as the patients in GOG-0240,” Naumann said, referring to the frontline standard of bevacizumab and chemotherapy received in that trial. “The median survival was not reached for the Combo B arm [in the first line], and it was an almost 26-month median overall survival for patients who had previous chemotherapy. Those are incredible numbers. Data on dose expansion have not yet been presented,” he said.


Whereas the approved single-agent immunotherapy pembrolizumab has response rates hovering in the low teens, combination 

response rates for different immunotherapy trials have ranged from 20% to 40%, Matulonis said. Between PD-1 or PD-L1 inhibitors and anti-CTLA-4 therapies, there are a lot of possible combinations, she added.

The low pembrolizumab monotherapy response rate “basically tells you that we are desperate for second-line agents in cervical cancer. The bar [isn’t] very high,” Naumann said. However, the duration of the responses that were achieved was impressive, he noted. Naumann said he would not be excited by a chemotherapy response rate of 14%, adding, “but if I had a few patients with a CR that was long-lasting, I would be excited about it even if it was 14%. I suspect that if we find the right regimens, we’ll have good, long response rates with a median overall survival [measured] in years, [not months].” 

As time goes on, more data will become available about the situations in which to use immunotherapy and whether it would be best to give at initial diagnosis or combined with chemotherapy. Investigators and clinicians still need to determine the right combination for each patient and optimize the sequence in which these agents are given. “I’m excited about new options in terms of treating patients with cervical cancer,” Naumann said.

1. Naumann RW, Hollebecque A, Meyer T, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial. 

. 2019;37(31):2825-2834. doi:10.1200/JCO.19.00739

2. FDA approves Genentech medicine for women with advanced cervical cancer. News release. Genentech. August 14, 2014. Accessed December 3, 2020. https://bit.ly/3mF5yPt

3. Tewari KS, Sill MW, Long HJ. Improved survival with bevacizumab in ad-vanced cervical cancer. N Engl J Med. 2014;370(8):734-743. doi:10.1056/NEJMoa1309748

4.Treatment options for cervical cancer, by stage. American Cancer Society. January 3, 2020. Accessed December 3, 2020. https://bit.ly/36Cf9B9

5.O’Malley DM, Oaknin A, Monk BJ, et al. Single-agent anti–PD-1 bals-tilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): preliminary results of two independent phase II trials. 

l. 2020;31(suppl 4):S1164-S1165. Abstract LBA34. doi:10.1016/annonc/annonc325

6.Agenus receives fast track designation for balstilimab in advanced cer-vical cancer. News release. Agenus. April 7, 2020. Accessed December 3, 2020. https://prn.to/37yKHqJ

7.Hong DS, Concin N, Vergote I, et al. Tisotumab vedotin in previous-ly treated recurrent or metastatic cervical cancer. 

. 2020;26(6):1220-1228. doi:10.1158/1078-0432.CCR-19-2962

8.Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. 

l. 2020;31(suppl 4):S11422-S1215 doi:10.1016/j.annonc.2020.08.2262

9.Genmab and Seattle Genetics present data from tisotumab vedotin innovaTV 204 pivotal trial in recurrent or metastatic cervical cancer at ESMO Virtual Congress 2020. News release. Genmab and Seattle Genetics. September 21, 2020. Accessed December 3, 2020. https://bit.ly/2JrbiOK

10.Vergote I, Concin N, Mirza MR, et al. Phase Ib/II trial of tisotumab vedotin (TV) ± bevacizumab (BEV), pembrolizumab (PEM), or carbo-platin (CBP) in recurrent or metastatic cervical cancer (innovaTV 205/ENGOT-cx8/GOG-3024). 

l. 2020;38(suppl 15):TPS6095. doi:10.1200.JCO.2020.38.15_suppl.TPS6095

11.Genmab announces phase 3 trial of tisotumab vedotin in recurrent or metastatic cervical cancer. News release. Genmab. January 4, 2021. Accessed January 6, 2021. https://bit.ly/38hJHsB

12.Lan C, Shen J, Wang Y, et al. Camrelizumab plus apatinib in patients with advanced cervical cancer (CLAP): a multicenter, open-label, sin-gle-arm, phase II trial. 

. 2020;38(34):4095-4106. doi:10.1200/JCO.20.01920

13.Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US. FDA. September 17, 2019. Accessed December 3, 2020. https://bit.ly/39GQAF8

14.FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. FDA. Updated June 13, 2018. Accessed December 3, 2020. https://bit.ly/2KX1v36

15.Chung HC, Ros W, Delord JP, et al. Efficacy and safety of pembroli-zumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. 

. 2019;37(17):1470-1478. doi:10.1200/JCO.18.01265

16.Lorusso D, Colombo N, Coleman RL, et al. ENGOT-cx11/KEY-NOTE-A18: A phase III, randomized, double-blind study of pembrolizum-ab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer. 

. 2020;38(suppl 15):TPS6069. doi:10.1200/JCO.2020.38.15_suppl.TPS6096

17.Naumann RW, Oaknin A, Meyer T, et al. Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/met-astatic (R/M) cervical cancer: Results from CheckMate 358. 

. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394“


Articles

Investigators treating patients with gynecologic malignancies are optimistic that multiple clinical trials exploring new second-line cervical cancer treatments will result in a much-anticipated breakthrough for the field.

New Metastatic Cervical Cancer Treatments Give Hope

Targeted agents with activity against the VEGF pathway are showing promising efficacy in the treatment of bone and soft tissue sarcomas (STS) and may offer new therapy options for patients with these rare tumor types.

Although investigators are working to determine which patients see the most benefit from VEGF inhibition, the data indicate that it has activity in patients across most sarcoma types.

STS is a highly vascular disease, and inhibiting angiogenesis by way of the VEGF signaling pathway and corresponding receptors (VEGFRs) has shown promising activity in sarcomas.1 Prior research revealed that high expression of VEGFR2 is significantly associated with lower rates of patient survival, and platelet-derived growth factor receptor &szlig; and VEGFR1/2/3 are significantly correlated with higher tumor grading.

The current standard of care in both STS and osteosarcoma includes surgical resection when possible and systemic therapy. In osteosarcoma, the standard of care includes chemotherapy combinations.

Pazopanib (Votrient), an antiangiogenetic agent, is the only targeted therapy with an FDA-approved indication and activity against VEGFR in nongastrointestinal stromal tumor (GIST) sarcomas. Additionally, the National Comprehensive Cancer Network Guidelines recommend regorafenib (Stivarga) as a single-agent regimen in STS with nonspecific histologies based on the phase II REGOSARC trial, in which the agent significantly extended progression-free survival (PFS) compared with placebo in patients with non-GIST STS stubtypes.

Based on the ongoing and positive data observed with VEGFR targeted therapies, novel tyrosine kinase inhibitors (TKIs) and those already approved for other disease indications may become available to patients with bone and soft tissue sarcomas.

Investigators on a phase II study in treatment-naïve patients with resectable, nonmetastatic, high-risk STS tested whether preoperative devascularization would improve local control and outcomes following surgery. Pazopanib, a TKI with antiangiogenic properties, was administered preoperatively in 21 patients, and although the study did not show effectiveness in the overall cohort, relevant treatment effects were seen in a single patient, suggesting that efficacy in this setting may apply to certain patient subgroups.

Results from the phase II ARST1321 study, which used chemoradiation with or without pazopanib preoperatively in adult and pediatric patients &ge;2 years with unresected and newly diagnosed nonrhabdomyosarcoma STS, were presented at the 2019 American Society of Clinical Oncology Annual Meeting. Patients received preoperative radiation therapy and ifosfamide plus doxorubicin, with half of patients receiving concurrent pazopanib, followed by resection at week 13 and then adjuvant chemotherapy. The rate of near complete pathologic response (&ge;90%) was significantly greater at 58.3% with the addition of pazopanib versus 22.2% with chemoradiation only (

&ldquo;There seems to be a role in making these tumors potentially more susceptible to chemotherapy and probably radiotherapy as VEGF inhibitors modify the tumor vasculature,&rdquo; said Lara E. Davis, MD, assistant professor of medicine at Oregon Health & Science University in Portland, in an interview with

Regorafenib inhibits the activity of VEGFR1/2/3 and other kinases in osteosarcoma. In the osteosarcoma cohort of the phase II SARC024 study led by Davis, 42 adult patients with measurable disease by RECIST who had &ge;1 prior therapy were randomized to either placebo or regorafenib. Results showed that median PFS with regorafenib was 3.6 months compared with 1.7 months with placebo (HR, 0.42; 95% CI, 0.21-0.85;

The investigators concluded that regorafenib should be considered a treatment option in this population. &ldquo;In regorafenib, the doubling of PFS... indicates that this tumor has some dependency on these pathways,&rdquo; Davis said. In the same study, regorafenib is being tested in patients with Ewing sarcomas, liposarcomas, and rhabdomyosarcomas; positive results have already been reported in the Ewing-sarcoma arm and the trial is ongoing.

This regimen did not appear to be much more toxic than existing chemoradiation regimens. &ldquo;I will be interested to see how the toxicity plays out in older adults in that population,&rdquo; Davis saidbalancing the toxicity with efficacy is important.

The phase II REGOBONE study examined the safety and efficacy of regorafenib for progressive metastatic disease after &ge;1 prior treatment in 4 independent arms: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. In the osteosarcoma cohort, the primary outcome measure was the proportion of patients showing no disease progression at 8 weeks, with 65% in the regorafenib arm (n = 26) and none in the placebo group (n = 12) reaching that endpoint. The other trial arms are ongoing.9

Median PFS was 16.4 weeks (95% CI, 8.0-27.3) for those in the regorafenib arm compared with 4.1 weeks (95% CI, 3.0-5.7) in the placebo arm. Median OS was 11.3 months (95% CI, 5.9-23.9) with regorafenib versus 5.9 months (95% CI, 1.3-16.4) with the placebo. Investigators suggested that regorafenib has activity in advanced disease and in those with a high risk of relapse and is a potential complementary agent with chemotherapy.

&ldquo;We have known for a while that multikinase inhibitors seem to have an impact in the relapsed and refractory setting for osteosarcoma,&rdquo; said Davis, adding that osteosarcoma is a genomically complex tumor. &ldquo;Certainly, there is not only 1 growth factor responsible, but changing the microenvironment and some growth signals is seeming to help patients, with a reasonable toxicity.&rdquo; Even if multiple pathways play a role in the tumorigenesis of osteosarcoma, &ldquo;one constant is VEGF,&rdquo; she said.

Davis noted a small 2011 study of 35 patients with previously treated, high-grade osteosarcoma in which sorafenib (Nexavar) produced a median PFS of 4 months and a median OS of 7 months.

A 2015 study of 38 patients showed that sorafenib with everolimus (Afinitor) for patients with previously treated osteosarcoma produced significant toxicities, and the trial did not meet the prespecified target of 6-month PFS of &ge;50%. However, patients with tumors that overexpressed posphorylated (P) ERK1/2 and P&ndash;RPS6 had the greatest benefit from therapy, leading the investigators to be optimistic about advancements in the knowledge of osteosarcoma biology for targeting specific pathways.

Davis said that in osteosarcoma, investigators have had a difficult time getting immunotherapy to work, but small signals were observed in past studies.

&ldquo;Investigators are interested in how these 2 methods [immune and targeted therapy] can be combined in a rational and synergistic way to improve osteosarcoma outcomes,&rdquo; she said. Starting in the metastatic setting, with TKIs like regorafenib combined with immunotherapy, it&rsquo;s possible that these regimens will eventually be moved to the frontline setting.

A recent phase II trial of the novel VEGFR2 inhibitor apatinib (YN968D1) in metastatic sarcoma focused on safety and efficacy in 64 patients who had previously failed on chemotherapy. The median PFS was 7.93 months with a PFS rate of 74% at 12 weeks. The final objective response rate (ORR) was 15.25% with a disease-control rate of 57.63% in 59 evaluable patients, leading trial investigators to conclude that the TKI was effective and well tolerated. Although no patients showed a complete response (CR), 25.49% had a partial response (PR) and 70.59% showed stable disease at some point.

Prior to this study, a review of clinical and preclinical data for apatinib showed that current evidence points to the agent&rsquo;s potential superiority over other targeted antiangiogenesis drugs for sarcoma, including pazopanib, sorafenib, and sunitinib (Sutent).

One recent phase II study showed the combination of apatinib plus camrelizumab, an antiPD-1 immune checkpoint inhibitor, extended PFS in patients with osteosarcoma over apatinib alone. The results in 41 patients showed an ORR of 21.95%.

&ldquo;We are hopeful it is a signal for something exciting,&rdquo; Davis said. &ldquo;We should learn more from figuring out how apatinib compares to other TKIs in targets and efficacy.&rdquo;

Axitinib/Pembrolizumab Combination in Advanced Sarcomas

In a phase II single-arm trial assessing the TKI axitinib (Inlyta) plus the antiPD-1 immune checkpoint inhibitor pembrolizumab (Keytruda) in 33 patients with advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS), the combination showed promising efficacy and a manageable toxicity profile. Patients had previously been treated with &ge;1 prior systemic therapy, except for those who declined therapy or for whom no standard treatment existed. With a median follow-up time of 14.7 months, the primary endpoint of 3-month PFS was achieved in 65.5% of patients in the overall cohort, 72.7% of patients with ASPS, and 61.9% of patients with non-ASPS disease. In the total cohort, 25% of patients achieved an objective response, made up of all partial responses (

&ldquo;Less than 20% of sarcomas will respond to these immune checkpoint drugs by themselves,&rdquo; said the trial&rsquo;s primary investigator, Breelyn A. Wilky, MD, associate professor of medicine/medical oncology at University of Colorado School of Medicine in Aurora. &ldquo;We think that may be because there is a lot of VEGF in sarcomas, which may create a negative environment to get immune cells where they need to go.&rdquo;

Investigators have been combining immunotherapy and VEGF inhibitors in multiple cancer types, especially renal cancer, she said. Published studies have shown that patients with kidney cancer have better outcomes with this particular drug combination versus either of the drugs alone.

&ldquo;That is what we wanted to test with sarcomas,&rdquo; she said.

When asked why patients with ASPS had the best responses, Wilky said, &ldquo;ASPS is a simpler sarcoma, with only 1 genetic abnormalitytranslocation. When those 2 genes come together, they start increasing other proteins in the cell, and several are blood vesseltype proteins like VEGF. We think in other types of sarcomas, there is a lot else going on; they are not as dependent on VEGF as ASPS.&rdquo;

In Wilky&rsquo;s study, 25% of all patients (54.5% with ASPS; 9.5% with non-ASPS) treated with the combination had a PR15; this was the first trial for this drug combination for ASPS or sarcomas in general, and some of the patients had responses lasting more than a year. One patient still has no detectable disease after being off treatment for more than a year, though previously she had rapidly growing disease.

The single-arm, phase II CaboGIST trial in 50 patients with GISTs who progressed on imatinib (Gleevec) and sunitnib (Sutent) and received cabozantinib (Cabometyx) met its primary endpoint with a 58.5% progression-free rate at 12 weeks. A median PFS and OS of 6.0 months (95% CI, 3.6-7.7) and 14.4 months (95% CI, 14.1-not evaluable), respectively, were observed. Although no CRs were achieved, 14% of patients had a PR and 66% had stable disease, for a clinical-benefit rate of 80%.

&ldquo;The study showed nice results in patients with GIST. This is the first time the drug has been shown effective in these patients,&rdquo; Wilky said. She added that she looks forward to seeing confirmation of the results in other studies.

Determining which sarcoma types or patients will most benefit from VEGFR inhibition is challenging, but this has not dampened the successes observed in many patients. &ldquo;When it works well, patients can be stable on the drugs for years,&rdquo; Wilky said.

Multiple antiangiogenic agents have clinical activity in repressing sarcoma growth, though none of the drugs tested or used so far have emerged as a home run, she said. It is difficult to know how to prioritize which drug to use for each patient or sarcoma type, she said: &ldquo;We don&rsquo;t really know how to tease apart which ones are useful.&rdquo; That is partly because no one knows what proteins are affected by the treatment, and so far, no studies prove that VEGF is the most important factor to target when treating sarcomas. &ldquo;Most of these drugs hit a dozen different proteins,&rdquo; Wilky said. &ldquo;Overall, we know that VEGF [expression] is a bad prognostic sign. Anything that suppresses blood vessel growth will be helpful.&rdquo;

Studies have shown that VEGF inhibition is most effective in vascular sarcomas, Davis said. Those with advanced angiosarcomas may have success with pazopanib or bevacizumab (Avastin), as have those with solitary fibrous tumors, which respond to VEGF inhibition in advanced settings.

In the future, investigators may need to try adding more drugs to their combination regimens, such as 2 immune checkpoint inhibitors working at different phases in the process, Davis said. The treatment outlook in these tumors may involve chemotherapy, targeted therapies, and then checkpoint inhibitors.

Combinations with chemotherapy are also interesting, Wilky said. One problem with using immunotherapy is that the immune cells may not easily recognize sarcoma cells because they look like normal cells. The signals and inflammation created by chemotherapy allow the immune system to better recognize the cancerous cells.

Wilky also thought that future trials will focus on subsets of sarcomas, since sarcomas are varied. &ldquo;It is like studying 100 different diseases,&rdquo; she said, and it is challenging to include multiple sarcoma types in a small study. Instead, smaller studies can look at 1 or 2 subtypes.

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Based on the ongoing and positive data observed with VEGFR targeted therapies, novel tyrosine kinase inhibitors and those already approved for other disease indications may become available to patients with bone and soft tissue sarcomas.

Debbie Abrams Kaplan | Authors

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