Antiangiogenics in Malignant Pleural Mesothelioma: Recent Research Context


Malignant pleural mesothelioma (MPM) is a tough treatment course to navigate. If anyone knows that, it is Anne S. Tsao, MD. of MD Anderson Cancer Center in Houston. Tsao is no doubt one of the world’s experts on MPM, having been “called” by the disease – one that is very rare and that generally occurs in older men (most often because of asbestos exposure) with comorbidities.

Tsao told the West Wind Podcast that she was intrigued by MPM early in her career because “it was so different than [non-small cell lung cancer]. I just started doing some preliminary research in it. I thought there may be something to an antiangiogenic pathway targeting the different molecules there, and that spanned into … what we are doing now with immunotherapies,” she said.

“It’s a highly immunogenic tumor,” Tsao explained to podcast host Jack West, MD, of City of Hope and founder of the nonprofit CancerGrace (Global Resource for Advancing Cancer Education). “We don’t have the typical biomarkers, as in the other solid tumors that correlate, and so it’s incumbent on us to figure out what makes this disease immunogenic, and what we can do to target it. It’s not going to be straightforward or simple, but that’s part of the challenge,” she said.

Tsao and colleagues faced such a challenge in their quest to find the optimal treatment for MPM: Disappointing results from the phase II SWOG S0905 trial that tested cediranib in combination with standard-of-care cisplatin and pemetrexed in chemotherapy-naive patients with unresectable MPM.

While the cediranib add-on did lead to some improvements, the “cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM,” Tsao’s group concluded.

Phase I of the S0905 trial laid the groundwork for the current study and established the maximum tolerated dose of cediranib at 20 mg/day when combined with cisplatin-pemetrexed.

For phase II, the researchers randomly assigned 92 MPM patients (75% epithelioid) to cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo. The primary endpoint was Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control, and safety/toxicity.

The team reported that cediranib improved PFS by RECIST v1.1 at 7.2 versus 5.6 months and increased modified RECIST v1.1 response. Also, by modified RECIST v1.1, cediranib numerically increased PFS at a median 6.9 versus 5.6 months. But no significant difference in OS was seen. Finally, the addition of cediranib to chemotherapy led to a higher rate of treatment-related adverse events versus placebo (100% vs 91%).

“On the basis of the minor survival improvement and toxicity profile, cediranib will not be developed further for mesothelioma,” the researchers stated.

Different Antiangiogenic MAPS?

Tsao and colleagues acknowledged that the MAPS trial “remains the only positive phase III trial with an antiangiogenic in a large number of patients with MPM.”

The open-label trial from France allocated patients to pemetrexed plus cisplatin with or without bevacizumab in 21-day cycles for up to six cycles, until progression or toxic effects. The primary outcome was OS in the intention-to-treat population. The MAPS researchers reported that the addition of bevacizumab did indeed boost survival.

Thus far, MAPS has been the best route for antiangiogenics in MPM. The treatment approach hit a road bump in the LUME-Meso trial on which Tsao served as an investigator. The phase II trial demonstrated a PFS benefit with the addition of nintedanib, a VEGF receptor inhibitor, to cisplatin-pemetrexed, but a phase III arm was negative for a PFS benefit.

Things went more smoothly in the phase II DREAM trial, in which durvalumab was added to first-line cisplatin and pemetrexed, and delivered higher rates of six-month PFS and objective response rate (ORR) versus chemotherapy alone, and with acceptable tolerability.

Taken together, do these results signal that antiangiogenics in MPM have reached the end of the road? Not necessarily, Tsao said. With LUME-Meso, “we saw that there was a 50% modified RECIST response rate compared to 20% in the placebo group,” she said in a talk at the 2018 World Conference on Lung Cancer (WCLC). “So I would point out that although the MAPS study to date is the only trial that has shown PFS and OS survival benefit, with bevacizumab, VEGFR TKIs did have patients that had great depth of response that was durable. My argument would be that there are some patients that benefit from the combination of chemo and antiangiogenics, but we still have yet to pick out who those patients are.”

As for DREAM, Tsao highlighted that there were a number of patients in the trial who had “enormous depth of response with this regimen,” and also that “there were two patients that had pseudoprogression that subsequently were confirmed to have significant responses. And so these two patients … were counted as progression of disease, but nevertheless you can see that they actually had quite robust responses afterwards.”

She also noted that the median six-month PFS rate was 57% and the one-year OS estimate was 65%, although the data at the time of Tsao’s WCLC talk were still immature.

While the median PFS in DREAM fell short of MAPS, “I would say that the median PFS is trending towards what we see with chemo alone … [DREAM] met its primary endpoint … and so certainly this warrants looking at this regimen further,” she said.

Other Avenues

A parallel road to MPM treatment may be with immunotherapy. For example, Tsao said, the MERIT trial in which nivolumab met the primary endpoint as second- or third-line treatment for MPM patients, showed promising efficacy and manageable toxicity.

In MERIT, “the median PFS for all patients was 6.1 months and for median OS it was 17.3 … there was a trend — not statistically significant — but a trend favoring those for both PFS and OS who had some PD-L1 expression,” she explained.

In May 2019, the FDA approved the NovoTTF-100L Tumor Treating fields (TTFields) system for use in conjunction with chemotherapy as initial treatment for unresectable MPM. The green light was based on results from the STELLAR trial that showed 50% improvement in median OS versus historical data.

Researchers at the 2019 WCLC in Barcelona conducted a study to quantify the clinical value of the TTFields treatment in MPM by applying ASCO and ESMO frameworks to the comparison of the STELLAR data to historical controls, and determined that “adding TTFields to pemetrexed and cisplatin or carboplatin in MPM patients may provide a significant clinical benefit.”

So are TTFields likely to put MPM specialists on a different road altogether, or just an optional detour? In the podcast, Tsao pointed out that STELLAR, and other work with TTFields, has been done almost exclusively in Europe.

“We have very little experience with TTF in the U.S.,” she said. In addition, patients must wear TTFields for several hours a day to receive treatment, and comes with toxicities, including grade 3 dermatitis.

Perhaps more importantly for what lies ahead for antiangiogenics in MPM, “the survival [with TTFields] was close to 18 months, which is similar to what we can achieve with bevacizumab triplet,” Tsao noted. “I think [it] is great that the FDA gave an approval for something that can potentially be used in mesothelioma, but it should always be considered as an adjunctive therapy; it should never be used to replace standard-of-care therapy.”

The SWOG S0905 trial was supported by the National Cancer Institute.

Tsao disclosed relevant relationships with Novartis, Boehringer Ingelheim, Genentech, MedImmune, Imedex, Eli Lilly, Bristol-Myers Squibb, Epizyme, AstraZeneca, Ariad Pharmaceuticals, EMD Serono, Takeda, Heron, Merck, Seattle Genetics, Millennium Pharmaceuticals, Polaris, and UpToDate, as well as serving as associate editor of the NEJM Journal Watch Oncology and Hematology; co-authors disclosed multiple relevant relationships with industry including Boehringer Ingelheim.

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