Operator: Good afternoon everyone.

Thank you for joining today's KOL call, focusing on KRAS mutated
non-small cell lung cancer. My name is Dante and I'll be the operator for today's call. All lines will be
muted during the presentation portion of the call with an opportunity for questions and answers at the
end. If you would like to ask a question, press star one on your telephone keypad. I would now like to
pass the conference over to our host, Gena Wang with Barclays. Ma'am, the floor is yours.

Gena Wang: Thank you, operator. Uh, my name is Gena Wang, I'm SMID-cap biotech analyst at the
Barclays. On the call, I will also have my colleague Carter Gould, who is a large cap biotech analyst who
covers Amgen. He will join us later. Uh, thank you everyone for joining our call today to discuss about
Mirati’s KRAS update at ESMO-IO. For disclosure, we will only discuss public information and please hold
your questions until the end. Uh, but as always, feel free to send me, uh, your questions, uh, at my
email, gena.wang@barclays.com if you prefer anonymously. Um, it is our great pleasure today to have
Dr. Mark Awad with us today. Uh, it is particular timely since we just saw Dr. Awad pooled analysis data
shared by Mirati. Uh, Dr. Awad is clinical director for the lower center for thoracic oncology at the Dana
Farber Cancer Institute, and is an assistant professor for medicine at Harvard Medical School. Um, his
translational research program focuses mechanisms of response and resistance to all immunotherapy in
lung cancers. He is involved in multiple KRAS clinical trials, including, Amgen, Mirati, Roche, Novartis and
Lilly’s compound clinical trials. Uh, thank you very much Dr. Awad for joining us today.

Dr. Mark Awad: Thank you. It's a pleasure to speak with you all today.

Gena Wang: Great. So, uh, Dr. Awad, I'm pretty sure you also saw the data, uh, released this morning.
Um, maybe, you know, just a very high level your impression of the data.

Dr. Mark Awad: Sure. Thank you. Um, yes, it was, uh, it was good to see the data from Mirati on the
combination of adagrasib and pembrolizumab. Um, I think, you know, at a high level, up to this point,
we've been asking whether there are distinguishing factors between adagrasib and sotorasib, you know,
sotorasib of course, being first to be approved for KRAS G12C has a great advantage of first, uh, primary
to market, and we've seen data on adagrasib monotherapy in lung cancer that looks roughly comparable
to the activity of some of the prior sotorasib trials. Uh, Mirati has presented some prospective data on,
uh, CNS efficacy of adagrasib, um, whereas we haven't really seen prospective data on that with
sotorasib. So I think, you know, by and large this up to this point, um, the drugs have looked roughly
comparable, but I think this presentation today, um, may offer a point of differentiation and distinction,
um, which is quite important, uh, between adagrasib and sotorasib.

Dr. Mark Awad: And, and that is, um, potentially a path forward for safe combinations with the
immune checkpoint inhibitors. We have seen prior data at ASCO about, uh, sotorasib's combination with
atezolizumab and pembrolizumab and showing high rates of, uh, hepatotoxicity and, and, you know,
proposed alternative strategies to, you know, have a lead in dose before the combination is added. And,
you know, seems like a, a difficult path forward for sotorasib. But here, I think the, um, data with
adagrasib pembrolizumab looked, uh, fairly promising. You know, it's a, a, you know, smaller size study,

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but still, um, between the KRYSTAL-1 Ph1b portion and KRYSTAL-7 Ph2, you know, several dozen
patients, um, were enrolled to the combination with a slightly lower dose of at adagrasib 400 milligrams
BID plus pembrolizumab. And, um, the administration was concurrent from, uh, day one.

Mark Awad: You didn't have to sort of have a kind of complex dosing of, uh, staggered starts. And I
think, um, generally speaking, it was quite, uh, promising where they didn't see any, uh, grade four or
certainly no grade five treatment related adverse events. I think the, um, uh, rate of grade three
hepatotoxicity seemed manageable at this, um, length of follow up, you know, eight to 9% grade three
AST/ALT increase. But, um, you know, I think promise, uh, promising data showing that the combination,
um, appears to be safe overall and, um, you know, whether this is more, um, uh, effective, um, in
certain populations I think is, is an important next question. But, um, but I think the first question to ask
with immunotherapy is combined with a small molecule, is, is this combination, uh, safe? Is there a path
forward? So I think, I think this study, um, you know, does offer a, a potential path forward for first line
trials, as I know Mirati, uh, discussed some considerations for planned first line phase three studies. So,
um, I, I think, um, you know, these are, these are promising, uh, safety data.

Gena Wang: Okay. Thank you very much. And I think we will also discuss about, uh, all the, uh, I think
also phase three trial, uh, we would discuss, certainly discuss about that later. And then, you know,
yeah, maybe, uh, starting with, uh, the, if we, you know, the check the box on the safety, do you think
that they actually at some cost of sacrificing efficacy? Because we did see, like if we look at the response
rate, like maybe if we, you know, now move forward to the response rate, uh, what is your impression
of their response rate, especially given the context on the second line? And then also certainly we were
asking based on the context on your natural history, like how do you see, you know, this response rate,
um, versus overall, and then if we break down by the TPS status, you know, how do you see that?

Dr. Mark Awad: Right. Uh, you know, uh, the, um, some of the phase two data on adagrasib as you're,
uh, I think alluding to was at a higher dose of 600 milligrams BID, a number of those patients had GI
toxicities and, and required dose modification, dose reductions. And so I think, you know, as, as, um, is
the trend in oncology trials, I think the FDA and companies are, are asking, you know, what is the, um,
not the maximum tolerated dose, but you know, the most effective and tolerable dose combination. So I
think from, from limited data, you know, we haven't kind of seen a comparison of, of efficacy of 600
versus 400, uh, milligram BID data, um, sort of side by side. But I think in general, um, you know, some
of the pharmacokinetic, uh, activity or, or assays, you know, seem, seem to show, you know, good target
inhibition at the 400 mg BID dosing.

Dr. Mark Awad: So I, I don't, I don't know that there's a big sacrifice in efficacy at this dosing level. Um,
you know, one general question with small molecule inhibitors is, um, do they work better in the first
line setting than in later lines of setting? And, and again, we haven't really seen too much data, um, with
regard to G12C inhibitors about the response rate and PFS in, uh, first line as compared to later line
settings. But, um, there, there are some, uh, theoretical, um, questions about, uh, perhaps, you know,

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these drugs will work better when the patients haven't had so many prior therapies. You know, there's a
slight precedent for this, um, with regard to, for example, capmatinib in MET exon 14 and lung cancer. It
seems to be, you know, more effective first line than in later line setting. But, um, you know, I think we
don't really know the answer to that question with KRAS.

Dr. Mark Awad: Um, with regards to the efficacy, you know, here we're, we're seeing the response
rate, and this is a mixed population of, um, uh, you know, all PD-L1 levels of negative, low positive,
which is one to 49%, and high positive is greater than equal to 50%. Um, and here it's a relatively early
look. They said the median follow up was, uh, 3.5 months. So that's, you know, still quite, uh, short
overall. And some of the responses, um, they said the, a couple of the unconfirmed responses were
confirmed after the data cut off and three remain unconfirmed. Um, so I, I think we don't know yet, um,
with longer follow up and, and larger (inaudible) population, uh, where the, uh, response rate will, will
settle out. But I think, you know, the other, the other piece just to mention is they said that, um, um,
you know, there were patients who discontinued therapy prior to the first scan for reasons not related
to treatment.

Dr. Mark Awad: And I, I don't think there was a lot of detail shared about, you know, patients that
discontinued. I think, however, those, you know, in the footnote of, of that slide 14, they said that the
response rate was 43%, if you include that total denominator of 61 patients. So I, I think, um, overall this
is encouraging. Um, we know that in the keynote 24 study of pembro monotherapy and the high PD-L1
population, the response rate was about 45%. Here they're saying that it's 59%, although it's a small
subgroup of 13 out of 22 patients. So, you know, I think, um, potentially promising efficacy signal, um, of
course, um, as important as the response rate is the, the duration of response or the median PFS and,
and overall survival, which, you know, they showed swimmers plots, but they didn't report out the
Kaplan Meier median PFS analysis.

Dr. Mark Awad: But I, I think, um, this is a promising early glimpse into the potential of these two
agents being combined not only safely, but hopefully there's some added efficacy. I think, you know, this
has been a question in lung cancer for several years. Um, can we combine a small molecule targeted
therapies with immunotherapy? And in the case, for example, of EGFR and ALK, there wasn't as much of
a rationale, um, in my mind, uh, to do that just because in EGFR and ALK positive lung cancer
immunotherapy does not tend to work very well. And so, you know, why do you combine a TKI with
immunotherapy if the immunotherapy doesn't work so well? But KRAS is different, and we do know that
in, uh, subsets of KRAS mutant lung cancer, we certainly can see good efficacy with immunotherapy and,
uh, these G12C inhibitors can work in the same population.

Dr. Mark Awad: So here, I think there's a clear clinical rationale to combine these therapies together.
Um, and if not, um, you know, a synergistic benefit, hopefully we'll see this, you know, added benefit
when used in the first line setting. So again, I, I think it's, it's a, you know, promising first look at, um, at
this combination and, and, um, you know, I think they are clearing that first sort of safety hurdle of, of,

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um, you know, being able to combine these drugs together. Again, just, you know, slight caveat with
that, this is limited follow up of 3.5 months. Sometimes, uh, when patients are on even immunotherapy
alone, um, sometimes we can see later onset immunotherapy toxicity, um, as patients are, are
continued to receive immunotherapy. So, you know, I think with longer follow up, you know, I don't
necessarily anticipate being, um, you know, doubling or, or, or, you know, a sharp increase in high grade
adverse events. But, um, I think, you know, this is a relatively short term follow up, uh, study with the,
this first data cut or data reporting. So it will be important to see not only how the toxicity settles out
with longer follow up and more patients, but also the efficacy signal. I, I do think it's a little too, sorry, go
ahead. Yeah,

Gena Wang: Yeah. Sorry, go ahead. Yeah,

Dr. Mark Awad: Yeah, I think it's a little bit early to know. Um, you know, the role in the sort of PD-L1
low, the one to 49%, or the negatives, um, you know, again, the numbers are small, but they said that in
the, the one to 49%, they reported a response rate of 48%, and then the negatives was, uh, three out of
10 or 30% response rate. So again, small, small numbers, but, um, you know, we wouldn't necessarily
expect a 48% response rate with pembro monotherapy, um, in the first line setting in that population.
So I, I think again, there, there's some, uh, you know, potential promise for, for, uh, activity in this
population, but, um, the, the numbers are quite small.

Gena Wang: Okay. Okay. That's very helpful. And I do have a few email questions. I will address all
these questions, um, in order, and then first I wanted to ask you, you mentioned that, you know, the
eight patient discontinue, um, I actually also asked them, uh, I think the footnote basically said is the,
uh, not, you know, the related to, oh, sorry. It's, uh, progressed. I think the footnote on the 11, uh, slide
11, uh, basically layout, uh, oh, sorry, it's not slide 11. Yeah. Uh, sorry. The one you mentioned that, uh,
the discontinuation, uh, let me see.

Dr. Mark Awad: Yeah, they, I have this, they said, um, eight patients, you're right on slide 11, they said
eight patients discontinued prior to the first scan. Um, five,

Gena Wang: Yeah. And discontinue

Dr. Mark Awad: Due to death and one to follow.

Gena Wang: Yeah. One loss to follow up. One is a adverse event not related to treatment, and it has,
one is global deterioration.

Dr. Mark Awad: Right,

Gena Wang: Right. So, you know,

Dr. Mark Awad: I think there, I think there's, you know, in this, um, in this, you know, I was curious
about the, you know, the details of those five deaths not related to treatment. Um, you know, this is a, a

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phase two study that's being run at at many sites, but, um, you know, these theoretically should be
done at, at sites that have experience with clinical trials and picking patients, um, you know, selecting
good patients with good performance status for trials. So five deaths within, you know, the, the first
period before scans. It's just, there's a little, little question mark in my mind as to what happened with
those five patients. So again, I usually

Gena Wang: I, you know, actually asked them regarding the ECOG status, I asked them about question
about the patient's, you know, status ECOG and TPS, and their comments is that TPS is, uh,
proportionally similar to the overall patient population. They did not talk too much about the ECOG
status. Um, and then later question, I, I do have a email question. Uh, when we look at the keynote 189,
the ECOG status is 0/1. Yes. 45 to 50, like a 45%, 54% is the ECOG status one. And then for, for this
study, uh, KRYSTAL-7 is 65, so it's a 35 65. So, you know, anything the patient population wise, you
know, is that, does that suggesting this patient population a little bit more severe than what we see in
the other studies?

Dr. Mark Awad: Uh, it, it, it could be, although ECOG performance status of 1 is still, you know, very
good. So, um, yes, ECOG PS does certainly impact, uh, long-term outcomes. But, um, I think zero and
one are, are, um, you know, ECOG 0 is essentially they have, you know, no, you know, almost no
symptoms that are affecting their sort of, um, day to day quality of life. So I think, um, I don't know that
that's, that split is, is sort of a explanation for why five patients died within the first period before the
first scan. So, um, but anyway, I think

Gena Wang: Six weeks, yeah, six weeks. So basically that's before six weeks.

Dr. Mark Awad: I see. Yeah. It seemed like they were well enough to get onto the trial and start the
combination, but, um,

Gena Wang: So, um, Dr. Awad, so what, like, you know, when I, if I talk to the company, like, what
would you like to know this, uh, five deaths?

Dr. Mark Awad: Well, you know, they say it's not related to treatment. Um, and so, you know, I guess if
they say, you know, if it's not an adverse event, does that mean that the, these were all deaths, um, due
to disease progression? And I guess, you know, one question is why, why did the, you know, how did
the, what, what were the circumstances around these deaths or what do we know about these
patients? For example, you know, were these five patients all PD-L1 negative, and so maybe, you know,
they, there's less benefit from pembrolizumab and, and maybe they just didn't respond to adagrasib
either or, you know, I think there's, there's just a question mark, you know, were these patients, uh, did
these patients die due to rapid disease progression? And if so, what do we know about them or co-
mutation status or, or other factors.

Dr. Mark Awad: But, you know, again, I think that in their overall, um, efficacy table on slide 14 where,
um, you know, they say that in the footnote when they, um, include those patients that discontinued

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prior to the first scan, the response rate is 46, uh, 43%. So, you know, again, these are kind of smaller
details, but, um, you know, I think when it's a relatively small size and, and you, you know, move
patients around in terms of who's evaluable or not evaluable, sometimes the response rate can really
shift. So again, I think we don't, um, you know, have all the details there, but, um,

Gena Wang: Okay.

Dr. Mark Awad: You know, generally speaking, I think the, the response rate seemed, um, at least, you
know, promising in, in this overall population. Okay.

Gena Wang: Okay. And then if we go to, I think there are another question regarding longer follow up.
One is the efficacy, you know, the, uh, patient turning like stable disease or turning to responder. And
then the other is where you mention, you know, the, where we see additional, uh, liver elevation or
toxicity. So if we first go to the response, um, I think that's a slide 18, 17 and 18. Um, so that's the
patient. Yeah. So, uh, patient, yeah, I think the 18 is the same. Slide 18, you know, the patient follow, uh,
uh, enroll for over six months. So that total 25 patient that remaining, uh, swimmer plots, and then I
calculate the response was 14. Uh, so that translated 56% response rate out of this 14 six showed up
after second scan, or like x second, I think three second scan, and then the three was like, uh, third or
fourth of fifth scans.

Gena Wang: So do you think this is a very representative in the way that, uh, another like, uh, basically
the question is because I counted that they still have a 28 patient remaining, right? Total 53 patient. So
28 patient, like whatever shaded the, the graded, uh, patient, uh, they should have, I think about nine to
10 patients still responding. I counted all those, like with the arrow there, nine to 10 patients still
responding, uh, but they haven't reached the second scan. So basically the question out of a remaining
patient, uh, they have a total 26 response. If we subtract that, that 14 out of 25, right? So that we still
have a 12 patient, uh, so, uh, responding and then you have nine to 10 patients to, um, uh, sorry, they
haven't had the PR or the stable disease, like, um, how many of these, you know, you think that will also
turning to, is that the right ratio? Six divided by 14, like less than half?

Dr. Mark Awad: Right? You know, it, it's a good question. And, um, I think it's, it's just, uh, like a little
too early to know how, how things will, will settle out and, and, um, as, as they described, you know,
this data cut, I think was August 30th, 2022, and, and now we're, you know, 4, 5, 4 months later, you
know, they did say that, um, two of the unconfirmed PRs were subsequently confirmed and, and three
remain unconfirmed, but the patient's still on treatment. So, um, it, it could be that, um, there are some
sort of slower decreases in tumor metrics that, um, given more time, some of these, uh, you know,
stable disease or unconfirmed PRs will continue to shrink and, and be in the confirmed PR category. But
I, I think it's a little bit, um, you know, conjecture at this point with, um, such short follow up in the
overall population. So, um, you know, in general, I, I think it's, um, again, we, we know that
immunotherapy can work well in many types of KRAS mutant lung cancer in the frontline setting and,
and G12C inhibitors are active in this population. So I, I think there's a clear rationale to combine these,

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and it really does open the door for Mirati to, um, you know, forge ahead with the first line, uh, phase
three studies compared to the standard standards of care. But, um,

Dr. Mark Awad: Yeah.

Gena Wang: Uh, um, okay. Well, thank you. I, I think, uh, uh, that makes sense. It just like too early and
we would just have to wait and see. And regarding the safety, uh, that's another thing, like do you think
like, uh, I mean right now the rate looks very good, like 8%, 9%, uh, with longer follow up, uh, like any
concern there, like you mentioned that, like, could that be additional elevation? At what point you think
we should not be worried about safety anymore? Like how many months? I'm kind of thinking like
mechanistically, uh, and also how long at what point we should be okay. Thinking the safety that should
not be hurting the efficacy or like, you know, impact the efficacy?

Dr. Mark Awad: Right, right. Well, um, you know, I think, um, I'm trying to remember on this, on this
study, how often, uh, labs were checked either on the Phase 1b portion or the Phase 2 portion because
with a, a median follow up of 3.5 months, you know, if, if, uh, half of the patient's, you know, or a good
portion of the patients didn't have blood work checked, you know, um, frequently then, you know,
there, there's a, a chance that just with more time or longer follow up there, there could be changes in
the blood work. But I, I think, you know, I would hope to see, um, with a follow up of six months or so,
um, you know, stability in terms of the toxicities, there can be some low grade immunotherapy toxicities
that accumulate after lengthy exposures. So for example, you know, rheumatologic arthritis and things
or, or dermatologic toxicities can sometimes accumulate after one year or 18 months or longer of
immunotherapy. But those, you know, are often kind of lower grade, um, nuisance of side effects. But I,
I would, I would guess that, you know, with a six month follow up period on the study population, we
would, you know, kind of reveal the stable better toxicity rate.

Gena Wang: Mm-hmm. <affirmative>. Okay. Uh, going back to the late onset response, uh, any
thoughts on what could causing that, like mechanistically, why that, that will, you know, take a longer
time for this patient population to show response?

Dr. Mark Awad: Uh, I don't, I don't think it, it's necessarily taking a longer time. It's just, um, with, uh,
with immunotherapy studies, um, for example, in the frontline pembro studies, the median time to
response, and in those trials, the first scan was often done at around nine weeks. Um, and the median
time to response was 2.2 months, which is, you know, the first scan for, for those patients. But that was
just the median time to response, meaning that, um, there were, you know, many patients that just had
sort of, uh, some slower disease shrinkage. So it, it's not unusual for immunotherapy trials that, you
know, many patients will respond by the first scan, but sometimes if the, um, you know, if the, uh,
shrinkage is, is just a little bit lower than it might be by the second scan. So, you know, with a median
follow up of three, uh, months, I don't know, you, there may be just many patients that, that only had
one scan and you just haven't had a confirmatory scan. So I, I think it's, um, you know, the, the kinetics
of immunotherapy response, I think, you know, generally people respond, um, within the first couple of

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scans. I think it, it just means that this study is a little bit immature and, and, you know, it seems like
there are many patients that at the time of the data cut only maybe had one scan or, or maybe there are
second scan. So I, I think it just needs a little bit more time for follow up.

Gena Wang: Okay. Okay. So basically there's no major differences between, you know, the onset like
target therapy versus immunotherapy regarding the response, like, seems like targeted therapy usually
the first scan most of the time, and then PD-1 also pretty similar, like

Dr. Mark Awad: Mm-hmm.

Gena Wang: <affirmative>. Okay. Okay. So now if we go to slide 21, that's basically your data. Uh, so
you know, here we have, so the keynote, I believe the 189 and KEYNOTE 24, that's all comers, wild-type
plus the mutation KRAS, and then the mutation part is your data. Uh, so that as benchmark, you know, if
we use this, your benchmark, you know, the different TPS status, so the response rate, you know,
maybe we walk through the response rate, it is a small number patient, like how, you know, how
convincing you are with this data and, uh, you know, how much more like a what, uh, say the delta you
think would be very convincing that for you that would show superiority there. Uh, and then what is,
maybe, you know, we'll start like that. The, uh, uh, if we start with the TPS <1, 1-49 and over 50?

Dr. Mark Awad: Right. Well, I think, um, certainly there, there's a, a need for, for better therapies for
this, uh, PD-L1 negative and, and low positive population. And, um, you know, we have retrospective
data, um, that we've been working on with other sites to kind of get a sense of how these patients do.
Um, with the caveat being these are, you know, retrospective analyses in, um, tertiary academic, you
know, US medical centers and, and that may not be representative of larger global populations, um, for
example, phase three study population. So, um, but certainly I think the, the PD-L1 negative population,
um, you know, does not, does not have much, you know, benefit from the incorporation of
immunotherapy to chemotherapy. I think it, it, you know, has been an important, uh, backbone regimen
from the chemo 189 and (inaudible) study. Um, so we tend to use chemo plus immunotherapy in the
PD-L1 negative and, and low positive.

Dr. Mark Awad: But we, we know and understand that these patients certainly do not do as well. Um,
you know, an important question is, you know, what factors predict for the, the outcomes to any of
these regimens? And, um, you know, we and others have been looking at co-mutations and STK 11 and
kEAP-1 and, you know, certainly these patients don't do quite as well with immunotherapy or chemo
immunotherapy. I think what we don't know is in the G12C targeted therapy population, um, you know,
very few pieces of data have been presented on sotorasib or adagrasib in, uh, STK 11 or KEAP-1 co-
mutant cases. You know, we've seen, uh, bar charts showing the response rate, you know, looks roughly
comparable to these STK11 KEAP-1 wild type KRAS mutant cancers. But these are very small numbers
and it was just a response rate.

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Dr. Mark Awad: We haven't, haven't seen the PFS or OS and we don't know if these markers are, are
prognostic in, uh, G12C inhibitor studies or, or not. So, um, you, you know, I think there is, um,
definitely, you know, room to improve outcomes for these, um, PD-L1 low and negative populations,
um, as well as the high PD-L1 high populations as well. So, um, so these, these are, you know, important
benchmarks, um, both in prospective, uh, studies like, you know, like KEYNOTE 189 or 24, as well as, um,
in retrospective analyses in the G12C population.

Gena Wang: Okay. Um, actually, when, when should we see the, uh, paper published?

Dr. Mark Awad: Uh, it's under, uh, review now, it’s submitted, so, um, so I don't know yet.

Gena Wang: Okay. Okay. Um, how many studies were pooled? I think the numbers seems pretty high,
like 264 patients….

Dr. Mark Awad: I'm sorry, you say your, what was the question again one more time?

Gena Wang: Oh, like the, uh, question is like, you know, that 264, uh, patient, you know, was that like
how many study were pooled together to do this?

Dr. Mark Awad: Yeah, there, there have been several different institutions, uh, pooling these data
together, but again, you know, these are, are, um, large academic referral centers so that the patient
population is maybe a little bit fitter than the kind of global KRAS lung cancer population. I see. Um, it
was several different academic medical centers.

Gena Wang: Okay. Okay. So then, um, if you are, you know, thinking those already fitter patient, oh,
sorry, less fitter or less fitter patient, the, the number here, would, would that be skewer, you know, to
better response in the real world? Would that be worse or?

Dr. Mark Awad: Uh, and I think, I think in general, you know, um, prospective clinical trial patients do
the best and then, um, a retrospective analysis at large academic medical centers, um, you know, the
patients have to be healthy enough to travel here. Though, um generally speaking, you know, the
population might do a little bit better than say a nation-wide or a global sort of analysis of all patients
diagnosed with KRAS mutant lung cancer, where some of them don't even receive any first line therapy.
So, um, you know, and this is sort of, you know, one question about the CodeBreak 200 phase three
study versus docetaxel is the, you know, the response rate was more modest and the PFS was a bit
shorter in CodeBreak 200, uh, than in the Phase 1 and studies of sotorasib. So, you know, I think with a
phase three study where, you know, the enrollment is is, you know, very widespread and global, I think
there can be some, um, dilution of the efficacy signals mm-hmm.

Gena Wang: <affirmative>. I see, I see. Okay. And then, uh, if we just look at the response, like how
much more response, like the delta we need to see that will feel comfortable that the clinical trial will be
positive, if we look at the PFS, like how much room of or like the, the clinical benefit will be real if we

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just, you know, if we starting with the response rate, um, if we starting with like, yeah, TPS less than
one, right? That's 25 to 26% and then 36 and then 46, like how much more delta we need to…

Dr. Mark Awad: Right, exactly. Yeah. Cause it seems like, you know, they're, um, Mirati is discussing
different population trials, so I think, you know, there may be a little bit of a different discussion, um, in,
in these different tumor proportion score categories. So, you know, from their, they had a, you know,
big picture overview slide. Not a lot of details provided on the study design or schema, but, um, you
know, in the PD-L1 high population, so I, I just, just to make sure I'm answering your question correctly.
Cause in the PD-L1 low population less than 50%, they were suggesting a trial comparing adagrasib
pembro to chemo pembro. Um, so I wasn't sure if you meant the delta there or, or, um, compared to,
you know, a different backbone. So,

Gena Wang: So maybe like two different questions. I think that's slide 29, they lay out the TPS less than
50 clinical trial design. Yeah. Um, also over 50. Right. So then if we go back, I mean, that's the control
arm if we look at it as pembro plus, uh, chemo, but they have a, pemetrexed. So, uh, the one you use is
the PD-1 plus chemo. So if we look at maybe, you know, just your thoughts, their study design, um, how
do you think of the, uh, study design and how, what would be the right benchmark for the control arm
there?

Dr. Mark Awad: Right, right. So, you know, I think the, um, I'll come come to your question in a
moment. I think the cleanest trials are ones where, you know, the control regimen, um, is also used in
the experimental arm and you add an additional therapy to that. So I think for the high PD-L1 phase
three design where they're planning the comparator arm is pembrolizumab monotherapy. That seems
like a very clean, straightforward trial and it will answer this question. So, uh, PD-L1 TPS greater than or
equal to 50% use pembrolizumab monotherapy versus pembrolizumab plus adagrasib. And, uh, you
there, assuming that the pembro monotherapy response rate recapitulates what we see in Keynote 24,
which is a, a response rate of about 45%. You know, I would hope that the addition of adagrasib, um, to
pembro would, would bump the response rate to, you know, at least, you know, 60%.

Dr. Mark Awad: I think that would be a meaningful improvement in response. And, and hopefully that
will translate to prolongation of, of PFS and OS. I think in the less than 50% category, um, this schema is
a little bit more, uh, complicated, um, because you're comparing different backbones where one arm,
uh, you have chemotherapy, um, plus pembrolizumab, and then the adagrasib pembro arm, they omit
the chemotherapy. So I, I think this is a little bit of a, a riskier strategy. I think a cleaner design, although
we don't have any safety, safety data presented on chemo pembro plus adagrasib, so a four drug
regimen, I think a cleaner study would be comparing chemo pembro versus chemo pembro plus
adagrasib in this PD-L1 low population. Um, here, I think, um, you know, we know there's a role for
chemotherapy. It's the standard of care. Um, I think ideally they would've added adagrasib to chemo
pembro from cycle one, day one, or once you start maintenance therapy.

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Dr. Mark Awad: But, you know, there may be some concern about the, the side effect or toxicity
profile of a four drug regimen. And so I, I don't know if that's the impetus behind this kind of
chemotherapy free design. I think the other important question of this trial, um, you know, I don't know
if they've finalized their, the power this, you know, study design and sample size, um, power
calculations, um, and you know, the co if there's co-primary endpoints of PFS plus OS. But a key question
in this trial design is also about on trial crossover or effective crossover. So for example, if a patient gets
chemo pembro and progresses, um, does the trial allow crossover to adagrasib monotherapy in the
second line setting? Um, in which case that would likely, you know, blunt a, uh, overall survival signal… If
it does not allow crossover to adagrasib monotherapy…

Dr. Mark Awad: Um, the key question is, you know, in this, uh, trial where they're converting the phase
two to the phase three study in these sites across the world is, um, is a different G12C inhibitor available
either approved or, uh, or on trial. And that would also likely blunt the, um, survival benefit. And you
know, that, that question came up with the CodeBreak 200 study where there was no overall survival
benefit of sotorasib versus docetaxel. But in patients who received docetaxel, many of them went on to
subsequently receive a G12C inhibitor through other means. So, um, I I do think there's, there's a little
bit more risk in, um, in this study design of the less than 50%. But, um, I wonder if it's driven by, by the
concern of, um, tolerability of a four drug regimen. Mm-hmm.

Gena Wang: I see. So maybe going back to the chemo, you know, the, the three drug, uh, regimen, the,
uh, chemo combo, the pembro chemo combo, like how's this, you know, if we go back to your slides, the
data, you know, uh, this is also, uh, chemo immunotherapy data. Uh, we saw the PFS there, you know,
the different breakdown of the PFS, right? And then the overall response rate, and then we also saw the
OS there. So, so is that the right benchmark? You know, the, the study you pooled together, is that the
representative, you know, is that a control arm is a good representative? When we look at the slide 21,
the red numbers here is a good benchmark for slide 29, this purple (inaudible) purple, you know, the,
uh, uh, TPS less than 50%, uh, uh, control arm…

Dr. Mark Awad: I mean, I, I think, um, that's, that's, you know, the goal of our, of our retrospective
analyses is to, you know, develop a, a kind of benchmark or understanding. So, you know, a lot of the
prospective trials, um, you know, not all of them have, have kind of reported out a lot of details of the
KRAS allele or, you know, they've kind of reported a mix of, of, you know, KRAS mutant KRAS wild type
lung cancers. So, you know that that's one of the reasons we were doing this retrospective analysis was
to try to, um, you know, establish some benchmarks for which we might, um, think about trial design.
So, uh, you know, I would hope that these benchmarks on this slide 21 are, you know, representative of
what we might see in a prospective clinical trial. Yes, mm-hmm.

Gena Wang: Okay. And I do have an email question, uh, wanted to ask you, uh, you know, uh, do you
think, uh, based on the current data, uh, do you think that they will have a chance to show superiority
over these comparators,

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Dr. Mark Awad: Um, over, over the other KRAS G12C drugs? Is that,

Gena Wang: Oh, no, just the, the, uh, sorry. The, uh, I think it wasn't clear. So, uh, the question is
simply, uh, if we look at 29 a slide 29, um, given the data we have seen so far, you know, how confident
you think that their Phase three will be positive? Yeah. I mean, for both, like maybe TPS over 50 and less
than 50. Yeah?

Dr. Mark Awad: Yeah. I do think, um, the over 50 trial design is, is, you know, very clean and
straightforward, simple. It asks a simple question, um, of, you know, pembro plus or minus adagrasib.
And, um, I, I again, haven't really, you know, seen the primary endpoint if it's, if it's overall survival or
PFS, if there are co-primary endpoints. But, um, I, I would guess that that, um,

Gena Wang: For the, sorry, so, uh, just a little bit clarity… for the TPS less than 50% will be a PFS and
OS co-primary endpoint. For over 50%? We don't know.

Dr. Mark Awad: Okay. Right. Right. So I, I would think that the over 50%, um, trial, you know, I have
more confidence that that would be a positive study. Um, you know, again, assuming that the
combination is safe, I, I think hopefully the, the adagrasib pembro combo would, would outperform
pembro monotherapy. With the less than 50% trial, if this is the, if this is the final design here, uh, um,
again, I, I don't really know if, if they're planning to do, um, crossover or, or what, but I'm less confident
in this being a positive study just because, um, you know, I know they're stratifying by PD-L1 expression,
but, um, you're really omitting an active therapy in this experimental arm. You're omitting platinum
doublet chemotherapy, and, and we, you know, certainly know there's activity there. And, um, I would
just worry about the omission of the chemotherapy sort of blunting the efficacy of adagrasib pembro in
this PD-L1 low negative population.

Gena Wang: So will you be worried about the OS benefit or would that be also PFS benefit?

Dr. Mark Awad: I think PFS as well. Mm-hmm.

Gena Wang: Yeah. Okay. Okay. And then I do have another email question ask you, do you think, uh,
uh, can they do non-inferiority for this study? If you know these two, would that be sufficient rather
than the superiority?

Dr. Mark Awad: Um, you know, I think that would, you know, likely have to be a very different trial
design. And I think, um, you know, the chemo pembro combination has, has become so entrenched as a
standard of care. You know, if you show a different regimen is, is non-inferior, um, there may be some
patients in whom you would choose adagrasib pembro over chemo pembro, like for example, if they
have renal insufficiency, kidney dysfunction, where you normally avoid pemetrexed. So there may be a
occasional patient in whom you would choose adagrasib pembro instead. But I, I think what we're really
looking for here is, is, uh, you know, a regimen that outperforms the standard of care in order to have
significant uptake in the kind of community. And, um, you know, I don't know that a non-inferiority

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designed is planned or if, um, if that would, uh, really convince people to use this regimen as opposed to
keynote 189. So I, I think, um, a positive, uh, superiority study is going to have greater impact than, um,
than showing that these regimens are sort of comparable to each other.

Gena Wang: Okay. Okay. Very helpful. Um, so maybe going back to the same question, when the data
become more mature, uh, and then what kind of a response rate? Uh, I know it's all like a stretch, you
know, so, but what kind of a response rate will make you feel more confident, increase your confidence
that the PFS? That TPS less than 50% could be positive, and if we break down the TPS less than 1% and
also 1 to 49%?

Dr. Mark Awad: Well, I, I do, um, I'm not sure that the response rate would, would be the, the right,
um, signal for me because, you know, the response rate, the G12C inhibitor monotherapies has been,
depending on the study, you know, 30 to 40%, um, and the PFS five, to six to seven months. And, and in
some trials, platinum doublet chemotherapy in the frontline setting, you know, also has a response rate
of 30% in the median PFS of six months. So I think I would probably need to see more of a, you know,
kind of PFS numbers to what kind understand whether... Yeah, I mean, I think in the PD-L1 negative,
yeah, I think in the PD-L1 negative, um, with, adagrasib pembro, if you could see a response rate, or I'm
sorry, a PFS median of like nine months, I think, you know, that that would be, you know, hopefully,
quite promising to kind advance it beyond chemo pembro. I see. I'm suspicious that, um, you know, the
pembro won't be that active in the PD-L1 negatives, so that you're relying on adagrasib to do, you know,
all of the work in the PD-L1 negatives and I, I don't know that, um, it can, it can outperform chemo
pembro.

Gena Wang: I see. So if it's nine months, you'll be relatively confident that could work and, um, what
about the low, PD-L1 low, like 1 to 49? How many months you will be looking? PFS?

Dr. Mark Awad: Yeah, I mean, again, you know, again, if we can see something, um, closer to 11, 12
months, which again, I know it's asking a lot, but, um, but for this to outperform chemo pembro, I think
we really need to see, um, kind of a meaningful, you know, extension of, of progression.

Gena Wang: Okay. Uh, okay. You're pointing 12 months and then we see here the number is all comers
is nine months, and then your data is 5.5 to six months, the PFS…

Dr. Mark Awad: Mm-hmm. <affirmative>.

Gena Wang: Okay. Okay. Okay. Um, good. I know my colleague Carter, are you on Carter? Okay. Uh,
maybe. Um, okay. Then I will ask you, um, doctor, like your current practice with Lumakras and how
would you use, and based also on today's data, how would you use Lumakras versus adagrasib? Uh,
assuming they will get approval, uh, by PDUFA date, which will be one week from now, December 14.
Um, so maybe firstly, how, how are you using Lumakras right now?

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Dr. Mark Awad: Right, so, you know, generally speaking, um, with metastatic lung cancer KRAS G12C, if
the PD-L1 is greater than equal to 50%, we'll use pembro monotherapy. And then, uh, typically, you
know, on progression switch to platinum doublet chemotherapy and then Lumakras in the third line
setting. Um, if the PD-L1 is less than 50% will use chemo plus pembro in the first line setting and
sotorasib in the second line setting. Um, I think if adagrasib gets approved, um, you know, next week or,
or in, you know, the next few weeks, I don't know that it that we'll use it, um, in place of sotorasib yet.
Um, you know, it does have a little bit more data publicly available about CNS activity. Um, I think the
one place where it may be helpful is if, um, a patient has just progressed on immunotherapy and you
need to switch from immunotherapy to, um, a G12C inhibitor, uh, because the immunotherapies have
long half-lives that there's the potential risk if you stop immunotherapy and switch to sotorasib, you
might see hepatotoxicity.

Dr. Mark Awad: Um, so you know, if the overlap is safer with adagrasib and this is just conjecture, then
perhaps if a patient is like coming off immunotherapy, you know, we might have to discuss whether to,
to use adagrasib instead. I think the GI toxicities of adagrasib, and again, I don't know if their approval
will be at the 600 milligram twice a day dose or 400, but I think the GI toxicities with adagrasib
monotherapy are, you know, generally higher than sotorasib, um, and it's a twice a day instead of once a
day dosing regimen. So I, I think there are some advantages to sotorasib as well. So I'm not sure how
much adagrasib monotherapy will be used after its approval if the indication is overlapping with
sotorasib.

Gena Wang: Mm-hmm. <affirmative>. Okay. So, uh, maybe, uh, if the new patient, like, um, you know,
if we just using, uh, your characterization… If the new patient comes in, like how would you, if you give a
rough estimate, how would you, uh, split, you know, these two drugs, like percentage wise, what
percentage patient you will be putting on for adagrasib vs Lumakras? Yeah.

Dr. Mark Awad: Yeah, I think 90% sotorasib and 10% or less of adagrasib.

Gena Wang: Okay. So that's for new patient, not the, if if the new patient…

Dr. Mark Awad: I'm sorry.

Gena Wang: Oh no, the second line, you mean second line, like, oh, no, no, no, like a second line, uh,
based on the approved, you know, right now both of both of them, let's say they will all get approval,
uh, in a second line. And how would you use patient then the new patient in second line?

Dr. Mark Awad: Yeah, I think over 90% sotorasib use.

Gena Wang: Okay. Okay.

Dr. Mark Awad: Is that your, was that your question? I'm sorry if I missed

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Gena Wang: Out. Yes, yes, yes. That, that was my question. So, so with the, with the drug approval,
and you will still continue with sotorasib, majority of the patients, yeah.

Dr. Mark Awad: Yep.

Gena Wang: Okay. And then, uh, what percentage of patient will be, uh, right come off PD-1?

Dr. Mark Awad: What percent of patients will be what, I'm sorry,

Gena Wang: Like, uh, from first line, if they progress the (inaudible) come off PD-1, like is that common
or?

Dr. Mark Awad: Um, I think about a third of patients have high PD-L1 expression, so they might start
with PD-1 monotherapy, and then two-thirds would be on chemo plus pembro. So, um, you know, after
PD-1 monotherapy, you might switch to chemo before a G12C inhibitor, but in two-thirds of patients
they might get chemo immunotherapy and then switch to a G12C inhibitor. So it's a large population
where you would switch from a, an immunotherapy containing regimen onto a G12C inhibitor. But in
general, um, you know, in the sotorasib trials, you know, most patients did get prior chemo and
immunotherapy and their, the rate of hepatoxicity was not, you know, very high. So I, I don't think that's
a big concern now or in the community. So I don't think, um, people will say, oh, well, you know, the
adagrasib combo data looks better, so let's use adagrasib after immunotherapy compared to sotorasib
because the sotorasib hepatotoxicity was not too, too high, um, in the previously reported publications.

Gena Wang: Mm-hmm, I do have an email question ask you, uh, what about the patient in the, you
know, patient with CNS? How do you use these two?

Dr. Mark Awad: Right? Well, yeah, I mean I think there are more data, um, about adagrasib and CNS
efficacy. So, you know, that is one scenario until we see data about sotorasib, and CNS efficacy. I think,
you know, there's only a case report about, um, CNS response to sotorasib. So there, you know, we may,
um, use adagrasib more, but we might also use radiation therapy. It kind of depends on if these are
asymptomatic and small brain metastases. Um, you might treat them with adagrasib or you might treat
them with radiation. So, um, that, that might be one scenario where there's a little bit more data, um,
for adagrasib use. But, um, you know, we may see more data about sotorasib in the CNS as well, so.

Gena Wang: Okay. Okay. Good. Uh, well thank you. I think we are right on time. Uh, thank you very
much. Uh, I think, uh, um, maybe just see, operator, do we have any questions?

Operator: No, ma'am. At the moment we do not have any questions.

Gena Wang: Okay, good. Um, so we cover all the ground. Thank you, uh, Dr. Awad. Uh, thank you very
much and, uh, we, uh, look forward to talking with you in the future.

Dr. Mark Awad: Thank you so much for the invitation. It was a pleasure.

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Gena Wang: Thank you. Operator, uh, we can conclude today's call.

Operator: Fantastic. And with that, we will conclude today's KOL call, focusing on KRAS mutated non-
small cell lung cancer. Thank you for your participation. You may now disconnect your line.

Dr. Mark Awad: Thank you.

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